Immunological properties of mesenchymal stem cells and clinical implications
Shyam A. Patel, Lauren Sherman, Jessian Munoz and Pranela Rameshwar
Abstract
The rapid evolution of experimental data has acknowledged the critical relevance of immune biology in stem cell research. It appears that efficient transfer of stem cells to patients requires robust analyses of the immune properties as well as the responses of the stem cells to immune mediators. This review discusses the biology of adult human mesenchymal stem cells (MSCs) in the context of immunology. MSCs are pluripotent, self-renewing cells with the potential for tissue regeneration, for example the repair of bone, cartilage, tendon, ligament, skeletal muscle, and cardiac muscle. MSCs have also been shown to transdifferentiate into cells of ectodermal origin, such as neurons. MSCs are located in perfused areas of adult bone marrow, whereas hematopoietic stem cells are located in poorly perfused areas of the same organ. MSCs show bimodal, i.e. anti-inflammatory and immune-enhancing, immune responses. MSCs also regulate immune responses such as the regulation of antibody production by B cells, alterations in T cell subtypes, and immune tolerance of allogeneic transplants. MSCs also have the potential for gene delivery. This review explores the diverse clinical potential for MSCs and discusses the limitations and advantages of their immunomodulatory properties.
Key words: mesenchymal stem cells, bone marrow, interferon γ, hematopoiesis, cytokines, immune stimulator.
Rewinding the DISC
Benjamin Chaigne−Delalande, Jean−François Moreau and Patrick Legembre
Abstract
Fas (CD95/APO-1) belongs to the tumor necrosis factor receptor family and its signaling pathway has been extensively studied over the past 15 years. Blockade of the Fas-mediated apoptotic signal leads to abusive lymphoproliferation, auto-immunity, and an increased risk of developing lymphoma and leukemia. Fas engagement drives the formation of a complex termed DISC (death-inducing signaling complex), which contains the adaptor molecule Fas-associated protein, two members of the caspase family caspase-8 and -10, and a pseudo-caspase termed c-FLIP. According to different authors, DISC formation relies either on the redistribution of Fas into the lipid rafts or the recruitment of the actin cytoskeleton and receptor endocytosis or the production of ceramide. However, the accurate molecular ordering upstream from the formation of DISC remains very puzzling and is highly debated. Herein we review some of the factors that would potentially facilitate or limit the formation of the DISC.
Key words: apoptosis, CD95, DISC, Fas, lipid rafts.
Modulating the immune response
by oral zinc supplementation:
a single approach for multiple diseases
Silke Overbeck, Lothar Rink and Hajo Haase
Institute of Immunology, RWTH Aachen University Hospital, Aachen, Germany
Received: 2007.10.16, Accepted: 2007.11.19, Published online first: 2008.02.05
Abstract
Zinc is required for multiple cellular tasks, and especially the immune system depends on a sufficient availability of this
essential trace element. During the last decades, many studies attempted to affect the outcome of various diseases by zinc
supplementation. These efforts either aimed at supporting immunity by zinc administration or at correcting a loss of zinc sec-
ondary to the disease to restore the zinc-dependent functions of the immune system. This review aims to summarize the
respective findings and to discuss possible molecular mechanisms by which zinc could influence viral, bacterial, and parasitic
infections, autoimmune diseases, and the response to vaccination. Zinc supplementation in diseases such as diarrhea, chron-
ic hepatitis C, shigellosis, leprosy, tuberculosis, pneumonia, acute lower respiratory infection, and leishmaniasis seems ben-
eficial. In contrast, the results for the common cold and malaria are still not conclusive, and zinc was ineffective in most vac-
cination and rheumatoid arthritis studies. For AIDS and type 1 diabetes, zinc supplementation may even be a risk factor for
increased mortality or deterioration of the glucose metabolism, respectively. In these cases, zinc supplementation should be
used with care and limited to clearly zinc-deficient individuals.
Key words: zinc, trace elements, infection, vaccination, autoimmunity.
Possible disease-modifying factors:
the mannan-binding lectin pathway and infections
in hereditary angioedema of children and adults
Maciej Cedzyński1, Kazimierz Madaliński2, 3, Hanna Gregorek2, Anna S. Świerzko1,
Ewa Nowicka2, Krystyna Obtułowicz4, Katarzyna Dzierżanowska−Fangrat2,
Urszula Wojda2, Daniel Rabczenko5 and Masaya Kawakami6
1 Laboratory of Immunobiology of Infections, Center of Medical Biology, Polish Academy of Sciences, £ódŸ, Poland
2 Departments of Clinical Microbiology and Immunology; Allergology, Child Health Memorial Institute, Warsaw, Poland
3 Department of Immunopathology, National Institute of Hygiene, Warsaw, Poland
4 Department of Industrial Allergology, Jagiellonian University Medical School, Cracow, Poland
5 Department of Medical Statistics, National Institute of Hygiene, Warsaw, Poland
6 Kitasato University, Sagamihara, Japan
Received: 2007.01.09, Accepted: 2007.10.25, Published online first: 2008.02.05
Abstract
Introduction: Hereditary angioedema (HAE) is caused by mutations in the C1inh gene, leading to dysfunction of the
C1-esterase inhibitor (C1-INH). C1-INH interacts with MASP-1 and MASP-2 proteases, participating in the mannan-bind-
ing lectin (MBL) pathway of complement activation. The aim of the study was to investigate the contribution of possible
changes in MBL/MASP-2 complex activity and Helicobacter pylori, hepatitis B virus (HBV), and hepatitis C virus (HCV)
infections to the severity and frequency of clinical symptoms of HAE.
Materials and Methods: The study was performed in 65 patients with HAE and 113 healthy persons. The parameters mea-
sured were C1-INH, C4, MBL concentration and MBL/MASP-2 complex activity, and serological markers of H. pylori, HBV,
and HCV infection. Scores for the frequency and severity of HAE symptoms were determined.
Results: HAE scores were significantly higher in patients whose C1-INH activity did not exceed 10% than in patients with
activity of 10–52% (p=0.016). No significant differences were found in the median levels of MBL concentration and
MBL/MASP-2 complex activity between patients and the control group. There was a slight association between contact with
H. pylori in patients and HAE symptom score (p=0.052, not significant). Adult patients showed a 2.6-times higher frequen-
cy of anti-HBc than the general population. HBV DNA was negative in anti-HBc(+) patients.
Conclusions: These results suggest that the MBL complement activation pathway itself does not contribute to the frequency
of angioedema attacks. Infections with H. pylori and HBV may slightly influence the disease score (not significant).
Key words: hereditary angioedema, C1-inhibitor, mannan-binding lectin complement pathway, H. pylori, hepatitis B and
C infections.
Expression of naive/memory (CD45RA/CD45RO) markers
by peripheral blood CD4+ and CD8+ T cells
in children with asthma
Edyta Machura1, Bogdan Mazur2, Wojciech Pieniążek1 and Krystyna Karczewska1
1 Chair and Department of Pediatric Gastroenterology, Allergology, and Developmental Disorders,
Medical University of Silesia, Zabrze, Poland
2 Department of Microbiology and Immunology, Medical University of Silesia, Zabrze, Poland
Received: 2007.06.22, Accepted: 2007.10.25, Published online first: 2008.02.05
Abstract
Introduction: The role of CD4+ T cells in the immunopathogenesis of asthma is well documented. Little is known about the
role of CD8+ T cells. The aim of this study was to assess peripheral blood subsets of CD4+ and CD8+ T cells expressing
naive/memory markers (CD45RA+/RO+) and the activation marker (CD25+) in children with allergic asthma.
Materials and Methods: Peripheral blood mononuclear cells were isolated from children with allergic asthma and healthy chil-
dren. T cell subsets were analyzed by flow cytometry for the expressions of CD45RA, CD45RO, and CD25. In this study,
some differences in the memory compartment of peripheral blood T cells between asthmatic children and healthy controls
were detected.
Results: The absolute number of CD8+ T cells expressing CD45RO was significantly elevated and the percentages of CD3+
T cells expressing activation marker CD25 and of CD4+ T cells expressing memory marker CD45RO were significantly lower
in children with asthma compared with controls. No correlation was found between severity of asthma and peripheral blood
lymphocyte subsets.
Conclusions: There were some differences in the memory compartment of peripheral blood T cells between asthmatic chil-
dren and healthy controls. The increase in the number of CD8+ T cells expressing the memory marker (CD45RO) in chil-
dren with allergic asthma may indicate that CD8+ T cells play a role in the pathogenesis of asthma.
Key words: lymphocyte, children, asthma.
Whole-body cryotherapy as adjunct treatment
of depressive and anxiety disorders
Joanna Rymaszewska, David Ramsey and Sylwia Chładzińska−Kiejna
Department of Psychiatry, Wroc³aw Medical University, Wroc³aw, Poland
Received: 2007.04.27, Accepted: 2007.10.25, Published online first: 2008.02.05
Abstract
Introduction: Rheumatism has been treated using whole-body cryotherapy (WBCT) since the 1970s. The aim of this study
was to assess the efficacy of WBCT as an experimental, adjunctive method of treating depressive and anxiety disorders.
Materials and Methods: A control (n=34) and a study group (n=26), both consisting of outpatients 18–65 years old with
depressive and anxiety disorders (ICD-10), received standard psychopharmacotherapy. The study group was additionally
treated with a series of 15 daily visits to a cryogenic chamber (2–3 min, from –160°C to –110°C). The Hamilton’s depression
rating scale (HDRS) and Hamilton’s anxiety rating scale (HARS) were used as the outcome measures.
Results: After three weeks, a decrease of at least 50% from the baseline HDRS-17 scores in 34.6% of the study group and
2.9% of the control group and a decrease of at least 50% from the baseline HARS score in 46.2% of the study group and in
none of the control group were noted.
Conclusions: These findings, despite such limitations as a small sample size, suggest a possible role for WBCT as a short-term
adjuvant treatment for mood and anxiety disorders.
Key words: depression, anxiety, adjuvant therapy, experimental treatment method, whole-body cryotherapy.
Experimental anti-GBM nephritis as an analytical tool
for studying spontaneous lupus nephritis
Yong Du, Yuyang Fu and Chandra Mohan
Department of Internal Medicine/Rheumatology and Immunology, University of Texas Southwestern Medical School,
Dallas, TX 75390, USA
Received: 2007.11.20, Accepted: 2007.12.19, Published online first: 2008.02.05
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease that results in immune-mediated damage to multiple organs.
