CONTENTS
Review
- Immunomodulatory Effects of HMG-CoA Reductase Inhibitors
Farhad R. Danesh1, Ramon L. Anel1, Lixia Zeng1, Jon Lomasney2, Atul Sahai3 and Yashpal S. Kanwar2 (Departments of 1Medicine, 2Pathology and 3Pediatrics, The Feinberg School of Medicine of Northwestern University, Chicago, IL, USA)Abstract. 3-Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins are competitive inhibitors of the rate limiting enzyme in cholesterol synthesis. Several clinical trials have shown a marked reduction in cholesterol levels associated with decreased cardiovascular mortality in patients treated with statins. However, more recent observations have suggested that the clinical benefits of statins may be, at least in part, independent of the effect of statins on cholesterol synthesis. These so-called pleiotropic or cholesterol-independent effects of statins could be the result of reduction in the formation of intermediaries in the mevalonate pathway as statins by inhibiting L-mevalonic acid synthesis also prevent the production of isoprenoids in the cholesterol biosynthetic pathway. Isoprenoids serve as important lipid attachments for the posttranslational modification of a variety of proteins such as small GTP-binding proteins of the Ras superfamily implicated in intracellular signaling. The list of different pleitropic effects of statins is still growing and include among others direct effects of statins on modulating endothelial function, decreasing oxidative stress, and more recently anti-inflammatory and immunomodulatory actions of statins. For instance, statins decrease T cell activation, the recruitment of inflammatory cells into atherosclerotic lesions, and inhibit IFN-gamma expression of MHCII on antigen-presenting cells. This review article summarizes the anti-inflammatory and immunomodulatory effects of statins and thus provides a new rationale to use statins as a new class of immunosuppressive agents.
Keywords: HMG-CoA reductase inhibitors; immunomodulation; transplantation; inflammation.
- Experimental Models of Inflammatory Bowel Disease
Antoni Stadnicki1 and Robert W. Colman2 (1Department of Internal Medicine, Medical University of Silesia, Katowice, Poland, 2Sol Sherry Thrombosis Research Center, Temple University, School of Medicine, Philadelphia, PA 19140, USA)Abstract. The etiology and pathogenesis of inflammatory bowel disease (IBD) remains unsolved but improved experimental models of enterocolitis have led to progress. Intestinal inflammation can be induced by chemical or dietary factors or by microbial products and experimental IBD. Many animal models of IBD can be used to evaluate new anti-inflammatory drugs. These models, however, usually demonstrate acute, self-limiting colitis. The spontaneous colitis models developed in the monkey, cotton-top tamarin, and C3H/HeJBir mouse mimic more features of human IBD. Inflammation is chronic and is under genetic control. The differential genetic susceptibility of inbred rat strains to chronic inflammation have been exploited. Lewis rats injected with bacterial products, peptidoglycan polysaccharide or indomethicin develop chronic relapsing enterocolitis, whereas closely related Buffalo or Fisher rat strains develop only transient inflammation and the specific inhibition of inflammatory mediators and target molecules have been tested. Over-expression (transgenic) or deletion (knockout) of specific genes have led to the development of rodent models of spontaneous colitis. Inflammation arises from a number of mutations of immunomodulatory molecules supporting the concept of genetic heterogeneity for IBD. The results obtained from experimental models have generated new hypotheses, expanded human studies, and suggested novel forms of therapy for IBD patients.
Keywords: experimental enterocolitis; kininogen; plasma kallikrein; intestinal inflammation; animal models.
- Wegener’s Granulomatosis – Autoimmunity to Neutrophil Proteinase 3
Ewa Wątorek, Maria Boratyńska and Marian Klinger (Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Traugutta 57/59, 50-417 Wrocław, Poland)Abstract. Wegener’s granulomatosis is a small vessel vasculitis, associated with various clinical manifestations, among which the most common are respiratory tract disease and glomerulonephritis leading to renal failure. Pathogenesis of vascular injury in Wegener’s granulomatosis is ascribed to antineutrophil cytoplasmic antibodies directed (ANCA) mainly against proteinase 3, an enzyme from neutrophil granules. The reasons for breakdown of self-tolerance to proteinase 3 are unknown and together with molecular mechanisms underlying this immunoinflammation are the subject of research. Standard treatment of Wegener’s granulomatosis consists of cyclophosphamide and corticosteroids. In patients resistant to that therapy or with the refractory disease some alternative strategies involving tumor necrosis factor blocade, polyclonal antithymocyte globulin or monoclonal anti-T cell antibodies are applied.
Keywords: Wegener’s granulomatosis, ANCA, proteinase 3.
- CSF-1 as a Regulator of Macrophage Activation and Immune Responses
Matthew J. Sweet and David A. Hume (CRC for Chronic Inflammatory Diseases, Institute for Molecular Bioscience and Departments of Microbiology/Parasitology and Biochemistry, University of Queensland, Qld, 4072, Australia)Abstract. Macrophage activation is a key determinant of susceptibility and pathology in a variety of inflammatory diseases. The extent of macrophage activation is tightly regulated by a number of pro-inflammatory cytokines (e.g. IFN-gamma, IL-2, GM-CSF, IL-3) and anti-inflammatory cytokines (e.g. IL-4, IL-10, TGF-beta). Macrophage colony stimulating factor (CSF-1/M-CSF) is a key differentiation, growth and survival factor for monocytes/macrophages and osteoclasts. The role of this factor in regulating macrophage activation is often overlooked. This review will summarise our current understanding of the effects of CSF-1 on the activation state of mature macrophages and its role in regulating immune responses.
