CONTENTS
Review
- Differential Effects of CD40 Stimulation on Normal and Neoplastic Cell Growth
JAMIE L. ZIEBOLD1, JULIE HIXON2, ANN BOYD3 and WILLIAM J. MURPHY2Abstract. CD40 is a molecule in the tumor necrosis factor receptor/nerve growth factor receptor (TNFR/NGFR) family that is present on both normal and neoplastic B lineage cells. It is also expressed on carcinoma and melanoma cells and can be augmented with interferon g. CD40 stimulation in normal B cells has been demonstrated to promote normal B cell differentiation and growth in vitro. In contrast to these effects, CD40 stimulation by either anti-CD40 antibodies or a recombinant soluble CD40 ligand can inhibit the growth of human breast carcinomas and aggressive histology B lymphomas in vitro and in vivo. This is believed to occur by activation- -induced cell death (AICD) in which stimuli that promote the growth of normal cell types inhibit the growth of neoplastic counterparts. This occurs through the induction of apoptosis, necrosis and/or cell cycle arrest. Thus, CD40 stimulation may be of potential clinical use in the treatment of carcinomas and B cell lymphomas. This review shall provide an overview of the various effects of CD40 stimulation on both normal and neoplastic cell types.
Keywords: CD40; apoptosis; transformed; lymphoma; interferon g.
- Rethinking Globally Relevant Vaccine Strategies to Human Immunodeficiency Virus Type-1
CLIVE M. GRAY and ADRIAN J. PURENAbstract. According to the latest UNAIDS figures for 1999 there were an estimated 30. 6 million people living with HIV-1, with 16000 new HIV infections per day. The only global strategy of combating new HIV infections is to make a vaccine that is affordable to developing countries, where greater than 90% of new infections occur, and that has enough efficacy to interrupt high rates of transmission. This review critically examines: 1) important immune parameters that should be considered which will allow an understanding of preventative vaccine design and 2) the mechanisms underlying immune destruction during HIV-1 infection that will facilitate design of therapeutic vaccines. A realistic goal of a preventative vaccine is to elicit protective immune responses in vaccinees that would prevent HIV-1 from replicating extensively in the host. Components of protective immunity are thought to include neutralizing antibodies (NAB) and cytotoxic T lymphocytes (CTL). Rethinking vaccine strategies has to take into account that HIV-1 vaccines must elicit primary cellular and humoral immunity via dendritic cell and Langerhan cell priming. It is only under these conditions that boosting immunity with subsequent vaccinations will allow high enough CTL effector cells and NAB titres to impede or to prevent HIV-1 replication. Success of therapeutic vaccine strategies, has to take into consideration the pathology of persistent immune stimulation by chronic HIV-1 infection. To re-stimulate immunity and re-direct immune responses, chronic immune stimulation by HIV-1 has to be alleviated by reducing high levels of viral antigen presentation by suppressing virus with antiretroviral agents. Such treatment courses may only have to be transient, long enough for immunity to respond to an immunogenic stimulus. Short-course drug therapy may then be an affordable option for many countries already carrying a high burden of HIV-1/AIDS.
Keywords: vaccines; protective immunity; cytotoxic T lymphocytes; neutralizing antibodies; dendritic cells; antiretroviral drugs.
- The Immunological Effects of Interleukin 2 Therapy in HIV+ Patients
PAOLO DE PAOLIAbstract. Human immunodeficiency virus (HIV) infection produces a profound impairment of immune functions that antiretroviral therapy is unable to restore. Because of its immuno-enhancing properties, interleukin 2 (IL-2) has been used as a therapeutic tool in HIV+ subjects. IL-2 produces an increase of CD4 and CD8 lymphocyte absolute counts that is preferentially due to the expansion of the “naive” cells. In addition, IL-2 increases cytokine production from the cells of the immune system and is able to up-regulate the expression of cytokine receptors, such as the chemokine receptors CCR-5 and CXCR-4. Less informations on the IL-2 activity on the CD8 subset are available at the moment. The advent of highly active antiretroviral therapy has changed this scenario, making the IL-2 effects less clear-cut than previously hypothesized. We suggest that the ongoing studies will define the precise role of IL-2 in the therapy of HIV infection.
Keywords: HIV infection; interleukin 2; CD4 lymphocytes; CD8 lymphocytes; immunological function.