Among these, kidney involvement is the most common and fatal. Spontaneous lupus nephritis (SLN) in mouse models has
provided valuable insights into the underlying mechanisms of human lupus nephritis. However, SLN in mouse models takes
6–12 months to manifest; hence there is clearly the need for a mouse model that can be used to unveil the pathogenic
processes that lead to immune nephritis over a shorter time frame. In this article more than 25 different molecules are
reviewed that have been studied both in the anti-glomerular basement membrane (anti-GBM) model and in SLN and it was
found that these molecules influence both diseases in a parallel fashion, suggesting that the two disease settings share com-
mon molecular mechanisms. Based on these observations, the authors believe the experimental anti-GBM disease model
might be one of the best tools currently available for uncovering the downstream molecular mechanisms leading to SLN.
Key words: autoantibodies, mouse models, SLE, therapy, glomerular disease.
Neutrophil recognition of bacterial DNA
and Toll-like receptor 9-dependent
and -independent regulation of neutrophil function
Driss El Kebir, Levente József and János G. Filep
Research Center, Maisonneuve-Rosemont Hospital and Department of Pathology and Cell Biology, University of
Montreal, Montreal, QC, Canada
Received: 2007.10.29, Accepted: 2008.01.09, Published online first: 2008.02.05
Abstract
Neutrophils are essential for host defense and detect the presence of invading microorganisms through recognition of
pathogen-associated molecular patterns. Among these receptors are Toll-like receptors (TLRs). Neutrophils express all
known TLRs except for TLR3. TLR9, localized intracellularly, is to date the best characterized sensor for bacterial DNA,
containing short sequences of unmethylated CpG motifs, though TLR9-independent intracellular DNA recognition mecha-
nism(s) may also exist. Bacterial DNA has profound impact on neutrophil functions; it promotes neutrophil trafficking in
vivo, induces chemokine expression, regulates expression of adhesion molecules, enhances phagocyte activity, and rescues
neutrophils from constitutive apoptosis. TLR9 stimulation results in alterations in cellular redox balance, peroxynitrite for-
mation, activation of the mitogen-activated protein kinase, PI3-kinase, and Jun N-terminal kinase pathways and/or nuclear
factor κB and AP-1. These features identify an important role for bacterial DNA and TLR9 signaling in the regulation of
neutrophil functions that are critical for optimal expression as well as for resolution of the inflammatory response.
Key words: neutrophils, bacterial DNA, Toll-like receptor 9, apoptosis, inflammation.
1-Methylnicotinamide and nicotinamide:
two related anti-inflammatory agents that differentially
affect the functions of activated macrophages
Rafał Biedroń1, Marta Ciszek1, Marianna Tokarczyk1, Małgorzata Bobek1,
Maria Kurnyta1, Ewa M. Słominska2, Ryszard T. Smoleński2 and Janusz Marcinkiewicz1
1 Department of Immunology, Jagiellonian University College of Medicine, Kraków, Poland
2 Department of Biochemistry, Medical University of Gdañsk, Poland
Received: 2007.07.10, Accepted: 2007.10.25, Published online first: 2008.03.31
Abstract
Introduction: 1-Methylnicotinamide (MNA), a major metabolite of nicotinamide (NA), is known to exert anti-inflammatory
effects in vivo. Treatment of inflammatory skin diseases by topical application of MNA provides certain advantages over the
use of NA. However, in contrast to NA, the molecular mechanisms of the anti-inflammatory properties of MNA are not well
known. In this study the influence of exogenous MNA and NA in vitro on the generation of inflammatory mediators by
macrophages (Mφ) was investigated.
Materials and Methods: Peritoneal Mφ of CBA/J mice were activated in vitro with lipopolysaccharide and incubated with
MNA or NA. The effect of these compounds on biological functions of Mφ was measured by evaluation of the production
of reactive oxygen species (ROS) by luminol-dependent chemiluminescence, cytokines and prostaglandin E2 (PGE2) by
ELISA, and nitric oxide (NO) by the Griess method. Moreover, the expressions of inducible NO synthase and cyclooxyge-
nase-2 were measured by Western blotting.
Results: It was shown that at non-cytotoxic concentrations, NA inhibits the production of a variety of pro-inflammatory
agents, such as tumor necrosis factor α, interleukin 6, NO, PGE2, and the generation of ROS. In contrast to NA, exogenous
MNA inhibited only the generation of ROS, while its effect on the synthesis of other mediators was negligible.
Conclusions: These results indicate that the anti-inflammatory properties of MNA demonstrated previously in vivo do not
depend on its capacity to suppress the functions of immune cells, but more likely may be related to its action on vascular
endothelium. The authors suggest that the limited permeability for exogenous MNA, in contrast to that for NA, may be
responsible for its lack of suppressor activity against Mφ.
Key words: 1-methylnicotinamide, nicotinamide, inflammation, macrophages, ROS, cytokines.
Live attenuated
Leishmania vaccines:
a potential strategic alternative
Ricardo Silvestre1, 2, 4, Anabela Cordeiro−da−Silva1, 2 and Ali Ouaissi1, 3, 4
1 Departamento de Bioquímica, Faculdade de Farmácia da Universidade do Porto, Portugal
2 Instituto de Biologia Molecular e Celular da Universidade do Porto (IBMC), Portugal
3 INSERM, UMR 554, CNRS 5048, Centre de Biochimie Structurale, Montpellier, France
4 IRO UR008, Centre IRD de Montpellier, France
Received: 2007.10.16, Accepted: 2008.01.25, Published online first: 2008.03.31
Abstract
Leishmaniasis causes significant morbidity and mortality worldwide, constituting an important public health problem.
Leishmania infections cause a wide spectrum of diseases, ranging in severity from spontaneously healing skin lesions to fatal
visceral disease. Attempts to develop an effective vaccine to control leishmaniasis have been shown to be feasible, but no vac-
cine is in active clinical use. The ability to create genetically modified parasites by eliminating virulence or essential genes is
considered a powerful alternative in the development of an effective protective vaccine. Here, recent findings related to
genetically defined live attenuated Leishmania parasites as promising vaccine candidates are reviewed.
Key words: Leishmania, leishmaniasis, live attenuated vaccines, genetically modified organisms, reverse vaccinology.
Quantification of the CD8+ T cell response against
a mucin epitope in patients with breast cancer
Konrad Kokowski1, Ulf Harnack1, David C. Dorn1, 2 and Gabriele Pecher1
1 Medical Clinic of Oncology and Hematology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
2 Current address: Laboratory of Developmental Hematopoiesis, Cell Biology Program, Memorial Sloan-Kettering Cancer
Center, New York, NY 10021, USA
Received: 2007.08.14, Accepted: 2008.01.25, Published online first: 2008.03.31
Abstract
Introduction: Mucin 1, encoded by the MUC1 gene, is a tumor-associated antigen expressed on the surface of breast cancer
cells. It would be of interest to see whether there is a naturally existing T cell immune response against mucin epitopes in
cancer patients.
Materials and Methods: Using tetramer and interferon-γ assays, the immune response to one MUC1 peptide epitope in the
peripheral blood of breast cancer patients was quantified. The data were compared with the clinical course of the patients.
Results: CD8+ T cells capable of recognizing the HLA-A*0201-restricted STAPPVHNV epitope were detected in 9 of 19
patients with a frequency ranging 0.01–0.082%. No significant difference was found between the occurrence of epitope-spe-
cific CD8+ T cells of patients with progressive disease and disease-free patients. However, all patients with stable disease
showed a specific immune response, including both patients with the highest frequency.
Conclusions: The results of this study provide further evidence that a natural specific cellular immune response against this
mucin epitope exists in breast cancer patients.
Key words: breast cancer, mucin, T cells, tetramer, IFN-γ assay.
Application of two different kinds of sera against
the
Proteus penneri lipopolysaccharide core region
in search of epitopes determining cross-reactions
with antibodies
Agata Palusiak1, Monika Dzieciątkowska2 and Zygmunt Sidorczyk1
1 Department of General Microbiology, Institute of Microbiology and Immunology, University of £ódŸ, Poland
2 Department of Immunochemistry, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences,
Wroc³aw, Poland
Received: 2007.07.24, Accepted: 2007.10.25, Published online first: 2008.03.31
Abstract
Introduction: Proteus penneri lipopolysaccharide (LPS) core regions are characterized by a greater structural variability than
that observed in other Enterobacteriaceae. This fact and the small amount of published data concerning the serological activ-
ity of this part of P. penneri LPS prompted an examination of which fragment might determine cross-reactions with anti-
bodies. To date, such epitopes have been found in the LPS core regions of P. mirabilis and P. vulgaris strains.
Materials and Methods: Proteus sp. LPSs were tested with unabsorbed rabbit antisera by enzyme-linked immunosorbent assay
(ELISA), sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blot, and once again by ELISA or passive
immunohemolysis after the absorption of these antisera with selected LPSs.
Results: The serological studies of P. penneri 8 LPS demonstrated antibodies in the tested antisera recognizing a common epi-
tope located in the core regions of six of the LPSs, i.e. P. penneri 8, 34, 133, 7, 14, and 15. Additionally, another type of antibody
directed against some fragment of P. penneri 13 and the core regions of other LPSs investigated was observed in one antiserum.
Conclusions: A distal, trisaccharide fragment of the P. penneri 8 LPS core region is suggested to determine the cross-reac-
tions of the tested antisera with the six P. penneri LPSs.
Key words: Proteus penneri, lipopolysaccharide, core region, anti-conjugate serum, epitope
Current advances in the management of urticaria
Ahmad T. Khalaf, Wang Li and Tan Jinquan
Department of Immunology, Laboratory of Allergy and Clinical Immunology, Institute of Allergy and Immune-Related
Diseases and Center for Medical Research, Wuhan University School of Medicine, 430071 Wuhan, China
Received: 2007.08.26, Accepted: 2007.12.28, Published online first: 2008.03.31
Abstract
Urticaria is a relatively common autoimmune/autoreactive skin disorder that may severely impair quality of life. Although
rarely life-threatening, widespread urticaria and its associated angioedema can be an extremely disabling and difficult-to-
-treat condition. Patients may suffer symptoms such as pruritus and disfigurement due to wheals for years or decades.
