CONTENTS
Reviews
- Regulation of Immunological Mucosal Tolerance
Georg Kraal (Department of Molecular Cell Biology, Vrije Universiteit, Amsterdam, The Netherlands) and Danielle A.W. Wolvers (Department of Immunology, UNILEVER Health Institute, Vlaardingen, The Netherlands)Abstract. Mucosal tolerance is an immunological phenomenon specific to mucosal surfaces as found in the lungs and gastro-intestinal tract. It results in the suppression of immune responses to inhaled or ingested antigens and prevents the body from unwanted and unnecessary immunological responses to harmless molecules, such as grass-pollen or food constituents. This imposes the difficult task for the immune system of keeping a balance between reacting and non-reacting, and disturbances of this balance result in allergies and possibly autoimmunity, as well as opportunistic infections and even an escape from tumor surveillance. Understanding the mechanisms that underlie mucosal tolerance is, therefore, important from different viewpoints. Maintenance or (re)induction of mucosal tolerance to, e.g., food proteins, airborne allergens or autoantigens is desirable to prevent or cure allergies and autoimmune diseases. However, induction of mucosal tolerance is an unwanted phenomenon in mucosal vaccination and in the case of mucosal tumors.
Keywords: tolerance; mucosa; nasal; lymph node.
- Liver Sinusoidal Endothelial Cells: a New Type of Organ-Resident Antigen-Presenting Cell
Andreas Limmer and Percy A. Knolle (Zentrum für Molekulare Biologie Heidelberg (ZMBH), Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany)Abstract. The induction of peripheral immune tolerance in the liver is a well-known phenomenon that is operative in different situations such as tolerance to organ transplants and tolerance to oral antigens. The mechanisms leading to peripheral immune tolerance in the liver are still incompletely understood. While different cell populations of the liver have been implicated in and probably contribute in concert to the induction of hepatic immune tolerance, one hepatic cell type in particular seems to be suited for tolerance induction: liver sinusoidal endothelial cell (LSEC). LSEC are microvascular endothelial cells with a unique phenotype reminiscent of dendritic cells and a unique function as antigen-presenting cells for CD4+ T cells. The hepatic microenvironment, i.e. portal venous constituents and soluble mediators from sinusoidal cell populations, tightly control antigen presentation by LSEC to avoid immune-mediated damage. LSEC, in contrast to other endothelial cells, have the capacity to prime naive CD4+ T cells and induce cytokine release. Importantly, naive CD4+ T cells primed by antigen- presenting LSEC differentiate into regulatory T cells whereas T cells primed by bone marrow-derived professional antigen presenting cells differentiate into Th1 cells. Thus, LSEC represent a new type of organ resident “non-professional” antigen-presenting cell that appears to be involved in the local control of the immune response and the induction of immune tolerance in the liver.
Keywords: local immune response; antigen presentation; immune tolerance.
- Two Receptor Theory in Innate Activation: Studies on the Receptors for Bacillus Culmet Guillen-Cell Wall Skeleton (BCG-CWS)
Tsukasa Seya, Misako Matsumoto, Shoutaro Tsuji, Midroi Nomura (Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka 537, Japan, The Organization for Pharmaceutical Safety and Research (OPSR), Tokyo 113, Japan), Nasim A. Begum (Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka 537, Japan), Ichiro Azuma (Hakodate National College of Technology, Tokura 14-1, Hakodate 042-8501, Japan), Akira Hayashi and Kumao Toyoshima (Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka 537, Japan)Abstract. Activation of the innate immune system is a prerequisite for the maturation of dendritic cells (DC) and macrophages (Mo) followed by clonal expansion of the lymphocytes, targeting cells expressing „non-self” angitens. Microbes usually have a component competent to active DC/Mo for antigens presentation. This component has been colled adjuvant, but recently renamed pathogen-associated molecular pattern (PAMP) or modulin based on its molecular identification. Here, we propose the hypothesis that DC/Mo express two sorts of receptors for PAMP, whose signaling pathways lead to a sufficient antigen (Ag)-presenting state. In bacterial infection, a Toll-like receptor (TLR) and an uptake receptor participate in DC maturation and Mo activation. Likewise, with a number of viruses, two of the receptors with short consensus repeats (SCR), immunoglobulin-like domains or chemokine receptor-like motifs etc. induce functional modulation of DC/Mo. In immune therapy for cancer, primary activation of the innate system would be essential for tumor Ag-specific T cell augmentation. Cancer cells express tumor-associated Ag but barely co-express PAMP, which situation does not allow for the activation of innate immune responses. Supplementing tumor-associated Ag with PAMP may be an effective therapy for patients with cancer. Here, we discuss the possibility of an innate immune therapy for cancer with references to bacillus Culmet guillen cell-wall skeleton (GCG-CWS).
Keywords: modulin; pattern-recognition receptors; leucine-rich repeat (LRR); short consensus repeat (SCR); antigen-presenting cells (APC).