- Cellular Immune Activation, Neopterin Production, Tryptophan Degradation and the Development of Immunodeficiency
BERNHARD WIDNER1, BARBARA WIRLEITNER1, GABRIELE BAIER-BITTERLICH1, GÜNTER WEISS2 and DIETMAR FUCHS1Abstract. Cellular (Th1-type) immune response is centrally involved in the pathogenesis of various diseases. Within the immunological cascades of Th1-type immunity, interferon g (IFN-g), among other cytokines, is critically involved. It triggers a series of immune-relevant reactions mostly directed towards forward regulation of the antigen specific immune response. However, in chronic states of immune activation, systemically increased IFN-g is no longer antigen specific and is associated with the development of immunodeficiency. IFN-g also stimulates the production of neopterin, a low-mass compound, in human monocytes/macrophages. Accordingly, neopterin concentrations in humans reflect the degree of Th1-type immune activation. Since IFN-g also stimulates the release of reactive oxygen species (ROS) from immunocompetents cells, the amount of neopterin produced also serves as an indirect estimate of oxidative stress. In parallel, IFN-g activates the degradation of tryptophan, which appears to limit the growth of intracellular pathogens and the proliferation of cells, including T lymphocytes. Thus, during persisting states of immune activation, the production of IFN-g is not only associated with forward regulation of the immune response, but also with immunosuppressive mechanisms. The increased formation of neopterin and degradation of tryptophan may result in a drecreased T cell responsiveness and development of immunodeficiency.
Keywords: cellular immune response; neopterin; tryptophan; immunodeficiency.
- Role of Immune-Derived Diffusible Mediators in AIDS-Associated Neurological Disorders
FABRIZIO ENSOLI, VALERIA FIORELLI, MARIA DE CRISTOFARO, DONATELLA SANTINI MURATORI, ARIANNA NOVI, ANTONELLA ISGRO and FERNANDO AIUTIAbstract. Neurologic abnormalities are common in HIV-1 infected patients and often represent the dominant clinical manifestation of pediatric AIDS. Although the neurological dysfunction has been directly related to CNS invasion by HIV-1, the pathogenesis of neurologic disorders remains unclear. This review will first discuss the spectrum of potential interactions between HIV-1 and neural (neuronal and glial) cells, in the face of experimental data. Next, we will focus on the role of immune-derived cytokines and other soluble compounds which have been proposed to act as neurotoxic mediators and appear to play a role in the pathogenesis of AIDS-associated neurodegeneration.
Keywords: AIDS patients; neurological disorders; neural cells.
- B Cell Development and Primary Immunodeficiencies with Hypogammaglobulinemia
SHO HOKIBARA, KAZUNAGA AGEMATSU and ATSUSHI KOMIYAMAAbstract. The differentiation of B cells along the pathway of B cell development has been well characterized. In the bone marrow, the differentiation from pro-B cells to immature B cells can be defined by several surface antigens, such as a surrogate light chain. Immature B cells become mature B cells and then circulate in the peripheral blood as naive B cells. In the peripheral lymphoid tissues, naive B cells differentiate into memory B cells, which express the CD27 molecule, or plasma cells. Primary immunodeficiencies with hypogammaglobulinemia are caused by defects of the specific molecules which are needed for the B cell differentiation. Recent studies of the genes responsible for such immunodeficiencies have clarified B cell development as well as their pathogenesis. We discuss here the molecules affecting the B cell development and primary immunodeficiencies with hypogammaglobulinemia.
Keywords: B cell development; primary immunodeficiency; hypogammaglobulinemia; CD27; memory B cells.
- Macrophages and HIV-1-Associated Dementia
LEONIE A. BOVENAbstract. One of the strongest predictors for HIV-1-associated dementia is the presence of monocytic infiltration in perivascular areas of the brain. Therefore, macrophages have been suggested to play a major role in the development of this disease. This review focuses on possible mechanisms through which the macrophage may enhance disease progression by mediating neuronal damage.
Keywords: HIV-associated dementia; macrophages.