Urticaria is caused by cutaneous mast-cell degranulation attributed to immunological, non-immunological, and idiopathic
causes. The last decade has seen some notable advances in the understanding of the etiology and pathogenesis of common
forms of urticaria and their management. Furthermore, the wide diversity in urticaria subtypes has been identified and this
reflects a partial understanding of the causes or factors that trigger it as well as the molecular and cellular mechanisms that
are involved in its physiopathology. In addition, new instruments for diagnosing urticaria variants and for assessing quality
of life in urticaria patients have been developed. Finally, several clinical trials have demonstrated the efficacy of novel treat-
ment approaches for urticaria, while other therapeutic concepts are under development. The objective of this article was to
review the literature to be able to offer the readers comprehensive and updated information on the basic etiological and
physiopathological mechanisms and to make special emphasis on the current management of urticaria, thus promoting con-
tinuous medical education.
Key words: urticaria, wheal, autologous serum skin test, autoimmune urticaria, mast cells, antihistamines, FcεRIα autoanti-
bodies.
The role of B lymphocytes as antigen-presenting cells
Xinjian Chen and Peter E. Jensen
Department of Pathology, University of Utah, Salt Lake City, Utah, USA
Received: 2007.10.30, Accepted: 2008.01.25, Published online first: 2008.03.31
Abstract
B lymphocytes are regarded as professional antigen-presenting cells (APCs) despite their primary role in humoral immuni-
ty. Over the last two decades, studies designed to define the role of the B cells as APCs have generated discrepant results,
showing that B cells are either unnecessary or required for T cell priming and either immunogenic or tolerogenic to T cells.
The reasons for these discrepancies are not clear. Here we review mechanisms regulating B cell antigen presentation and the
data derived from the major studies conducted by different groups representing each school of thought. In general it is clear
that B cells process and present specific and nonspecific antigens differently. The presentation of specific antigen through
the B cell antigen receptor occurs with very high efficiency and is associated with B cell activation, resulting in the activation
of cognate T cells. In contrast, the presentation of nonspecific antigen by B cells is minimized and dissociated from B cell
activation. As a result, B cells inactivate T cells that recognize nonspecific antigenic epitopes presented by B cells, or they
induce regulatory T cell differentiation or expansion. These mechanisms serve to ensure effective production of high-affini-
ty antigen-specific antibodies but minimize the production of nonspecific antibodies and autoantibodies.
Key words: B lymphocytes, antigen presentation, HLA-DO, regulatory T cells.
Mechanisms regulating the development
and function of natural regulatory T cells
Sonal Gupta1, Weirong Shang2 and Zuoming Sun1, 3
1 Department of Microbiology and Immunology, School of Medicine, University of Illinois, Chicago, IL 60612, USA
2 Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA 30308, USA
3 Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
Received: 2007.10.08, Accepted: 2008.02.04, Published online first: 2008.03.31
Abstract
The key of the immune system is to protect the host from foreign threat posed by pathogens and from the internal threat
posed by self-attacking lymphocytes. The ability to discriminate self versus non-self ensures that only “non-self” pathogens,
but not the self antigens, are attacked. Such tolerance to “self” arises from the central tolerance mechanisms that include the
deletion of thymocytes with high reactivity to self antigens and also the induction of unresponsiveness of autoreactive T cells
in the periphery. Natural regulatory T cells (nTregs) directly inhibit effector T cells, and keep their proliferation in control.
Apart from preventing autoimmune reactions, Tregs also contribute to peripheral immune homeostasis as evidenced by the
excessive lymphocyte accumulation in peripheral lymphoid organs and intestinal inflammation in the absence of nTregs.
Here we discuss the molecular aspects of the development and suppressive function of naturally occurring Tregs.
Accumulating evidence shows the importance of these Tregs in autoimmunity, tumor immunity, organ transplantation, aller-
gy, and microbial immunity.
Key words: development, Treg, T cell activation, signaling, PKC-θ
Role of response gene to complement 32 in diseases
Sonia I. Vlaicu, Cornelia Cudrici, Takahiro Ito, Matthew Fosbrink, Cosmin A. Tegla,
Violeta Rus, Petru A. Mircea and Horea Rus
Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA
Received: 2007.12.06, Accepted: 2008.02.21, Published online first: 2008.03.31
Abstract
The role of response gene to complement (RGC)-32 as a cell cycle regulator has been attributed to its ability to activate cdc2
kinases and to induce S-phase entry and mitosis. However, recent studies revealed novel functions for RGC-32 in diverse
processes such as cellular differentiation, inflammation, and fibrosis. Besides responding to C5b-9 stimulation, RGC-32
expression is also induced by growth factors, hormones, and cytokines. Transforming growth factor β activates RGC-32
through Smad and RhoA signaling, thus initiating smooth muscle cell differentiation. Accumulating evidence has drawn
attention to the deregulated expression of RGC-32 in human malignancies, hyper-immunoglobulin E syndrome, and fibro-
sis. RCG-32 expression is up-regulated in cutaneous T cell lymphoma and colon, ovarian, and breast cancer, but down-reg-
ulated in invasive prostate cancer, multiple myeloma, and drug-resistant glioblastoma. A better understanding of the mech-
anism by which RGC-32 contributes to the pathogenesis of these diseases will provide new insights into its therapeutic poten-
tial. In this review we provide an overview of this field and discuss the most recent research on RGC-32.
Key words: RGC-32, cell cycle, differentiation, cancer, cdc2.
Manipulating B cell homeostasis: a key component
in the advancement of targeted strategies
Laura S. Treml, William J. Quinn III, John F. Treml, Jean L. Scholz
and Michael P. Cancro
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia,
PA 19104-6082, USA
Received: 2007.11.29, Accepted: 2008.01.04, Published online first: 2008.05.30
Abstract
Understanding the homeostatic mechanisms governing lymphocyte pools achieves critical importance as lymphocyte-target-
ed therapies expand in use and scope. The primacy of B lymphocyte stimulator (BLyS) family ligands and receptors in gov-
erning B lymphocyte homeostasis has become increasingly clear in recent years, affording insight into novel opportunities
and potential pitfalls for targeted B cell therapeutics. Interclonal competition for BLyS-BR3 interactions determines the size
of naïve B cell pools and can regulate the stringency of selection applied as cells complete maturation. Thus one of the pre-
dicted consequences of ablative therapies targeting primary pools is relaxed negative selection. This suggests that BLyS lev-
els and B cell reconstitution rates may serve useful prognostic roles and that BLyS itself might be targeted to circumvent
relapse. Alternatively, manipulations that allow rare, minimally autoreactive specificities to survive and mature may lead to
opportunities in cases where antibody-based vaccine development has heretofore been unsuccessful. BLyS family ligands and
receptors also play a role in activated and memory B cell pools, suggesting they might likewise be targeted to promote or
delete particular antigen-experienced subpopulations in a similar way.
Key words: B cell, homeostasis, BLyS, targeted therapy.
The significance of Treg cells in defective tumor immunity
Agata Kosmaczewska1, Lidia Ciszak1, Stanisław Potoczek2 and Irena Frydecka1, 2
1 Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroc³aw, Poland
2 Department of Hematology, Wroc³aw Medical University, Poland
Received: 2007.08.13, Accepted: 2007.12.14, Published online first: 2008.05.30
Abstract
Regulatory T cells (Treg) enriched in FoxP3+, glucocorticoid-induced TNF receptor+, and cytotoxic T-lymphocyte-associat-
ed antigen-4+ exert a potential to suppress effector T cells in the periphery. These cells exist in markedly higher proportions
within tumor-infiltrating lymphocytes, peripheral blood lymphocytes, and/or regional lymph node lymphocytes of patients
with cancer and their frequencies are suggested to be strongly related to tumor progression and inversely correlated with the
efficacy of treatment. Tumor-specific Treg cells require ligand-specific activation and cell-to-cell contact to exert their sup-
pressive activity on tumor-specific effector cells (CD8+ cytotoxic T lymphocytes and CD4+ Th cells), which includes
decreased cytotoxity, proliferation, and Th1 cytokine secrection. Depletion or blockade of Treg cells can enhance immune
protection from tumor-associated antigens that are expressed as self antigens. Recent studies revealed that lymphoma T cells
might adopt a Treg profile as well. Studies assessing the influence of chemotherapy on Treg cells have also been included in
this review.
Key words: Treg cells, FoxP3, immunosuppression, tumor immunity
A direct comparison of rejection by CD8 and CD4 T cells
in a transgenic model of allotransplantation
Paige M. Porrett1, Major K. Lee IV1, Moh Moh Lian1, Jing Wang1, Andrew J. Caton2,
Shaoping Deng3, James F. Markmann3 and Daniel J. Moore1, 4
1 Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania,
Philadelphia, PA 19104, USA
2 The Wistar Institute, Philadelphia, PA 19104, USA
3 Division of Surgery, Department of Transplantation, Mass. General Hospital, Boston, MA 02114, USA
4 Department of Pediatrics, Division of Endocrinology and Diabetes, Vanderbilt Children’s Hospital, Nashville, TN 37232,
USA
Received: 2007.09.12, Accepted: 2008.01.08, Published online first: 2008.05.30
Abstract
Introduction: The relative contributions of CD4+ and CD8+ T cells to transplant rejection remain unknown. The authors inte-
grated a previous model of CD4-mediated graft rejection with a complementary model of CD8-mediated rejection to direct-
ly compare the function of graft-reactive CD4+ and CD8+ lymphocytes in vivo in a model where rejection requires transgenic
T cells. These studies allow direct comparison of CD4 and CD8 T cell responses to the same antigen without the confound-
ing effects of T cell depletion or homeostatic proliferation.
Materials and Methods: Clone 4 and TS1 mice possess MHC class I- and II-restricted CD8+ and CD4+ T cells, respectively,
which express transgenic T cell receptors that recognize the influenza hemagglutinin antigen (HA). We compared the in vivo
response of CFSE-labeled, HA-specific transgenic CD8+ and CD4+ T cells after adoptive transfer into syngeneic
BALB/c mice grafted with HA-expressing skin.
Results: As in the authors’ CD4+ model, HA104 skin was consistently rejected by both Clone 4 mice (n=9, MST: 14.2) and
by 5×105 Clone 4 lymphocytes transferred to naive BALB/c hosts that do not otherwise reject HA+ grafts. Rejection corre-
lated with extensive proliferation of either graft-reactive T cell subset in the draining lymph nodes, and antigen-specific
CD4+ and CD8+ cells acquired effector function and proliferated with similar kinetics.