- Regulation of Immune Responses by Natural Killer T Cells
Shayan Sharif and Terry L. Delovitch (Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, and Departments of Microbiology and Immunology, and of Medicine, University of Western Ontario, London, Ontario N6G 2V4, Canada)Abstract. Natural killer T (NKT) cells, which comprise a minor population of T cells in primary and secondary lymphoid organs, possess phenotypic characteristics of both NK and T cells. NKT cells respond to various external stimuli by an early burst of cytokines, including IL-4 and IFN-g. Thus, a key immunoregulatory role has been attributed to them. Autoimmune diseases, especially type I diabetes (TID), may be caused by dysregulation of the immune system, which leads to hyporesponsiveness of regulatory T helper 2 (Th2) cells and promotion of autoimmune Th1 cells. Furthermore, several lines of evidence exist to support the notion that an NKT cell deficiency in individuals at risk of TID may be causal to TID. As a result, targeting NKT cells using immunotherapeutic agents may prove beneficial in the prevention or recurrence of TID. Indeed, our data demonstrate that stimulation of NKT cells with a specific ligand prevents the onset and recurrence of TID in non-obese diabetic (NOD) mice.
Keywords: immunoregulation; autoimmunity; type I diabetes; alpha galactosylceramide.
- The Social Life of NK Cells
Alfonso Martín-Fontecha (Department of Tumor Immunology, Scientific Institute San Raffaele, Via Olgettina 58, 20132 Milano. Italy) and Ennio Carbone (Microbiology and Tumor Biology Center, Karolinska Institutet, S-171-77 Stockholm Sweden; Cattedra di Immunologia, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita di Napoli Federico II, 80131 Naples, Italy)Abstract. Natural killer (NK) cells represent a distinct population of lymphocytes that was originally identified by its ability to kill transformed cell lines in vitro. It is now clear that these cells also play an important role in the innate immune response against a variety of pathogens, such as virus, bacteria and parasites. In the past few years, different protocols have been developed to activate NK cells ex vivo, allowing a detailed molecular analysis of the interaction of these cells with their cellular targets. NK activity is regulated by signals generated by both inhibitory and stimulatory receptors expressed by target cells. Indeed, recent results indicate that, while major histocompatibility complex class I molecules (MHC-I) expressed on target cells inhibit NK lytic activity by engaging surface inhibitory receptors, costimulatory molecules such as B7-1, B7-2 and CD40, are able to actively trigger NK activity. This review discusses the most recent findings on the role of costimulation on NK activation and forsees the possible consequences of the interaction between NK cells and dendritic cells (DC) on the development of an adaptive immune response.
Keywords: NK cells; costimulation; dendritic cells; B7-1; B7-2; CD40.
- Local Tissue Complement Synthesis – Fine Tuning a Blunt Instrument
James E. Marsh, Wuding Zhou and Steven H. Sacks (Department of Nephrology and Transplantation, Floor 5, Thomas Guy House, Guy’s Hospital, King’s College, London, SE1 9RT, UK)Abstract. Complement is important to host defense and the regulation of inflammation. The liver is overwhelmingly the major source of circulating complement. However, many other organs are capable of synthesizing some or all of the complement components in a regulated tissue-specific manner. There is increasing evidence that this locally generated complement is biologically active and exerts powerful effects within the local environment. We review the role of local complement synthesis within different organs and speculate on its implication for immune and metabolic functions.
Keywords: complement; kidney; brain; bone marrow; adipocyte; glomerulonephritis.
- Role of Antigen-Presenting Cells in Innate Immune System
Toshiaki Ohteki and Shigeo Koyasu (Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, shinjuku-ku, Tokyo 160-8582, Japan)Abstract. Activation of antigen-presenting cells (APC) and natural killer (NK) cells initiates the production of various proinflammatory cytokines, including interleukin 12 (IL-12), interferon gamma (IFN-g) and nitric oxide (NO), which are important in the innate immune response for controlling infection by intracellular pathogens. In this review, we focus on these cytokines produced by APC and summarize the current understanding of how APC functions are regulated by cytokines in innate immunity.
Keywords: dendritic cells; macrophages; IL-12; IL-15; IFN-g; NO; gc; IL-2/15Rb.
Original papers
- Effect of Cyclosporine A on the Nonspecific, Innate Antiviral Immunity of Mice
EWA ZACZYŃSKA and ZOFIA BŁACH-OLSZEWSKA (Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wrocław, Poland)
Abstract. Different infections are the most common complication of immunosuppressive therapy. In this context, the effect of cyclosporine A (CsA) on the innate antiviral immunity of mice was studied. The presence of immunity was shown by infection of resident peritoneal cells (RPC) of BALB/c mice with herpes virus type 1 (HSV-1) and vesicular stomatitis virus (VSV). While the cells infected immediately after isolation were resistant to the viruses, the cells cultured for several days before infection lost immunity. The lack of activity to neutralize HSV-1 and VSV in the sera of the mice excluded a participation of specific antibodies in the resistance. To study the effect of CsA on innate immunity, BALB/ c mice were intraperitoneally (i. p.) injected with cyclosporine (20 or 100 mg/ mouse, twice a day) for three days. The other group of animals was injected in the same way with PBS only. Then the peritoneal cells were isolated and infected with VSV immediately after cell isolation. The kinetics of viral replication in the control and the CsA-treated groups was compared. While in the cells from the control group VSV did not multiply, in the cells from the CsA-treated mice the virus reached considerable titers. The cyclosporine effect on VSV replication was dose-dependent and statistically significant. We conclude that innate antiviral immunity was suppressed in the cyclosporine-treated mice and that this mechanism may be involved in the high susceptibility of patients to viral infections during immunosuppressive therapy.
Keywords: innate immunity; viral infections; cyclosporine.