CONTENTS
Review
- Antigen Receptor Signaling Is Subverted by an Immunomodulatory Product Secreted by a Filarial Nematode
MARGARET M. HARNETT (Departments of Immunology, University of Glasgow, Glasgow G11 6NT, UK) and WILLIAM HARNETT (University of Strathclyde, Glasgow G4 ONR, UK)Abstract. ES-62 is a phosphorylcholine (PC)-containing glycoprotein secreted by the rodent filarial nematode Acanthocheilonema viteae which is able to inhibit antigen receptor-stimulated proliferation of B and T lymphocytes in vitro and in vivo. The active component of ES-62 appears to be PC as the results obtained with ES-62 are broadly mimicked by PC conjugated to bovine serum albumin or PC alone. Such desensitization of lymphocyte responsiveness appears to reflect an uncoupling of the antigen receptors from key intracellular proliferative signaling events, such as the phosphoinositide-3-kinase (PI-3K), protein kinase C (PKC) and Ras mitogen-activating protein kinase (RasMAPK) pathways. ES-62 mediates such immunomodulatory effects at concentrations equivalent to those found for PC-containing molecules in the bloodstream of parasitized humans and, thus, ES-62 provides a model system for dissecting the mechanisms of immune evasion induced by related PC-containing glycoproteins expressed by human filarial nematodes.
Keywords: filarial nematode; immune evasion; lymphocyte; phosphorylcholine; signal transduction
- Enhancing Cytotoxic T Cell Responses with Altered-Peptide Ligands
RUI ZHAO and EDWARD J. COLLINS (Department of Microbiology and Immunology, and Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599)Abstract. Interest in class I MHC-mediated immunotherapy is growing rapidly. In order to fight a virus or cancer effectively, a successful immunotherapeutic must activate a large number of specific CD8+ T cells and also generate immunological memory. Attempts to generate immune responses towards tumor- or virus-derived peptides have frequently been frustrated by the nature of the peptide antigen itself. Either the peptide does not bind well to its cognate MHC, or the T cells directed towards it have been functionally inactivated in vivo. Altered-peptide ligands are an effective way to circumvent these problems. However, generating enhanced binding of altered peptides to class I MHC while still maintaining recognition of the wild-type peptide is not straightforward. Many groups design enhanced binding peptides by substituting the observed anchor residues with those that are most preferred by the class I MHC molecule. For many antigenic peptides, this approach does not work. Furthermore, if a higher affinity peptide is designed, the substitutions may result in reduced recognition by CD8+ T cells. Therefore, the design of an altered-peptide ligand requires careful testing of each candidate therapeutic in terms of affinity for class I MHC and immunological reactivity. Lastly, immunotherapy using class I MHC must also take into account the large genetic heterogeneity in the population. A therapeutic that is only effective for 5-10 percent of the population is not as attractive as one that works for over 90% of the population. The use of MHC supertypes (groups of class I MHC allotypes that share similar peptide-binding characteristics) shows great promise in overcoming this problem.
Keywords: class I MHC, T cell receptor, ligand design, immunotherapy, x-ray crystallography
- Multi-Functional Roles of Stat3 Revealed by Conditional Gene Targeting
KIYOSHI TAKEDA and SHIZUO AKIRA (Department of Host Defense, Research Institute for Microbial Diseases, and CRSET of Japan Science and Technology Corporation, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan)Abstract. Signal transducer and activator of transcription (STAT) is a family of transcription factors composed of seven members. Gene-targeted mice of each STAT family protein displayed defective responses to cytokines, demonstrating an important role in cytokine-mediated biological responses. However, unlike the mice lacking other STAT proteins, Stat3-deficient mice died during their early embryogenesis. Therefore, in an attempt to avoid the lethality and assess the role of Stat3 in cytokine-mediated functions in mouse adult tissues, conditional gene targeting utilizing a Cre-loxP system was achieved. By this method, Stat3 was disrupted in several types of tissue, including T cells, macrophages, skin, and mammary gland. Analyses of these Stat3-mutant mice revealed important roles of Stat3 in biological functions in each tissue.
Keywords: Stat3, conditional gene targeting, cytokine, signal transduction
- Redox Control of Cellular Function by Thioredoxin; a New Therapeutic Direction in Host Defence
YUMIKO NISHINAKA, HAJIME NAKAMURA, HIROSHI MASUTANI and JUNJI YODOI (Department of Biological Responses, Institute for Virus Research, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo, Kyoto 606-8507, Japan)Abstract. Compelling evidence has suggested that oxidative stress mediates various cellular reponses, and control of reduction/oxidation (redox) is importan in maintaining the homeostatsis of an organism. The thioredoxin (TRX) system, along with as well as the glutathione system, is one of the key system in controling cellular redox statuts. TRX is a small ubiquitous protein with the redox-active site sequence -Cys-Gly-Pro-Cys-. It has been demonstrated to be a multifunctional protein, which has regulatory roles in cellular signaling and gene transcription in addition to cytoprotective activities through the quenching of reactive oxygen species. Various oxidative stimuli, such as as UV irradiation, cytokines and some chemicals, promptly induce the xpression of TRX. Overexpression of TRX correlates with a wide variety of oxidative stress conditions and, in some cases, TRX has shown promising effects for clinical use, for instance in the attenuation of tissue injury in ischemia reperfusion models. The modulation of TRX functions in association with other redox-regulatory should give us a new therapeutic strategy in the treatment of oxidative stress-mediated disorders and diseases.