Conclusions: These data extend the authors’ unique transgenic transplantation model to the investigation of CD8 T cell func-
tion. The initial results confirm fundamental functional similarity between the CD4 and CD8 T cell subsets and provide
insight into the considerable redundancy underlying T cell mechanisms mediating allograft rejection.
Key words: CD4, CD8, proliferation, differentiation, transplantation, rejection.
Dual use and the ethical responsibility of scientists
Hans−Jörg Ehni
Institute of Ethics and History of Medicine, University of Tübingen, Germany
Received: 2008.02.19, Accepted: 2008.05.08, Published online first: 2008.05.30
Abstract
The main normative problem in the context of dual use is to determine the ethical responsibility of scientists especially in the
case of unintended, harmful, and criminal dual use of new technological applications of scientific results. This article starts
from an analysis of the concepts of responsibility and complicity, examining alternative options regarding the responsibility
of scientists. Within the context of the basic conflict between the freedom of science and the duty to avoid causing harm, two
positions are discussed: moral skepticism and the ethics of responsibility by Hans Jonas. According to these reflections, four
duties are suggested and evaluated: stopping research, systematically carrying out research for dual-use applications, inform-
ing public authorities, and not publishing results. In the conclusion it is argued that these duties should be considered as
imperfect duties in a Kantian sense and that the individual scientist should be discharged as much as possible from obliga-
tions which follow from them by the scientific community and institutions created for this purpose.
Key words: research ethics, dual use, responsibility, complicity.
Prevalence of human herpesvirus 6 antibodies
and DNA in allogeneic stem cell transplant patients:
two-year single centre experience
Tomasz Dzieciątkowski1, 2, Maciej Przybylski1, 2, Tigran Torosian3,
Agnieszka Tomaszewska3, 4 and Mirosław Łuczak1, 2
1 Chair and Department of Medical Microbiology, Medical University of Warsaw, Warsaw, Poland
2 Department of Microbiology, Public Independent Central Clinical Hospital in Warsaw, Warsaw, Poland
3 Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
4 Department of Hemopoetic Stem Cell Transplantation, Institute of Hematology and Transfusion Medicine,
Warsaw, Poland
Received: 2007.07.10, Accepted: 2008.02.04, Published online first: 2008.05.30
Abstract
Introduction: Human herpesvirus 6 (HHV-6) has been recognized as a potentially significant pathogen in hemopoietic stem
cell transplant (HSCT) recipients. Different clinical manifestations have been described, including fever, skin rash, bone
marrow suppression, and encephalitis.
Materials and Methods: A retrospective review of a group of 26 adult recipients of allogeneic HSCTs was conducted. Serum
samples taken before transplant were examined for the presence of specific anti-HHV-6 IgM and IgG antibodies. After
transplantation, quantitative real-time PCR was used to determine viral load in plasma samples from days 0–180 post-trans-
plant.
Results: HHV-6 DNA was detected in plasma samples in 8 (30%) of the 26 recipients between days 18 and 40 after trans-
plantation. All of them developed fever of unknown origin and over 50% had graft-versus-host disease features. Three indi-
viduals from this group died during detectable HHV-6 viremia. Another two recipients showed a single positive PCR result
at a later time. Infection with HHV-6 was thus confirmed in 10 (38.5%) of the 26 graft recipients.
Conclusions: There is a high frequency of detectable HHV-6 viral load in stem cell transplant recipients in Poland. Further
investigation to monitor HHV-6 reactivation in graft recipients will be important to improve outcome for these patients.
Key words: HHV-6, hemopoietic stem cells transplant, real-time PCR, GvHD.
Abnormal cytokine production by bone marrow
stromal cells of multiple myeloma patients
in response to RPMI8226 myeloma cells
Barbara Zdzisińska1, Agnieszka Bojarska−Junak2, Anna Dmoszyńska3
and Martyna Kandefer−Szerszeń1
1 Department of Virology and Immunology, Maria Curie-Sk³odowska University, Lublin, Poland
2 Department of Clinical Immunology, University Medical School, Lublin, Poland
3 Department of Hematooncology and Bone Marrow Transplantation, University Medical School, Lublin, Poland
Received: 2007.11.26, Accepted: 2008.03.17, Published online first: 2008.05.30
Abstract
Introduction: Recent studies indicate that bone marrow stromal cells (BMSCs) derived from patients with multiple myeloma
(MM) differ from those of healthy donors in their expression of extracellular matrix compounds and in cytokine production.
It is not known whether these abnormalities are primary or are acquired by BMSCs on contact with MM cells.
Materials and Methods: Interleukin (IL)-6, IL-11, IL-10, and tumor necrosis factor (TNF)-α production by CD166+ mes-
enchymal BMSCs and the CD38+/CD138+ RPMI8226 myeloma cell line cultivated in vitro in monocultures or co-cultivated
under cell-to-cell contact or non-contact conditions in the presence of a tissue culture insert were measured. Intracellular
cytokines were measured by flow cytometry analysis as the percentage of cytokine-producing cells or by mean fluorescence
intensity as the level of cytokine expression in cells. Additionally, ELISA was used to measure IL-6, soluble IL-6 receptor
(sIL-6R), IL-11, IL-10, TNF-α, B-cell-activating factor of the TNF family (BAFF), hepatocyte growth factor (HGF), and
osteopontin (OPN) production in the supernatants of the cultures and co-cultures.
Results: A higher ability of the BMSCs of MM patients than in controls was detected to produce IL-6, IL-10, TNF-α, OPN,
and especially HGF and BAFF in response to the RPMI8226 cells. Moreover, the BMSCs of the MM patients significantly
enhanced the production of sIL-6R by the RPMI8226 cells.
Discussion: Cytokines over-expressed by BMSCs of MM patients can function as growth factors for myeloma cells (IL-6,
IL-10, HGF), migration stimulatory factors for tumor plasma cells (TNF-α, HGF), adhesion stimulatory factors (HGF,
BAFF and OPN), stimulators of osteoclastogenesis (IL-6, TNF-α), and angiogenic factors (TNF-α). The results of this
experiment strongly suggest that the BMSCs from MM patients differed in spontaneous and myeloma cell-induced produc-
tion of cytokines, especially of HGF and BAFF, and these abnormalities were both primary and acquired by the BMSCs on
contact with the MM cells. This in turn suggests the presence of an undefined, autocrine stimulation pathway resulting in
a prolonged production of cytokines even in long-term cultures in vitro and in vivo. These abnormalities might provide opti-
mal conditions for the proliferation and differentiation of residual tumor cells or their precursors in the affected bone
marrow.
Key words: multiple myeloma, cytokines, bone marrow stromal cells.
Cancer stem cells as targets for cancer therapy:
selected cancers as examples
Sabine Hombach−Klonisch1*, Ted Paranjothy2*, Emilia Wiechec3, Paola Pocar4,
Tarek Mustafa5, 6, Anja Seifert7, Christian Zahl5, Klaus Luis Gerlach5,
Katharina Biermann8, Klaus Steger9, Cuong Hoang−Vu6, Klaus Schulze−Osthoff10
and Marek Los2, 11
1 Department Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada
2 Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada
3 Institute of Human Genetics, University of Aarhus, Aarhus, Denmark
4 Department of Animal Science, Faculty of Veterinary Medicine, University of Milan, Italy
5 Department of Oral and Maxillo-Facial Surgery, Faculty of Medicine, University Magdeburg, Germany
6 Experimental Surgery and Oncology Research Group, Department of General, Visceral and Vascular Surgery,
University of Halle-Wittenberg, Germany
7 Department Anatomy and Cell Biology, University of Halle-Wittenberg, Halle, Germany
8 Institute of Pathology, University Hospital Bonn, Germany
9 Department of Urology and Pediatric Urology, University of Giessen, Germany
10 Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany
11 BioApplications Enterprises, Winnipeg, Manitoba, Canada
* Shared first-authorship
Received: 2008.03.25, Accepted: 2008.05.17, Published online first: 2008.05.30
Abstract
It is becoming increasingly evident that cancer constitutes a group of diseases involving altered stem-cell maturation/differ-
entiation and the disturbance of regenerative processes. The observed malignant transformation is merely a symptom of nor-
mal differentiation processes gone astray rather than the primary event. This review focuses on the role of cancer stem cells
(CSCs) in three common but also relatively under-investigated cancers: head and neck, ovarian, and testicular cancer. For
didactic purpose, the physiology of stem cells is first introduced using hematopoietic and mesenchymal stem cells as exam-
ples. This is followed by a discussion of the (possible) role of CSCs in head and neck, ovarian, and testicular cancer. Aside
from basic information about the pathophysiology of these cancers, current research results focused on the discovery of mol-
ecular markers specific to these cancers are also discussed. The last part of the review is largely dedicated to signaling path-
ways active within various normal and CSC types (e.g. Nanog, Nestin, Notch1, Notch2, Oct3 and 4, Wnt). Different elements
of these pathways are also discussed in the context of therapeutic opportunities for the development of targeted therapies
aimed at CSCs. Finally, alternative targeted anticancer therapies arising from recently identified molecules with cancer-
-(semi-)selective capabilities (e.g. apoptin, Brevinin-2R) are considered.
Key words: Nanog, Nestin, Notch1, Notch2, Oct4, Wnt.
The top-ten in journal impact factor manipulation
Matthew E. Falagas1, 2 and Vangelis G. Alexiou1
1 Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece
2 Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA
Received: 2008.05.19, Accepted: 2008.06.20, Published online first: 2008.07.29
Abstract
A considerable part of the scientific community is, at least to some degree, involved in the “impact factor game”. Editors
strive to increase their journals’ impact factor (IF) in order to gain influence in the fields of basic and applied research and
scientists seek to profit from the “added value” of publishing in top IF journals. In this article we point out the most com-
mon “tricks” of engineering and manipulating the IF undertaken by a portion of professionals of the scientific publishing
industry. They attempt to increase the nominator or decrease the denominator of the IF equation by taking advantage of cer-
tain design flaws and disadvantages of the IF that permit a degree of artificial and arbitrary inflation. Some of these prac-
tices, if not scientifically unethical, are at least questionable and should be abandoned. Editors and publishers should strive
for quality through fair and thoughtful selection of papers forwarded for peer review and editorial comments that enhance
the quality and scientific accuracy of a manuscript.
Key words: scientific quality, scientific productivity, research funding, citation, self-citation, editorial policies.
Immunotherapy of type 1 diabetes
Li Li*, Zuoan Yi*, Roland Tisch and Bo Wang
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
*Both authors contributed equally.