Original Papers
- Ki-67 Reactivity in Primary Fallopian Tube Cancers
JERZY RABCZYŃSKI, AGATA KOCHMAN, PRZEMYSŁAW KOWALSKI and PIOTR ZIÓŁKOWSKIAbstract. Forty-four cases of primary cancer of the fallopian tube (PFTC) were analyzed as to Ki-67 expression, grade, stage and the cancer histological type. Among patients with an average age of 57. 5 years (range 38–70 years), 27 patients were FIGO I, 7 were FIGO II and 10 were FIGO III. Histological classification of PFTC revealed 18 cases of endometroid type, 9 serous, 7 undifferentiated, 6 urothelial, 2 clear-cell and 2 of other type. Histological grading revealed 11 cases of G1, 16 of G2 and 17 of G3 tumors. The quantity of Ki-67 positive cells was counted on 300 cancer cells in random high-power fields (10×40) and recorded as the labeling index (LI, %). Positive staining for Ki-67 was shown in the nuclei in all cases. Ki-67 LI values ranged from 14. 2 to 97. 2% (median 36. 1). Ki-67 LI values were graded as 3 36. 1% as high and <36. 1% as low. We did not find any significant differences in Ki-67 LI values among tumors of various clinical stages, histological grades and histological types. The p value was statistically significant only for stage as a prognostic factor.
Keywords: primary cancer of fallopian tube; Ki-67.
- Effect of Recombinant IFN-g on IgE-Dependent Leukotriene Generation by Peripheral Blood Leukocytes in Patients with Pollinosis and Asthma
MARYLA KRASNOWSKA, WOJCIECH MĘDRALA, JÓZEF MAŁOLEPSZY and RYSZARD KRASNOWSKIAbstract. Interferon g (IFN-g) is considered one of the causative and intensifying factors in inflammation. The reaction to allergens releases IFN-g, an immunomodulatory cytokine known to inhibit IgE synthesis and Th cell proliferation. The aim of the study was to evaluate the influence of IFN-g on leukotriene (LT) release in vitro, from human leukocytes of atopic patients with pollinosis and asthma. Thirty-eight patients were enrolled in the study: 15 with pollinosis and 23 asthmatics. In the presence of IL-3, leukocytes were stimulated with specific allergens. Other samples of leukocytes were preincubated with different concentrations of IFN-g for 15 min before allergen stimulation. The concentration of LT in supernatants was measured according to the CAST-ELISA procedure. We stated that IFN-g had significantly diminished LT release in a dose-dependent mode from the leukocytes of pollinotics. IFN-g did not change LT release in the asthmatic group, although, in leukocytes the small and medium basic production of LT, IFN-g caused a statistically significant fall in LT generation.
Keywords: asthma; pollinosis; interferon g; leukotriene.
- The Influence of Amifostine Used Alone or in Combination with 2-Chlorodeoxyadenosine on Normal and Chronic Myelogenous Leukemia Granulocyte-Macrophage Progenitor Cells in Vitro
ANNA KORYCKA and TADEUSZ ROBAKAbstract. We evaluated the influence of amifostine used alone or in combination with 2-chlorodeoxyadenosine (2-CdA) on the colony growth of normal and chronic myeloid leukemia (CML) granulocyte-macrophage progenitor cells (CFU-GM) in semisolid culture in vitro. Amifostine at a concentration of 1 mg/ml was either added directly to the culture medium of normal and CML CFU-GM, or mononuclear cells (MNCs) were first preincubated with amifostine at the same concentration, washed in Iscove’s modified Dulbecco minimum essential medium (IDMEM) and then added to the culture medium. Amifostine used alone inhibited the growth of CML CFU-GM colonies to a higher degree than those of normal CFU-GM, but the differences were not statistically significant. Amifostine preincubated with MNCs and used together with the highest concentration of 2-CdA significantly inhibited the colony growth of CML CFU-GM as compared to 2-CdA alone (p<<0.05). In contrast, the colony growth inhibition of normal CFU-GM was not significantly lower compared to 2-CdA used alone. Our studies suggest that 2-CdA used together with amifostine is more toxic to leukemic CFU-GM than to their normal counterparts.
Keywords: amifostine; 2-CdA; interaction; CFU-GM; chronic myelogenous leukemia; culture in vitro.