Keywords: CSF-1, macrophage, lipopolysaccharide, toll-like receptors, inflammation.
- Immunosuppressive Agents and Cytomegalovirus Infection
Kazuro Tanaka (Department of Infectious Diseases, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan)Abstract. Cytomegalovirus (CMV) infection is the major infectious complication observed after organ transplantation. As rejection episodes always occur in allograft-transplanted recipients, various kinds of immunosuppressive agnets are used to control such rejection episodes. Among the commonly used immunosuppressive agents, anti-pan T cell monoclonal antibody (OKT3) is known to increase the risk of viral infections. A new immunological techniques have recently been developed to measure CMV-specific CD4 and CD8 cells by flowcytometry. Using the techniques, the high frequencies of specific CD4 and CD8 T cells have been shown to be required to survey the CMV (re)activation in the persistent/latent phase of CMV infection. An excessive T cell depletion by OKT would deplete such surveying T cells, thus resulting in the occurrence of CMV-associated diseases.
Keywords: cytomegalovirus; transplantation; immunosuppression; MHC/antigen-tetramer; virus-specific T cell.
Experimental and Clinical Immunology
- 17b-Estradiol Treatment Profoundly Down Regulates Gene Expression in Spinal Cord Tissue in Mice Protected from Experimental Autoimmune Encephalomyelitis
Agata Matejuk1,2,3, Jami Dwyer2, Corwyn Hopke1,2, Arthur A. Vandenbark1,2,4 and Halina Offner1,2 (1Department of Neurology, Oregon Health and Science University, Portland, OR 97201, USA, 2Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97239, USA, 3L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland, 4Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97201, USA)Abstract. It is now well documented that experimental autoimmune encephalomyeltitis (EAE) can be effectively prevented by estrogen therapy. Previously, we identified a limited set of genes that were altered in spleens of mice protected from EAE by 17b-estradiol (E2) treatment. As a continuation of these studies, we here present transcriptional changes in genes expressed in spinal cord tissue. The Affymetrix microarray system was used to screen more than 12,000 genes from E2-treated double Tg (BV8S2 and AV4) female mice protected from EAE vs. control mice with severe EAE. We found that estrogen therapy had a profound inhibitory effect on expression of many immune-related genes in spinal cords. Estrogen significantly affected transcription of 315 genes, 302 that were down-regulated and only 13 that were up-regulated by >2.4 fold. A number of genes encoding the histocompatibility complex, cytokines/receptors, chemokines, adhesion molecules, and signal transduction proteins, were strongly down regulated (>20 fold) in estrogen treated mice to levels similar to spinal cord tissue from unmanipulated mice. The identification of genes with altered expression patterns in spinal cords of estrogen treated mice provides unique insight into the process that ultimately results in protection against EAE.
Keywords: 17b estradiol; EAE; microarray; spinal cord.
- Diagnostic Value of Pancreatic Elastase-1 in Human Acute Pancreatitis
Urszula Wereszczyńska-Siemiątkowska1, Monika Jedynak2, Barbara Mroczko3 and Andrzej Siemiątkowski2 (1Department of Gastroenterology, 2Departmentt of Anaesthesiology and Intensive Therapy, 3Deparmtnet of Biochemical Diagnostics, Medical University, Białystok, Poland)Abstract. The diagnosis of acute pancreatitis is usually confirmed by a significant increase of the serum amylase and/or lipase level. However, serum pancreatic elastase–1 (pEla-1) was found to be a more sensitive diagnostic marker in acute pancreatitis (AP), when assayed by RIA procedure. We analysed the serum concentration of pancreatic elastase-1, measured by ELISA technique in 46 patients with acute pancreatitis and in the control group of 12 healthy volunteers. At admission (day 1) we found significantly higher pEla-1 level in patients with AP when compared to the control group. During the following days, the concentration of pEla-1 rapidly decreased nearly to undetectable value on the third day. There was no significant difference between patients with mild and severe AP and according to aetiology. We suggest that pEla-1 has a little diagnostic value and does not provide additional information to that of cheaper and more widely available serum amylase and lipase.
Keywords: acute pancreatitis, pancreatic elastase-1, diagnosis, prognosis.
Immunogenetics
- Lack of Association between Exon 1 CTLA-4 Gene Polymorphism A(49)G and Multiple Sclerosis in Polish Population of the Lower Silesia Region
Dorota Boćko1, Małgorzata Bilińska2, Tadeusz Dobosz3, Magdalena Żołędziewska3, Katarzyna Suwalska1, Anna Tutak1, Ewa Gruszka2 and Irena Frydecka1, 4 (1Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland, 2Department of Neurology, 3Department of Forensic Medicine, 4Department of Hematology, Medical University, Wrocław, Poland)
Abstract. Multiple sclerosis (MS) a chronic inflammatory demyelinating disease of the central nervous system (CNS) is believed to have a T-cell mediated autoimmune etiology. The cytotoxic T lymphocyte antigen 4 (CTLA-4) gene is a strong candidate for the involvement in autoimmune diseases because CTLA-4 plays an important role in downregulation of early and late stages of T cell activation and maintenance of peripheral T cell tolerance. To examine the genetic association of the CTLA-4 gene locus with MS, we analyzed exon 1 CTLA-4 gen polymorphism A(49)G in 102 unrelated Polish MS patients in Lower Silesia region and 101 age and sex matched healthy subjects. The distribution of CTLA-4 exon 1 A(49)G genotype, phenotype and allele frequencies did not differ between patients with MS and healthy subjects.
Keywords: CTLA-4; A(49)G; multiple sclerosis; Lower Silesia.