Received: 2008.05.23, Accepted: 2008.06.27, Published online first: 2008.07.29
Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing β cells are destroyed. Diabetic patients man-
age their hyperglycemia by daily insulin injections. However, insulin therapy is by no means a cure. Accordingly, a significant
effort has been ongoing to develop immunotherapies that effectively prevent and/or treat T1D in the clinic. This review
focuses on antigen- and antibody-based immunotherapies and discusses the respective strengths and weaknesses of these
approaches.
Key words: antibody, antigen-specific, immunoregulatory T cells, tolerance.
Abnormalities in the handling of intracellular bacteria
in Crohn’s disease: a link between infectious etiology
and host genetic susceptibility
Anne−Lise Glasser and Arlette Darfeuille−Michaud
Pathogénie Bactérienne Intestinale, Université d’Auvergne, JE 2526, USC INRA 2018, Clermont-Ferrand, France
Received: 2008.04.11, Accepted: 2008.06.27, Published online first: 2008.07.29
Abstract
The etiology of Crohn’s disease (CD) is still poorly understood, but recent advances have highlighted the importance of the
innate immune system and the critical relationship between the gut flora and the intestinal mucosa. Several combinations of
genetic factors predisposing to CD have been described, with the most significant replicable associations including genes for
intracellular receptors of bacterial cell walls (NOD2/CARD15) and for bacterial clearance and antigen processing via
autophagy (ATG16L1 and IRGM). One theoretical link between susceptibility genes NOD2/CARD15, ATG16L1, and IRGM
is that CD is primarily induced by the presence of a dysfunctional immunological response to persistent infection by intra-
cellular bacterial pathogens such as Mycobacterium avium subspecies paratuberculosis or adherent-invasive Escherichia coli,
both first-rank candidates on the basis of host genetic susceptibility, which concerns impaired functions in the defense against
intracellular bacteria.
Key words: Crohn’s disease, Mycobacterium avium subspecies paratuberculosis, adherent-invasive E. coli, NOD2/CARD15,
ATG16L1, IRGM, autophagy.
Ras pathway activation in gliomas: a strategic target
for intranasal administration of perillyl alcohol
Clovis Orlando da Fonseca1, Rafael Linden2, Débora Futuro3, Cerli Rocha Gattass4
and Thereza Quirico−Santos4, 5
1 Serviço de Neurocirurgia, Hospital Universitário Antônio Pedro, Universidade Federal Fluminense, Niterói 24030-210,
RJ, Brazil
2 Laboratório de Neurogênese, Universidade Federal do Rio de Janeiro, Rio de Janeiro, R.J, Brazil
3 Faculdade de Farmácia, Universidade Federal Fluminense, Niterói 24030-210, RJ, Brazil
4 Laboratorio de Imunologia Celular, Universidade Federal do Rio de Janeiro, 21949-900 Rio de Janeiro, RJ, Brazil
5 Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense,
24020-150 Niterói, RJ, Brazil
Received: 2008.02.04, Accepted: 2008.06.28, Published online first: 2008.07.29
Abstract
Introduction: Targeted therapy directed at specific molecular alterations is already creating a shift in the treatment of cancer
patients. Malignant gliomas commonly overexpress the oncogenes EGFR and PDGFR and contain mutations and deletions
of the tumor suppressor genes PTEN and TP53. Some of these alterations lead to activation of the P13K/Akt and Ras/MAPK
pathways, which provide targets for therapy. Perillyl alcohol (POH), the isoprenoid of greatest clinical interest, was initially
considered to inhibit farnesyl protein transferase. Follow-up studies revealed that POH suppresses the synthesis of small
G proteins, including Ras. Intranasal delivery allows drugs that do not cross the blood-brain barrier to enter the central ner-
vous system. Moreover, it eliminates the need for systemic delivery, thereby reducing unwanted systemic side effects.
Materials and Methods: Applying this method, a phase I/II clinical trial of POH was performed in patients with relapsed
malignant gliomas after standard treatment: surgery, radiotherapy, and chemotherapy. POH was administrated in a concen-
tration of 0.3% volume/volume (55 mg) four times daily in an interrupted administration schedule. The objective was to eval-
uate toxicity and progression-free survival (PFS) after six months of treatment. The cohort consisted of 37 patients, includ-
ing 29 with glioblastoma multiforme (GBM), 5 with grade III astrocytoma (AA), and 3 with anaplastic oligodendroglioma
(AO). Neurological examination and suitable image analysis (computed tomography (CT), magnetic resonance imaging
(MRI)) established disease progression. Complete response was defined as neurological stability or improvement of condi-
tions, disappearance of CT/MRI tumor image, and corticosteroid withdraw; partial response (PR) as ≥50% reduction of
CT/MRI tumor image, neurological stability, or improvement of conditions and corticosteroid requirement; progressive
course (PC) as ≥25% increase in CT/MRI tumor image or the appearance of a new lesion; and stable disease as a lack of any
changes in the CT/MR tumor image or neurological status.
Results: After six months of treatment, PR was observed in 3.4% (n=1) of the patients with GBM and 33.3% (n=1) with
AO; stable disease in 44.8% (n=13) with GBM, 60% (n=3) with AA, and 33.3% (n=1) with AO; and PC in 51.7% (n=15)
with GBM, 40% (n=2), with AA and 33.3% (n=1) AO. PFS (sum of PRs and stable disease) was 48.2% for GBM, 60% for
AA, and 66.6% for AO patients.
Conclusions: The preliminary results indicate that intranasal administration of the signal transduction inhibitor POH is a safe,
noninvasive, and low-cost method. There were no toxicity events and the regression of tumor size in some patients is sug-
gestive of antitumor activity.
Key words: perillyl alcohol, intranasal administration, gliomas, Ras.
Host immune response
in B-cell lymphomas: friend or foe?
Przemysław Juszczyński1, Jacek Nowak2 and Krzysztof Warzocha2
1 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
2 Institute of Hematology and Transfusion Medicine, Warsaw, Poland
Received: 2008.04.07, Accepted: 2008.06.30, Published online first: 2008.07.29
Abstract
The interaction of B-cell malignancies with the host immune system is a dynamic and bilateral process. Certain lymphomas
more commonly arise within a background of autoimmunity or chronic infection. Initiation of these tumors is commonly
reliant on antigenic stimulation and/or T-cell help. Apart from its tumor-fueling role, the host immune response plays a crit-
ical role in cancer immunosurveillance and immunoediting. The concept of immunoediting holds that the immune system
sculpts the tumor’s immunogenicity in a dynamic process that involves three essential phases: elimination, equilibrium, and
escape. Data obtained by studying gene-targeted animals and human lymphomas that support the critical role of the immune
response in the initiation, progression, and immunoediting of lymphoid malignancies are summarized here. A thorough
understanding of this interaction will lead to the identification of more rational treatment targets and improved immunother-
apies in B-cell lymphomas.
Key words: lymphoma, immune escape, immunoediting.
Role of the Wnt/ββ-catenin network
in regulating hematopoiesis
Mirosława Wilusz and Marcin Majka
Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University Medical College,
Cracow, Poland
Received: 2008.01.22, Accepted: 2008.06.30, Published online first: 2008.07.29
Abstract
The Wnt/β-catenin pathway plays a significant role in several aspects of cell biology, including the stimulation of gene expres-
sion, growth, and mobility. Wnt proteins activate at least three cascades: Wnt/β-catenin, Wnt/Ca2+, and planar cell polarity.
β-Catenin is not only a very important element of many intracellular signaling pathways, including the Wnt pathway, but it
also takes part in creating intercellular adhesive junctions. When overexpressed or mutated it functions as an oncogen. The
Wnt/β-catenin signaling pathway has been shown to play an important role in controlling the proliferation, survival, and dif-
ferentiation of hematopoietic cells. Thus any aberrant signaling through this pathway may have a negative influence on
hematopoiesis. Indeed, some recent findings suggest that Wnt/β-catenin signaling is dysregulated in leukemias and lym-
phomas. All these data position the Wnt/β-catenin signaling network as a critically important regulator of hematopoiesis and
justify future efforts to better understand its role in the process of physiological and pathological hematopoiesis. The pre-
sent review summarizes recent advances in this field.
Key words: Wnt, β-catenin, hematopoiesis, stem cells, tumor cells.
Relationship between impaired apoptosis of lymphocytes
and distribution of dendritic cells in peripheral blood
and synovial fluid of children
with juvenile idiopathic arthritis
Elżbieta Smolewska1, 2, Barbara Cebula3, Henryka Brózik2 and Jerzy Stańczyk1
1 Department of Pediatric Cardiology, 2nd Chair of Pediatrics and Cardiology, Medical University of £ódŸ, £ódŸ, Poland
2 Rheumatological Clinic for Children, Medical University of £ódŸ, £ódŸ, Poland
3 Department of Hematology, Medical University of £ódŸ, £ódŸ, Poland
Received: 2008.03.19, Accepted: 2008.06.30, Published online first: 2008.07.29
Abstract
Introduction: The pathogenesis of juvenile idiopathic arthritis (JIA) is not fully understood. Recently the present authors
described disturbed apoptosis of JIA lymphocytes in both peripheral blood (PB) and synovial fluid (SF) as well as an abnor-
mal distribution of blood dendritic cells (BDCs) between the PB and SF in this disease. Possible relationships between these
events during the development of JIA process are assessed here.
Materials and Methods: Lymphocyte apoptosis and BDC counts were assessed in the PB and SF of untreated JIA children.
Lymphocyte apoptosis was analyzed by the Annexin-V/propydium iodide assay. Total DC (TDC) number was based on the
sum of three BDC subpopulations determined using a panel of monoclonal antibodies against BDC antigens (BDCA):
myeloid type 1 (mDC1, BDCA-1+/HLA-DR+/CD19–), myeloid type 2 (mDC2, BDCA-3+/HLA-DR+/CD14–), and plasma-
cytoid (pDC, BDCA-2+/HLA-DR+/CD123+). Cells were enumerated by the flow cytometric “single-platform” method. The
concentration of tumor necrosis factor (TNF)-α and the distribution of particular lymphocyte subtypes in both PB and SF
were also investigated.
Results: There was significant positive correlation between apoptosis of PB lymphocytes and SF TDC count (p=0.002) as
well as SF TNF-α concentration (p=0.007). SF TNF-α levels also correlated with SF TDC count (p=0.003). Moreover, JIA
SF was distinctly enriched with CD4+ and CD8+ T lymphocytes and included CD4+/CD25high cells as well. There was signif-
icant positive correlation between the number of CD4+/CD25high cells and SF JIA BDC count (p=0.015).
