Current Pharmaceutical Design - Volume 9, Issue 3, 2003

Natural killer T (NKT) cells are a subset of lymphocytes that express receptors characteristic of conventional T cells together with receptors typically found on natural killer cells. A key feature of NKT cells is the expression of a semi-invariant T cell receptor that is specific for glycolipid antigens presented by the unusual major histocompatibility complex class I-like molecule CD1d. While their precise immunological functions remain unknown, NKT cells have been implicated in the regulation of adaptive immune responses, including those directed against autoantigens. These findings raise the possibility that specific stimulation of NKT cells may be exploited for therapeutic purposes. A number of laboratories have tested this hypothesis, utilizing the sea sponge-derived agent α-galactosylceramide (α-GalCer), a specific agonist of NKT cells. Administration of α-GalCer to mice results in potent activation of NKT cells, rapid and robust cytokine production, and activation of a variety of cells of the innate and adaptive immune systems. Most notably, repeated administration of α-GalCer to mice favors the generation of conventional T lymphocytes producing T helper (Th) type 2 cytokines such as IL-4 and IL-10. These findings suggest that α-GalCer can modulate inflammatory conditions that are mediated by pathogenic Th1 cells. Indeed, recent studies have demonstrated that α-GalCer prevents the development of Type 1 diabetes in non-obese diabetic mice and central nervous system inflammation in mouse models of multiple sclerosis. Collectively, these studies provide a solid foundation for the development of NKT cell ligands as pharmacological agents for treatment of autoimmune diseases.

Dendritic cells (DC) are known for their remarkable ability to induce specific T cell responses. However, the existing views on the role of DC in maintaining tolerance to self-antigens and induction of autoimmunity are somewhat controversial especially when the basic physiology of DC migration, function and homeostasis is considered. This review attempts to provide a comprehensive overview on these topics with particular emphasis on DC homeostasis and presents implications for the generation of pathological autoimmune T cell responses. Furthermore, we advocate the need for a conceptual characterization of the immune system operating in vivo. With particular focus on the contribution of DC, we suggest that a ‘spatiotemporal’ view of the rules for T cell responses (antigen dose and availability, duration and mode of antigen presentation) permits a better understanding of the relevant factors contributing to the pathogenesis of autoimmune diseases.

The molecular interactions occurring at the interface between the antigen presenting cell (APC) and the T lymphocyte play an important role in the immune surveillance against infectious agents and tumors, as well as in autoimmunity and transplant rejection. The significance of the APC-T cell interaction in immunity is underscored by the observation that deficiencies in the function of either one of these two cell types cause extreme susceptibility to infections and tumor growth. Furthermore, a disregulated APC-T cell interaction can initiate autoimmunity. Thus, antigen recognition by T cells must be tightly regulated in order to ensure protection against pathogens and tumors, avoiding activation of self-reactive T cells. Efficient T cell activation requires two simultaneous signals provided by the APC: Antigen (or signal 1) and co-stimulation (or signal 2). The specificity of antigen recognition by T cells (signal 1) is controlled exclusively by the T cell receptor (TCR), an extremely diverse heterodimeric protein composed of disulfide-bonded α and β chains. While it is clear that the TCR recognizes antigens as small peptides bound to molecules of the Major Histocompatibility Complex (MHC), the molecular explanation for the specificity of antigen recognition by the αβTCR is just beginning to be elucidated. In this review are described some of the advances made in the understanding of the molecular interactions that define the antigen-specificity of the TCR, and the current models for T cell activation by antigen on APCs are discussed.

The intravenous administration of high doses of immunoglobulins pooled from the plasma of healthy donors (IVIg therapy) has beneficial effects in patients with a variety of autoimmune disorders. These clinical observations indicate that IVIg have potent antiinflammatory characteristics, and identification of the precise mode of action may open up perspectives for future therapeutic strategies. In certain tissue-specific autoimmune disorders like multiple sclerosis (MS), self-reactive T cells recognizing autoantigens play a significant role for disease pathogenesis, as these cells are able to initiate, maintain, and propagate the harmful immune attack in experimental animal models of disease. These findings render self-reactive T cells an important therapeutic target for autoimmune diseases.Here, we review the effects of IVIg on the homeostasis of T cells and discuss the possible therapeutic implications for multiple sclerosis. As supported by several experimental studies, IVIg regulate crucial steps of T cell-mediated immune responses. These effects involve the modulation of activation, proliferation, differentiation, apoptosis, and effector mechanisms of T cells. The pattern of IVIg-T cell interactions is complex, as IVIg may directly bind to regulatory structures on T cells, or modulate T cell functions indirectly via soluble or cellular components of the immune system.

Macrophages are professional scavengers of apoptotic and necrotic cells, and hence constantly take up self antigens. Paradoxically, macrophages are also professional antigen-presenting cells, which would seem to invite autoimmune disorders. Moreover, macrophages are effector cells in the tissue-destruction phase of autoimmune disorders, where they encounter additional self antigens in the stimulatory context of chronic inflammation. This review examines the array of immunosuppressive mechanisms which may help macrophages suppress unwanted T cell responses, and considers the consequences of a breakdown in these negativeregulatory systems in autoimmunity.

In patients with ALPS, defective homeostasis of lymphocytes is reflected in abnormal accumulation of lymphocytes, leading to lymphadenopathy, (hepato)splenomegaly and hypersplenism, autoimmunity due to a failure to remove autoreactive lymphocytes, and inappropriate survival of lymphocytes associated with an increased occurrence of lymphoma. Several of the laboratory findings are unique for ALPS and reflect defective Fas-mediated apoptosis and abnormal immune regulation. Much has been learned about the molecular mechanisms that underlie defective Fas-mediated apoptosis and the complex relationship between genotype, phenotype and disease penetrance. Family studies strongly suggest the contribution of one or more additional factors to the pathogenesis of ALPS. This may pertain to defective immunoregulation by an altered IL-2 / IL-2 receptor system, reflected in the specific loss of CD4+ / CD25+ T cells, and / or by the highly increased IL-10 levels, but other factors may equally be involved. Treatment strategies remain mostly targeted at the disease manifestations, but more specific therapies directed at the primary pathogenic defects themselves might become possible in the future. Continued efforts directed at both careful clinical follow-up and basic scientific investigation are needed to increase our understanding of the incidence, natural history, and pathogenesis of ALPS. In return, this may prove of benefit for the understanding of autoimmune disease in general.

Immunological manipulations are the basis for modern treatments of autoimmune diseases (AID). Targeted immune suppression with lymphopenic based chemotherapy, and monoclonal anti B or T lymphocytic antibodies, are integral part of the conditioning for stem cell transplantation (SCT). Immune manipulation by Cyclophosphamide (Cy), ATG, Campath and recently rituximab (RI), with or without stem cell support are the basis for emerging therapeutic modalities aiming to eradicate the autoreactive clone in various autoimmune disorders. Couple of hundreds of SCTs have been recently performed in various autoimmune disorders, mainly multiple sclerosis (MS), progressive systemic sclerosis (PSS), systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA). Preliminary results are encouraging. Better selection of patients and earlier treatment, before irreversible organ failure develops will probably improve results. Current ongoing multicenter studies are evaluating the role of SCT in MS, RA, SLE, and PSS.