- Serum Levels of Cytokines in Alcoholic Liver Cirrhosis and Pancreatitis
AGNIESZKA SZUSTER-CIESIELSKA1, JADWIGA DANILUK2 and MARTYNA KANDEFER-SZERSZEŃ1Abstract. Although altered cytokine homeostasis has been implicated in the pathogenesis of both alcoholic liver and pancreas diseases, the serum cytokine pattern characteristic of concomitant alcoholic liver cirrhosis and pancreatitis has not been examined. In this paper we examine the serum levels of proinflammatory cytokines, such as IL-6, IL-8, TNF-a, and also antiinflammatory ones, such as IL-10 and TGF-b, in 22 patients with alcoholic liver cirrhosis and 28 patients with chronic pancreatitis and compare them with those detected in the sera of 14 patients with concomitant alcoholic cirrhosis and pancreatitis. All patients were heavy alcohol drinkers, consuming more than 70 g of pure alcohol per day for at least 5 years. The control group consisted of 33 age- and sex-matched healthy subjects receiving an annual health examination. They were not addicted to alcohol and confirmed to be free of major cardiopulmonary, gastrointestinal and hepatobiliary-pancreatic diseases. The results indicated that the cytokine pattern in the sera of patients with concomitant liver cirrhosis and pancreatitis was characterized by increased levels of two proinflammatory cytokines: TNF-a, the concentration of which seemed to be influenced by both liver and pancreas injury, and IL-6, which seemed to be rather connected with pancreas injury. Increased levels of IL-8, which were detected in the sera of patients with cirrhosis, pancreatitis and concomitant cirrhosis and pancreatitis, were rather connected with exacerbation of the disease processes which occurred only in some of the patients. No significant changes in the levels of IL-10 or TGF-b were detected in the sera of patients with chronic pancreatitis and concomitant cirrhosis and pancreatitis, while in patients with cirrhosis significantly decreased levels of IL-10 were found. A significant imbalance between proinflammatory/antiinflammatory signals was especially characteristic of alcoholic cirrhosis and concomitant cirrhosis with pancreatitis.
Keywords: alcohol; compensated cirrhosis; chronic pancreatitis; interleukin 6, 8, 10; tumor necrosis factor a; transforming growth factor b.
- Screening for Germline p53 Mutations in Pediatric and Adult Patients of High-Risk Groups in Poland
ŁUCJA FISZER-MALISZEWSKA1, JERZY CZERNIK2, KRYSTYNA SAWICZ-BIRKOWSKA2, DANUTA PEREK3, 7, MARIA KOZERA3, 7, BEATA WOJCIECHOWSKA1, BERNARDA KAZANOWSKA4, PIOTR HUDZIEC5 and EWA KILAR6Abstract. Germline mutations of the p53 gene lead to cell transformation in various tissues. Such a complex cancer phenotype makes it difficult to recognize the carriers of the defective allele. Several studies undertaken to identify high-risk groups found germline p53 mutations in familial cancer aggregations and in patients with multiple tumors. We screened 189 pediatric and 48 adult patients. The high-risk groups comprised 41 patients with a family history of cancer and 35 with multiple neoplasms. Furthermore, 124 tumors were screened for somatic mutations. p53 exons 2 to 11 were analyzed by polymerase chain reaction and single strand conformation polymorphism (PCR-SSCP) followed by direct sequencing of abnormal DNA fragments. No germline p53 mutations were found and somatic mutations were detected in 5 of 59 sarcomas, globally, in 8 of 124 tumors. In conclusion, in Poland, p53 alterations do not seem very important for the predisposition to malignancy and development of sarcomas.
Keywords: p53 tumor suppressor gene; germline mutation; Li-Fraumeni syndrome; Li-Fraumeni-like families; PCR-SSCP; direct sequencing.
- Epstein-Barr Virus Association in Pediatric Abdominal Non-Hodgkin-Lymphomas from Turkey
MARIANNE TINGUELY1*, MARIE-ANNE BRÜNDLER1, SAFIYE GÖGÜS2, KATRIN KERL1 and BETTINA BORISCH1
Abstract. Recent sudies have shown marked geographic variation associated with Epstein-Barr virus (EBV) in pediatric Burkitt’s lymphomas and Hodgkin’s disease. In the present study we investigated 30 cases of pediatric extranodal high grade non-Hodgkin’s lymphomas (NHL) from Turkey with an abdominal localisation. To classify them histologically and to determine the role of EBV in these lymphomas, immunohistochemistry (IHC), in situ hybridisation (ISH) and polymerase chain reaction (PCR) were used. Our series contained two histologic types: the Burkitt’s or Burkitt’s-like lymphomas (BL/BLL) and high grade NHL. They all were of the B cell type. The immunoglobulin heavy chain gene rearrangement revealed monoclonality in 87% of the BL/BLL cases, in contrast to the NHL cases, showing monoclonality in only 43% of the cases. EBV was found in tumor cells in a high frequency, independent of the histological subtype. EBV strains A and B were detected in 9 cases, with a preponderance of the B subtype (4/9 BL/BLL; 4/9 NHL). Our data suggest that high grade NHLs with abdominal localisation of Turkish children show the pattern of immunodeficient lymphomas to some extent.
Keywords: Epstein-Barr virus; non-Hodgkin’s lymphoma; pediatric; Turkey.