Conclusions: These data suggest a possible link between impaired apoptosis of PB/SF lymphocytes and increased recruitment
of PB BDCs to SF and other elements of the immune system in JIA, including regulatory CD4+/CD25high cells.
Key words: juvenile idiopathic arthritis, dendritic cells, lymphocytes, apoptosis.
The evaluation of markers of prostatic inflammation
and function of the prostate gland in patients
with chronic prostatitis
Bożena Zdrodowska−Stefanow1, Iwona Ostaszewska−Puchalska2, Jerzy Badyda3
and Zofia Galewska4
1 Department of Dermatology and Venerology, Medical University, Bia³ystok, Poland
2 Center for Sexually Transmitted Diseases Research and Diagnostics, Bia³ystok, Poland
3 Outpatient Urology Clinic “Multimedica”, Bia³ystok, Poland
4 Department of Medical Biochemistry, Medical University, Bia³ystok, Poland
Received: 2007.09.25, Accepted: 2008.06.30, Published online first: 2008.07.29
Abstract
Introduction: The aim of the study was to determine the numbers of polymorphonuclear (PMN) leukocytes and PMN elas-
tase and citric acid concentrations in chronic prostatitis patients regardless of etiology and in those with Chlamydia tra-
chomatis infection of the prostate gland.
Materials and Methods: The study involved 46 patients with chronic prostatitis. Expressed prostatitc secretions (EPS) were
obtained to determine the leukocyte count, PMN elastase (ELISA) and citric acid concentrations (UV method), and the
occurrence of C. trachomatis infection (ligase chain reaction).
Results: Increased PMN cell counts (≥10 per high-power field) were found in 73.9% of patients and increased PMN elastase
concentration (<250 ng/ml) in 78.3%. In 44.4% of the patients the elastase concentration indicated moderate (250–1000
ng/ml) and in 55.6% acute infection (≥1000 ng/ml). Decreased citric acid concentration (<18.12 mg/ml) in the EPS was
found in 65.2% of the men. C. trachomatis prostate infection was detected in 17.4% of the patients and all of these men had
higher inflammation parameters and lower citric acid concentrations.
Conclusions: C. trachomatis prostate inflammation was accompanied by an increase in inflammation markers and a decrease
in citric acid concentration.
Key words: chronic prostatitis, Chlamydia trachomatis, citric acid, prostate gland, expressed prostatic secretions, PMN elastase.
Is it wise to target the late costimulatory molecule OX40
as a therapeutic target?
Mary Miranda Cavanagh and Tracy Hussell
Imperial College London, National Heart and Lung Institute, London, UK
Received: 2008.08.19, Accepted: 2008.09.22, Published online first: 2008.10.06
Abstract
The immune response triggered following pathogen recognition, though required to clear the infection, can be detrimental
if it is produced in excess or fails to resolve promptly. Excessive inflammation contributes to infectious and noninfectious
pathologies in the gut (such as inflammatory bowel disease), lung (such as bronchiolitis), and in a variety of autoimmune
conditions. T cells contribute significantly to pathology during inflammation. Global anti-inflammatory strategies can allevi-
ate the consequences of exuberant inflammation by suppressing T cell activity, but may leave the patient vulnerable to oppor-
tunistic infection. More specific therapies aim to suppress only those T cells involved in the disease process, and one such
approach is to target late costimulatory molecules. These are not expressed on naïve or resting memory cells. Rather, they
have a specific window of expression and their ligation results in the production of abundant inflammatory cytokines. By tar-
geting these molecules, it is hoped that inflammation will reduce, but that therapies will be specific enough to avoid, global
immune suppression. This review focuses on the late costimulatory molecule OX40, compare it with other T cell costimula-
tors, and highlight why it is a more suitable target for immune intervention than other immune suppressive strategies.
Key words: costimulatory molecules, autoimmunity, infection, OX40, immunopathology
Antigen-nonspecific activation of CD8+ T lymphocytes
by cytokines: relevance to immunity, autoimmunity,
and cancer
Sheela Ramanathan, Julien Gagnon and Subburaj Ilangumaran
Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, University of Sherbrooke;
Centre de recherche clinique Etienne-Le Bel, Centre Hospitalier de l’université de Sherbrooke, Sherbrooke, Québec, Canada
Received: 2008.05.02, Accepted: 2008.07.28, Published online first: 2008.10.06
Abstract
Development of T lymphocytes and their survival in the periphery are dependent on signals emanating from cytokine recep-
tors as well as the T cell antigen receptor (TCR). These two signaling pathways play distinct and complementary roles at var-
ious stages of T cell development, maturation, survival, activation and differentiation. During immune response to foreign
antigens initiated by TCR signaling, cytokines play a key role in the expansion of activated T cells. Even though the initial
activation of T cells occurs via the TCR, this requirement can be overcome under certain circumstances. During lymphope-
nia, cytokines trigger memory CD8+ T cells to undergo antigen non-specific homeostatic expansion, whereas naïve CD8+
T cells require both cytokines and TCR signaling. Recent reports show certain combinations of cytokines can induce prolif-
eration and effector functions of naïve CD8+ T cells without concomitant stimulation via the TCR. While such antigen non-
-specific stimulation of naïve T cells might significantly boost the adaptive immune response, it could also have an undesir-
able effect of triggering potentially autoreactive cells. Understanding the mechanisms and the regulation of cytokine-driven
stimulation of naïve CD8+ T cells may lead to novel strategies of intervention for autoimmune diseases. On the other hand,
in vitro expansion of naïve CD8+ T cells by certain combinations of cytokines could be used to generate tumor-specific cells
with ideal properties for cellular immunotherapy of cancer.
Key words: CD8+ T lymphocytes, cytokines, immune response, autoimmunity, cancer.
Immunochemical studies of the lipopolysaccharides
of
Hafnia alvei PCM 1219 and other strains
with the O-antigens containing D-glucose 1-phosphate
and 2-deoxy-2-[(
R)-3-hydroxybutyramido]-D-glucose
Ewa Katzenellenbogen1, Nina A. Kocharova2, Agnieszka Korzeniowska−Kowal1,
Andrzej Gamian1, 3, Maria Bogulska1, Bernadeta Szostko1, Alexander S. Shashkov2
and Yuriy A. Knirel2
1 Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroc³aw, Poland
2 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation
3 Department of Medical Biochemistry, Wroc³aw Medical University, Wroc³aw, Poland
Received: 2007.10.10, Accepted: 2008.06.30, Published online first: 2008.10.06
Abstract
Introduction: Hafnia alvei is the only species of the genus Hafnia, which belongs to the family of Enterobacteriaceae. These
Gram-negative bacteria are commonly distributed in the natural environment and are often the cause of human oppor-
tunistic infections. Their lipopolysaccharides (LPSs) are important surface antigens which are responsible for the serologi-
cal specificity and numerous cross-reactions with other enterobacterial genera. So far, 29 different O-polysaccharide (OPS,
O-antigen) structures in Hafnia LPSs have been established and for some of them the molecular basis of the serological activ-
ity has been elucidated.
Materials and Methods: OPS from H. alvei strain PCM 1219 was obtained by mild acid hydrolysis of the LPS followed by gel
permeation chromatography of carbohydrate material on Sephadex G-50 column. The polysaccharide structure was deter-
mined using chemical methods as well as 13C NMR and 1H NMR spectroscopy. For serological studies, SDS-PAGE,
immunoblotting, and passive hemagglutination tests were used.
Results: The serological studies revealed a cross-reactivity of the LPSs of H. alvei PCM 1219 and a group of H. alvei strains
with an O-antigen containing D-glucose 1-phosphate and [(R)-3-hydroxybutyramido]-D-glucose. The following structure of
the OPS was established: →2)-α-D-Glcp-(1-PO4-6)-α-D-GlcpNAcyl-(1→4)-α-D-GalpNAc-(1→3)-β-D-GalpNAc-(1→
3 6
↑
OAc 1
α-D-Glcp
where Acyl stands for (R)-3-hydroxybutyryl and the degree of O-acetylation is ∼70%. The structure of the core oligosaccha-
ride was found to be typical of the genus Hafnia.
Conclusions: Based on the OPS structure and serological results it was concluded that H. alvei strain PCM 1219 should be
classified in the same serogroup as the H. alvei type strain ATCC 13337 and five other strains containing D-glucose 1-phos-
phate and 2-deoxy-2-[(R)-3-hydroxybutyramido]-D-glucose in their O-antigens.
Key words: Hafnia alvei, enterobacteria, O-antigen, lipopolysaccharide, bacterial polysaccharide structure, serological cross-
-reactivity.
Opiate abuse, innate immunity,
and bacterial infectious diseases
Jinghua Wang1, Roderick A. Barke2, Jing Ma1, 3, Richard Charboneau2
and Sabita Roy1, 2, 4
1 Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
2 Department of Surgery, Veterans Affairs Medical Center, Minneapolis, MN, USA
3 Department of Immunology, Jilin University Norman Bethune Medical College, Changchun, China
4 Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
Received: 2008.05.23, Accepted: 2008.07.28, Published online first: 2008.10.06
Abstract
The first line of defense against invading bacteria is provided by the innate immune system. Morphine and other opiates can
immediately disrupt the body’s first line of defense against harmful external bacteria. Opiate, for example morphine, abuse
degrades physical and physiologic barriers, and modulates phagocytic cells (macrophages, neutrophils) and, nonspecific cyto-
toxic T cells (γδ T), natural killer cells, and dendritic cells, that are functionally important for carrying out a rapid immune
reaction to invading pathogens. In vitro studies with innate immune cells from experimental animals and humans and in vivo
studies with animal models have shown that opiate abuse impairs innate immunity and is responsible for increased suscepti-
bility to bacterial infection. However, to better understand the complex interactions between opiates, innate immunity, and
bacterial infection and develop novel approaches to treat and even prevent bacterial infection in the opiate-abuse popula-
tion, there is an urgent need to fill the numerous gaps in our understanding of the cellular and molecular mechanisms by
which opiate abuse increases susceptibility to bacterial infection.
Key words: opiate, morphine, innate immunity, macrophages, neutrophils, dentritic cells, NK cells, γδ T lymphocytes, cyto-
kines, bacterial infection.