Keywords: redox regulation, thoredoxin, reactive oxygen species, therapy
- Cytokine-Based Immunotherapy of Allergic Disease
IAN P. LEWKOWICH and KENT T HAYGLASS (Department of Immunology, University of Manitoba, Winnipeg, Canada)Abstract. Human immediate hypersensitivity diseases are strongly associated with an excessive type 2 response to normally innocuous environmental antigens, and are a growing health care concern in developed nations. Commonly prescribed treatments provide effective symptomatic relief, but are unable to consistently ameliorate the underlying cause of allergic disease: the excessive generation of allergen specific Th2 cells. IL-12 and IL-18 are potent inducers of type 1 immunity, and, as such, have been proposed as candidates for treatment of allergic diseases. This review critically assesses the potential of recombinant IL-12 and IL-18 immunotherapy to redirect both de novo and established allergic responses in animal models of human allergic disease to clinically protective immune responses.
Keywords: IL-12, IL-18, immunotherapy, immediate hypersensitivity
- Evidence for an Immunoregulatory Role of OX2 with Its Counter Ligand (OX2L) in the Regulation of Transplant Rejection, Fetal Loss, Autoimmunity and Tumor Growth
REG M. GORCZYNSKI (CCRW 2-855, The Toronto Hospital, University Health Network, Toronto, Canada, and Departments of Surgery and Immunology, University of Toronto, Toronto, Canada)Abstract. Transplantation has emerged as an effective treatment for patients with end-stage organ failure. Current regimens of non-specific immunosuppressive drug treatment, which are needed life-long to prevent graft rejection, have numerous adverse side effects and increase the risk of opportunistic infections and malignancy. A major goal is to develop immunotherapeutic protocols that achieve specific tolerance. Such protocols would decrease and eventually eliminate the reliance on non-specific drug therapy. We showed that portal vein (pv) delivery of donor antigen prolongs the survival of vascularized and non-vascularized allo- and xeno-grafts, and that increased graft survival is associated with altered cytokine production and augmented expression of the molecule OX2. This review documents further evidence for a more general immunoregulatory role for the interactions of OX2 and its ligand, OX2L.
Keywords: OX2; immunoregulation; tolerance; transplantation; autoimmunity; fetal loss syndrome
Clinical Immunology
- The Levels of IL-1beta, IL-4 and IL-6 in the Serum and the Liver Tissue of Chronic HCV-Infected Patients
TADEUSZ WOJCIECH ŁAPIŃSKI (Department of Infectious Diseases, Medical Academy of Białystok, Żurawia 14, 15-540 Białystok, Poland)Abstract. The pro-inflammatory interleukines play a major role in the progress of chronic hepatitis C. Among the patients with chronic HCV infection, the morphology of the liver was assessed and the levels of serum and liver-tissue IL-1beta, IL-4 and IL-6 were determined. The levels of the cytokines were related to the liver tissue changes. RNA-HCV was measured by the RT-PCR method. Cytokine levels of the serum and liver tissue were measured by the Quantikine High Sensitivity test. The levels of serum IL-1beta, IL-4 and IL-6 (0.221, 0.104 and 1.393 pg/ml) in all HCV patients were higher in comparison with healthy adults (0.188, 0.025 and 0.600 pg/ml). The levels of liver tissue IL-1beta, IL-4 and IL-6 (4291.3, p<0.05; 1624.6, p<0.05; 1158.7 pg/g protein) in all HCV patients were higher compared to the patients with liver cirrhosis without HBV or HCV infection (2319.9, 553.6 and 756.2 pg/g protein). Patients with HCV infection demonstrated significant correlation between serum and liver-tissue levels of IL-1beta (Pearson: 0.61, p<0.05) and IL-4 (Pearson: 0.51). The level of serum IL-6 in patients with moderate chronic active hepatitis was higher when compared to the patients with mild chronic persistent hepatitis. Among the patients with mild chronic persistent hepatitis, the levels of liver tissue IL-6 were higher compared with those with moderate chronic active hepatitis. There was no correlation between histology changes and the levels of serum and liver-tissue IL-1beta and IL-4.