Mesenchymal stromal cells: tissue engineers
and immune response modulators
Lieke C. J. van den Berk, Carl G. Figdor and Ruurd Torensma
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Nijmegen, the Netherlands
Received: 2008.05.28, Accepted: 2008.09.12, Published online first: 2008.10.06
Abstract
Mesenchymal stromal cells (MSCs) show significant immune-suppressive properties both in vitro and in vivo. Based on their
immune-stealth properties, allogeneic MSCs are used to treat several diseases, for example the injection of MSCs in infarct-
ed heart tissue or their use in bone-cartilage regeneration. The most spectacular treatment was recently described. MSCs
were able to down-regulate the severity of graft-versus-host disease, leading to an impressive 20 to 50% increase in the two-
-year survival of bone marrow transplantation patients. Here the current literature is reviewed to elucidate the different
mechanisms involved in these two clinical treatment modalities of MSCs.
Key words: MSC, T cell proliferation, DC differentiation and maturation, transplantation, immunomodulation, GVHD.
Structure and physiological functions of the human
peroxisome proliferator-activated receptor γγ
Andrzej Zieleniak*, Marzena Wójcik* and Lucyna A. Woźniak
Department of Structural Biology, Chair of General Endocrinology, Medical University of £ódŸ, £ódŸ, Poland
Received: 2008.01.23, Accepted: 2008.08.22, Published online first: 2008.10.06
Abstract
The peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily. To date,
three different PPAR isotypes, namely PPAR-α, –δ, and –γ, have been identified in vertebrates and have distinct patterns of
tissue distribution. Like all nuclear receptors, the human PPAR-γ (hPPAR-γ) is characterized by a modular structure com-
posed of an N-terminal A/B domain, a DNA-binding domain with two zinc fingers (C domain), a D domain, and a C-termi-
nal ligand-binding domain (E/F domain). Human PPAR-γ exists in two protein isoforms, hPPAR-γ1 and –γ2, with different
lengths of the N-terminal. The hPPAR-γ2 isoform is predominantly expressed in adipose tissue, whereas hPPAR-γ1 is rela-
tively widely expressed. Human PPAR-γ plays a critical physiological role as a central transcriptional regulator of both adi-
pogenic and lipogenic programs. Its transcriptional activity is induced by the binding of endogenous and synthetic lipophilic
ligands, which has led to the determination of many roles for PPAR-γ in pathological states such as type 2 diabetes, athero-
sclerosis, inflammation, and cancer. Of the synthetic ligands, the thiazolidinedione class of insulin-sensitizing drugs (ciglita-
zone, pioglitazone, troglitazone, rosiglitazone) is employed clinically in patients with type 2 diabetes.
Key words: PPAR-γ, adipogenesis, insulin resistance, thiazolidinediones.
A commentary on misuses of the impact factor
Andrzej K. Wróblewski
The proper use of citation data in journal management
Catherine M. Ketcham
Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville,
FL, USA
Received: 2008.10.03, Accepted: 2008.10.27, Published online first: 2008.12.01
Abstract
Journal impact factors (IF) are often maligned in editorials found in scientific publications, yet citation data can be used
appropriately in journal management. The editors of Laboratory Investigation have found that weekly tracking of citation
data for this and other highly ranked pathology journals provides valuable feedback on editorial performance and enables
us to predict accurate IFs at least six months in advance. Once the IFs are released, it is useful to quantify the contributions
of specific article categories, such as reviews and research articles, to the official IFs. In an ongoing attempt to understand
the relationship between article downloads and eventual citations, we also analyze the citation rate of papers that had pre-
viously been the most frequently accessed on our web site. Finally, as a measure of editorial judgment, the papers that con-
tributed no citations to the journal’s IF are examined as are the papers that were rejected by Laboratory Investigation (Lab.
Invest.) but subsequently published elsewhere. Thus the editors of Lab. Invest. use citation data in several ways to measure
our progress in elevating the quality of the journal and understand the citation dynamics of papers we publish, while remain-
ing true to the journal’s fundamental operating premise: Publish high-quality original work relating to the mechanisms of
disease.
Key words: impact factor, Web of Science, editorial policy, pathology
A new generation of relational charts
for comparative assessment of citation impact
Wolfgang Glänzel1, 2, Andreas Schubert2, Bart Thijs1 and Koenraad Debackere1
1 Katholieke Universiteit Leuven, Steunpunt O&O Indicatoren and Department of MSI, Leuven, Belgium
2 Institute for Research Policy Studies, Hungarian Academy of Sciences, Budapest, Hungary
Received: 2008.10.07, Accepted: 2008.10.27, Published online first: 2008.12.01
Abstract
A common problem in comparative bibliometric studies at the meso and micro level is the differentiation and specialization
of research profiles of the objects of analysis at lower levels of aggregation. In this study, institutional profile clusters are used
to examine which level of the hierarchical subject classification should preferably be used to build subject-normalized cita-
tion indicators. It is shown that a set of properly normalized indicators can serve as a basis of comparative assessment with-
in and even among different clusters, provided that their profiles still overlap and such comparison is thus meaningful. Using
the example of 24 European universities, a new version of relational charts is presented for the comparative assessment of
citation impact.
Key words: citation analysis, scientometric indicators, subject normalization, relational charts.
Positive and negative regulatory mechanisms
in high-affinity IgE receptor-mediated mast cell activation
Kristy Roth1, Wei−Min Chen2 and Tong−Jun Lin1
1 Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
2 Department of Hematology, Fujian Provincial Hospital, Fuzhou, China
Received: 2007.12.31, Accepted: 2008.10.22, Published online first: 2008.12.01
Abstract
Mast cells are important effector cells in allergic inflammatory reactions. The aggregation of the high-affinity IgE receptor
(FcεRI) on the surface of mast cells initiates a complex cascade of signaling events that ultimately leads to the release of var-
ious mediators involved in allergic inflammation and anaphylactic reactions. The release of these mediators is tightly con-
trolled by signaling pathways that are propagated through the cell by specific phosphorylation and dephosphorylation events.
These events are controlled by protein kinases and protein phosphatases which either positively or negatively regulate the
propagation of the signal through the cell. This review summarizes the role of both positive and negative regulators of FcεRI-
induced mast cell activation.
Key words: mast cells, allergy, IgE, FcεRI, signal transduction.
The use of citation indicators to identify
and support high-quality research in Poland
Andrzej Pilc1, 2
1 Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
2 Institute of Public Health, Collegium Medicum of Jagiellonian University, Kraków, Poland
Received: 2008.10.07, Accepted: 2008.10.27, Published online first: 2008.12.01
Abstract
In large, mostly English-speaking countries, where the “critical mass” of scientists working in different subfields of science is
achieved, the peer review system may be sufficient to assess the quality of scientific research. However, in smaller countries,
outside the Anglo-American circle, it is important to introduce different systems to identify research of high quality. In
Poland, a parametric system for assessing the quality of research has been introduced. It was largely based on the impact fac-
tor of scientific journals. While the use of this indicator to assess research quality is highly questionable, the implementation
of the system in the Polish reality is even worse. Therefore it is important to change and improve the system currently used
by the Ministry of Science and Higher Education to both evaluate and, more importantly, finance science in Poland. Here,
a system based on three factors, i.e. the impact factor, the institutional h-index, and the institutional number of citations, is
proposed. The scientific quality of institutions in Division VI: Medical Sciences of the Polish Academy of Sciences were eval-
uated and the results were compared with the existing system. Moreover, a method to identify high-quality researchers and
institutions at the national level based on the quantity of highly cited papers is shown. Additionally, an attempt to identify
the highest quality Polish research on an international level is proposed. This is based on the number of individual citations,
the individual h-index, the number of publications, and the priority of the discovery.
Key words: h-ndex, citation number, impact factor, research quality.
“Publish or Perish” as citation metrics
used to analyze scientific output in the humanities:
International case studies in economics, geography,
social sciences, philosophy, and history
Audrey Baneyx
Institut Francilien “Recherche, Innovation et Société” (IFRIS)1, Paris, France
Received: 2008.10.16, Accepted: 2008.10.27, Published online first: 2008.12.01
Abstract
Traditionally, the most commonly used source of bibliometric data is the Thomson ISI Web of Knowledge, in particular the
(Social) Science Citation Index and the Journal Citation Reports, which provide the yearly Journal Impact Factors. This
database used for the evaluation of researchers is not advantageous in the humanities, mainly because books, conference
papers, and non-English journals, which are an important part of scientific activity, are not (well) covered. This paper pre-
sents the use of an alternative source of data, Google Scholar, and its benefits in calculating citation metrics in the humani-
ties. Because of its broader range of data sources, the use of Google Scholar generally results in more comprehensive cita-
tion coverage in the humanities. This presentation compares and analyzes some international case studies with ISI Web of
Knowledge and Google Scholar. The fields of economics, geography, social sciences, philosophy, and history are focused on
to illustrate the differences of results between these two databases. To search for relevant publications in the Google Scholar
database, the use of “Publish or Perish” and of CleanPoP, which the author developed to clean the results, are compared.
Key words: Web of Science, Google Scholar, citation analysis, bibliometrics, research evaluation in the humanities, Publish
or Perish.
Bronchial hyper-responsiveness, subepithelial fibrosis,
and transforming growth factor-ββ1 expression
in patients with long-standing
and recently diagnosed asthma
Aneta Tomkowicz1, Maria Kraus−Filarska2, Julia Bar3, Jerzy Rabczyński4, Michał Jeleń4,
Paweł Piesiak5, Andrzej Fal2 and Bernard Panaszek2
1 Department of Dietetics, Faculty of Public Health, Wroc³aw Medical University, Wroc³aw, Poland
2 Department of Internal Medicine and Allergology, Wroc³aw Medical University, Wroc³aw, Poland
3 Department of Clinical Immunology, Wroc³aw Medical University, Wroc³aw, Poland
4 Department of Pathological Anatomy, Wroc³aw Medical University, Wroc³aw, Poland
5 Department of Pulmonology and Lung Cancer, Wroc³aw Medical University, Wroc³aw, Poland
Received: 2008.04.29, Accepted: 2008.09.30, Published online first: 2008.12.01
Abstract
Introduction: Chronic inflammation in asthmatic airways leads to bronchial hyper-responsiveness (BHR) and the develop-
ment of structural changes. Important features of remodeling include the formation of subepithelial fibrosis due to increased
collagen deposition in the reticular basement membrane. Transforming growth factor (TGF)-β might be a central mediator
of tissue fibrosis and remodeling.
Materials and Methods: Immunohistochemistry was used to measure collagen III deposition and TGF-β1 expression in biop-
sies from patients with long-standing asthma treated with inhaled corticosteroids, patients with recently diagnosed asthma,
and control subjects. Computer-assisted image analysis was used to evaluate total basement membrane (TBM) thickness.
Results: Asthmatics, particularly those with long-standing asthma, had thicker TBMs than healthy subjects. Collagen III
deposition was comparable in the studied groups. BHR was not correlated with features of mucosal inflammation and was
lower in steroid-treated patients with long-standing asthma than in subjects with newly diagnosed asthma untreated with
steroids. Epithelial TGF-β1 expression negatively correlated with collagen III deposition and TBM thickness.
Conclusions: The study showed that TBM thickness, but not collagen III deposition, could be a differentiating marker of asth-
matics of different disease duration and treatment. The lack of correlation between BHR and features of mucosal inflam-
mation suggests the complexity of BHR development. Corticosteroids can reduce BHR in asthmatics, but it seems to be less
effective in reducing subepithelial fibrosis. The role of epithelial TGF-β1 needs to be further investigated since the possibil-
ity that it plays a protective and anti-inflammatory role in asthmatic airways cannot be excluded.
Key words: bronchial hyper-responsiveness, subepithelial fibrosis, airway remodeling, transforming growth factor-β
Implementation of the standard strategy
for identification of Ig/TCR targets
for minimal residual disease diagnostics in B-cell
precursor ALL pediatric patients: Polish experience
Małgorzata Dawidowska1, Justyna Jółkowska1, Tomasz Szczepański2, 3,
Katarzyna Derwich4, Jacek Wachowiak4 and Michał Witt1, 5
1 Department of Molecular and Clinical Genetics, Institute of Human Genetics, Polish Academy of Sciences, Poznañ, Poland
2 Department of Pediatric Hematology and Oncology, Silesian Academy of Medicine, Zabrze, Poland
3 Department of Immunology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
4 Department of Pediatric Hematology, Oncology, and Hematopoietic Stem Cell Transplantation,
University of Medical Sciences, Poznañ, Poland
5 International Institute of Molecular and Cell Biology, Warsaw, Poland
Received: 2008.04.15, Accepted: 2008.10.20, Published online first: 2008.12.01
Abstract
Introduction: Minimal residual disease (MRD), detected based on immunoglobulin and T-cell receptor (Ig/TCR) gene
rearrangements as markers of residual leukemic cells, is currently the most reliable prognostic factor in acute lymphoblastic
leukemia (ALL). A feasibility study is presented of the standard strategy for the identification of Ig/TCR targets for MRD
diagnostics in Polish ALL patients by identifying Ig/TCR gene rearrangement pattern using standard primer sets and proto-
cols.
Materials and Methods: The PCR-heteroduplex approach based on BIOMED-1 and BIOMED-2 protocols (recommended
as the European standard) was used to detect IGH, IGK-Kde, TCRD, TCRG, and TCRB rearrangements in 58 Polish B-cell
precursor ALL patients. Sequencing and homology analysis between the obtained and germline Ig/TCR sequences enabled
identification of the rearrangements. The U-Gauss test was used for statistical analysis of the Ig/TCR rearrangement pattern
in Polish patients compared with relevant data on other nationalities.
Results: The following pattern was identified: IGH: 83% (VH-JH: 74%, DH-JH: 9%), IGK-Kde: 41%, TCRD: 78% (incom-
plete TCRD: 55%, Vδ2-Dδ3: 45%, Dδ2-Dδ3: 21%, Vδ2-Jα: 35%), TCRG: 50%, and TCRB: 13%. Considerable convergence
of the Ig/TCR pattern in Polish patients and those of other nationalities (mainly West Europeans) was demonstrated.
Statistically relevant differences were only found between the incidence of DH-JH in Polish (9%) and Dutch patients (24%;
p<0.05) and Polish and Italian patients (19%; p<0.05), VH-JH in Polish (74%) and Chilean patients (100%; p<0.05), and
TCRG in Polish (50%) and Brazilian patients (69%; p<0.05).
Conclusions: The convergence of Ig/TCR patterns in Polish and European patients indicates that the strategy for Ig/TCR tar-
get identification based on standard primers and protocols might be directly used for the construction of Polish standards
and recommendations for MRD diagnostics.
Key words: minimal residual disease, Ig/TCR gene rearrangements, acute lymphoblastic leukemia, BIOMED-1, BIOMED-2.
Familial occurrence of warts, hypogammaglobulinemia,
infections, and myelokathexis (WHIM) syndrome
Maciej Siedlar1, Zbigniew Rudzki2, Magdalena Strach3, Elżbieta Trzyna4,
Anna Pituch−Noworolska1, Anita Błaut−Szlósarczyk1, Karolina Bukowska−Strakova1,
Marzena Lenart1, Tomasz Grodzicki3 and Marek Zembala1
1 Department of Clinical Immunology, Polish-American Institute of Pediatrics, Jagiellonian University Medical College,
Cracow, Poland
2 Department of Pathology, Jagiellonian University Medical College, Cracow, Poland
3 Department of Internal Medicine and Geriatrics, University Hospital, Jagiellonian University Medical College, Cracow,
Poland
4 Department of Transplantology, Polish-American Institute of Pediatrics, Jagiellonian University Medical College,
Cracow, Poland
Received: 2008.06.19, Accepted: 2008.10.20, Published online first: 2008.12.01
Abstract
Introduction: Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare immunodeficien-
cy disorder with an autosomal-dominant pattern of inheritance and low fatality rate but significant lifelong morbidity.
Materials and Methods: A 27-year-old mother of two children has been suffering from severe neutropenia and recurrent infec-
tions with the diagnosis of sporadic WHIM syndrome established by sequencing the CXCR4 gene and the finding of a het-
erozygous 1000 C→T nonsense mutation in the second CXCR4 exon. The first child was an apparently healthy boy delivered
at full term. Umbilical cord blood cells were obtained for genetic analysis. Peripheral blood cells were also analyzed at 8
months of life. Both analyses revealed the same mutation as that of his mother. The child was in a good condition, mani-
festing neutropenia without infections until 11 months of life. He subsequently developed pneumonia requiring a more
aggressive treatment. After that, the regular substitution of immunoglobulins (IVIGs) and G-CSF has been preventing seri-
ous infections. Six months ago the second boy was delivered who also demonstrated neutropenia without severe infections.
Genetic studies using cord blood and also peripheral blood cells in the fourth month showed an identical mutation of the
CXCR4 gene as in his mother. Moreover, the mother and her first son demonstrated monocytopenia.
Results: The results indicate that genetic defects connected with WHIM syndrome may influence not only the granulocyte,
but also the monocytic lineage. Moreover, a perinatal diagnosis of WHIM syndrome made by sequencing the CXCR4 gene
should be performed in cases where either parent is known to be affected with this disease.
Conclusions: This would facilitate an earlier detection of the deficiency in children, thereby allowing a more comprehensive
follow-up and administration of appropriate therapy.
Key words: WHIM syndrome, myelokathexis, CXCR4, primary immunodeficiency, CD14+CD16+ monocytes.
Natural and genetically engineered viral agents
for oncolysis and gene therapy of human cancers
Joseph G. Sinkovics1, 2* and Joseph C. Horvath2, 3**
1 St. Joseph’s Hospital’s Cancer Institute Affiliated with the H. L. Moffitt Comprehensive Cancer Center at the University
of South Florida College of Medicine, Tampa, FL, USA
2 Departments of Medical Microbiology and Immunology and Molecular Medicine, University of South Florida College
of Medicine, Tampa, FL, USA
3 Hemispherx BioPharma, Inc., New Brunswick, NJ, USA
Received: 2008.07.07, Accepted: 2008.09.22, Published online first: 2008.12.23
Abstract
Based on personal acquaintances and experience dating back to the early 1950s, the senior author reviews the history of viral
therapy of cancer. He points out the difficulties encountered in the treatment of human cancers, as opposed by the highly
successful viral therapy of experimentally maintained tumors in laboratory animals, especially that of ascites carcinomas in
mice. A detailed account of viral therapy of human tumors with naturally oncolytic viruses follows, emphasizing the first clin-
ical trials with viral oncolysates. The discrepancy between the high success rates, culminating in cures, in the treatment of
tumors of laboratory animals, and the moderate results, such as stabilizations of disease, partial responses, very rare com-
plete remissions, and frequent relapses with virally treated human tumors is recognized. The preclinical laboratory testing
against established human tumor cell lines that were maintained in tissue cultures for decades, and against human tumors
extricated from their natural habitat and grown in xenografts, may not yield valid results predictive of the viral therapy
applied against human tumors growing in their natural environment, the human host. Since the recent discovery of the onco-
suppressive efficacy of bacteriophages, the colon could be regarded as the battlefield, where incipient tumor cells and bac-
teriophages vie for dominance. The inner environment of the colon will be the teaching ground providing new knowledge on
the value of the anti-tumor efficacy of phage-induced innate anti-tumor immune reactions. Genetically engineered oncolyt-
ic viruses are reviewed next. The molecular biology of viral oncolysis is explained in details. Elaborate efforts are presented
to elucidate how gene product proteins of oncolytic viruses switch off the oncogenic cascades of cancer cells. The facts strong-
ly support the conclusion that viral therapy of human cancers will remain in the front lines of modern cancer therapeutics.
It may be a combination of naturally oncolytic viruses and wild-type viruses rendered oncolytic and harmless by genetic engi-
neering, that will induce complete remissions of human tumors. It may be necessary to co-administer certain chemothera-
peutic agents, advanced cancer vaccines, or even immune lymphocytes, and targeted therapeuticals, to ascertain, that remis-
sions induced by the viral agents will remain complete and durable; will co-operate with anti-tumor host immune reactions,
and eventually will result in cures of advanced metastatic human cancers.
Key words: naturally oncolytic viruses, viral oncolysates, human cancer immunity, interaction of resident viral flora with the
oncolytic virus, oncosuppressive bacteriophages, genetically engineered oncolytic viruses
Archivum Immunologiae et Therapiae Experimentalis
presents articles based on presentations delivered at the international conference
“The Past, Present, and Future of the Impact Factor and Other Tools of Scientometrics”
held in Warsaw, Poland, September 26, 2008
Part I*