Keywords: HCV infection, cytokines, histology changes
- Soluble Selectin Profiles Associated with Severe Trauma
ANDRZEJ SIEMIĄTKOWSKI (Department of Anesthesiology and Intensive Therapy), FRANCISZEK ROGOWSKI (Department of Nuclear Medicine), URSZULA WERESZCZYŃSKA-SIEMIĄTKOWSKA (Department of Gastroenterology), LIDIA MALINOWSKA (Department of Anesthesiology and Intensive Therapy) and JACEK BORKOWSKI (Department of Anesthesiology and Intensive Therapy, Medical Academy of Białystok, M. Skłodowskiej-Curie 24a, 15-276 Białystok, Poland)Abstract. Severe trauma acts as a trigger for the complex cascade of postinjury events leading to the release of different mediators and the development of generalized inflammation. Selectins are a family of adhesion proteins that are responsible for the adherence of polymorphonuclear neutrophils to the endothelium. This interaction plays an important role in the development of severe complications after multiple trauma. The aim of the present study is to follow the sequential alterations in circulating selectins level after severe injury and to evaluate the clinical significance of these mediators in monitoring prognosis and outcome. Thirty four severely traumatized patients were entered into the study. Serum sE-selectin, plasma sP-selectin and sL-selectin concentrations were measured and an APACHE II score was calculated on admission to the intensive care unit and during the subsequent 5 days. The patients were divided into survivors and nonsurvivors. Initial soluble P- and E-selectin concentrations were significantly elevated in all trauma patients. The highest values of these adhesion molecules were measured in all the observed days in patients with poor prognosis and outcome. In survivors we found a systematic decrease in the sP-selectin concentrations. On admission, the sL-selectin concentrations in all trauma patients were decreased. There were stable, very low values in nonsurvivors and a slow increase in circulating L-selectin in patients who survived. The pattern of soluble selectins in patients with severe trauma is characterized by increased levels of P- and E-selectin and a decreased concentration of L-selectin. These findings suggest a widespread microvascular endothelial activation on injury in the early posttraumatic period, which may be associated with increased neutrophil – endothelial adhesion, neutrophil extravasation and migration. We suppose that these parameters of endothelial cell activation/injury may be useful as another early prognostic factor in severe trauma.
Keywords: severe trauma, endothelium, selectins, prognosis
- Lactoferrin Regulates the Immune Responses in Post-Surgical Patients
MICHAŁ ZIMECKI (Department of Experimental Therapy, Institute of Immunology and Experimental Therapy, Polish Academy of Science, Weigla 12, 53-114 Wrocław, Poland), ANDRZEJ WŁASZCZYK (Department of Anesthesiology and Intensive Therapy Wrocław Academy of Medicine, Chałubińskiego 1a, 50-368 Wrocław, Poland), ROBERT WOJCIECHOWSKI (Department of Anesthesiology and Intensive Therapy Wrocław Academy of Medicine, Chałubińskiego 1a, 50-368 Wrocław, Poland), JANUSZ DAWISKIBA (First Clinic of General and Endocrine Surgery, Wrocław Academy of Medicine, Poniatowskiego 2, 50-326 Wrocław, Poland) and MARIAN KRUZEL (Department of Integrative Biology, Pharmacology and Physiology, University of Texas, Medical School at Houston Texas, USA)
Abstract. The effect of oral administration of lactoferrin (LF) was studied to determine if it could modify post-surgical immune response. The action of lactoferrin was evaluated in 18 LF-treated patients versus 28 placebo counterparts. Patients (women and men, mean age 50 years) were given daily oral doses (20 mg each) of LF for 5 consecutive days prior to thyroid surgery. The following immune response parameters were determined in blood samples taken from the patients one day before, one day after, and 5-7 days following surgery: cell morphology, the proliferative response of peripheral blood mononuclear cells (PBMC) to phytohemagglutinin (PHA), and the spontaneous and lipopolysaccharide (LPS)-induced production of tumor necrosis factor alpha (TNF-a) and interleukin 6 (IL-6). As a consequence of the thyroid surgery, the total leukocyte count increased on the postoperative day by about 50% in all patients and the percentage of lymphocytes fell by 26 and 35% in the control vs LF-treated group. The content of neutrophils, on the other hand, elevated on day 1 post-operation by 51 and 68%, respectively. The percent of neutrophil precursors was markedly higher in LF-treated patients, particularly on the day before and the day after surgery (4.1 and 4.8 vs 2.5 and 3.7%, respectively). The post-surgical values were, however, comparable in both groups for neutrophils. The proliferative response of lymphocytes showed a slight decrease in the control group and an increase in the LF-treated patients on day 5 post-operation (20% over control group). LPS-induced TNF-a production was higher in LF-treated patients in both one day before and one day following surgery (28 and 24% respectively). LPS-induced IL-6 production was comparable in both placebo and LF-treated patients before surgery, however, on day 1 and 5 following surgery, the production of IL-6 was higher in LF-treated patients by 65 and 27%, respectively. Taken together, the data presented in this study revealed increased immune responsiveness in all patients treated with lactoferrin subjected to the thyroid surgery. This suggests that treatment with lactoferrin could constitute an effective protective measure against post-surgical complications.
Keywords: lactoferrin, clinical insult, immunoregulation, prevention