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Short course immune induction therapy
Short Course Immune Induction Therapy or SCIIT, is a therapeutic strategy employing rapid, specific, short term-modulation of the immune system using a therapeutic agent to induce T-cell non-responsiveness, also known as operational tolerance.〔Getts, D.R., et al. ( "Have We Overestimated the Benefit of Humanized Antibodies?" ), ''mAbs'' November 2010〕〔Wood, K.J. & Sakaguchi, S. (“Regulatory T Cells In Transplantation Tolerance” ), ''Nature Reviews Immunology'' 3 March 2003〕 As an alternative strategy to immunosuppression and antigen-specific tolerance inducing therapies, the primary goal of SCIIT is to re-establish or induce peripheral immune tolerance in the context of autoimmune disease and transplant rejection through the use of biological agents (compare also tolerogenic therapy). In recent years, SCIIT has received increasing attention in clinical and research settings as an alternative to immunosuppressive drugs currently used in the clinic, drugs which put the patients at risk of developing infection, cancer, and cardiovascular disease.〔Lecher, RI, et al. (“Organ Transplantation – how much of the promise has been realized” ), ''Nature Reviews Immunology'' 6 June 2005〕
== Induction of Immunological Tolerance ==
Immune tolerance can be defined as the ability of the immune system to distinguish between self and non-self, or harmless and harmful. T-cells are able to distinguish between self and non-self largely through their T-cell receptor, or TCR. Immune tolerance is maintained by central and peripheral tolerance. During central tolerance, T-cells are selected in the thymus and allowed to enter the periphery based on the ability of the T-cell to recognize self-peptides (via its TCR) being presented in the context of self-MHC. If the TCR binds the peptide-MHC complex with high affinity, the T cell is deleted from the host. In a healthy individual this process eliminates the majority of T-cells that are self-reactive, although a few T-cells will escape thymic deletion. However, these potentially self-reactive cells in the periphery are held in check by a number of regulatory mechanisms such as active suppression by regulatory T cells(Tregs), clonal anergy, deletion, and ignorance.〔Miller, S.D., Turley, D.M., Podojil,.J.R. (“Antigen-specific strategies for the prevention and treatment of autoimmune disease” ), ''Nature Reviews Immunology'' 10 August 2007.〕 While autoimmunity is thought to result from the breakdown of central and peripheral tolerance, an undesirable immune responses such as transplant organ rejection occurs when the immune system is working properly and recognizes the transplanted organ as being non-self, leading to rejection of the transplanted tissue. In this context, manipulating the immune system to recognize the transplanted organ as self for the induction of immunological tolerance would be beneficial for the establishment of transplant tolerance.〔
As autoimmunity and organ transplant rejection are inextricably linked to T-cell activation and differentiation, it is apposite that T-cells are the primary target of modern tolerance induction strategies. Current strategies for the treatment of T-cell mediated pathologies employ long-term, broad immunosuppressive drugs, which are moderately effective in limiting T-cell responses, but carry unfavorable side effects, such as organ toxicity, risk of infection, and cancer.〔 Due to the adverse risks associated with immunosuppressive drugs, it became apparent that the ideal strategy would be antigen-specific: a therapy that was able to inhibit the antigen-specific T-cell response, but would still leave the remainder of the immune system intact to defend against infection.〔 These strategies employed the use of soluble peptide tolerance and oral peptide tolerance to great efficacy in experimental settings, however all have failed to translate into the clinic. One reason for the failure of these strategies is that T-cell mediated organ destruction is now understood to be a complex event involving epitope spreading to multiple tissue-specific antigens and cryptic epitopes. Thus, at any given stage of disease or rejection, the T-cell response is likely to be heterogenic, involving multiple TCR specificities, leading to difficulties in prescribing the antigen, dosing, and timing of administration required to induce tolerance. While antigen-specific tolerance induction is an attractive strategy,〔Chatenoud, L. & Bluestone, J.A. (“CD3-specific antibodies: a portal to the treatment of autoimmunity” ), ''Nature Reviews Immunology'' 20 July 2007.〕 it’s limited by a lack of knowledge, and because of its stringent requirements, a slightly broader approach is more practical.
SCIIT attempts to occupy the middle ground of immuno-therapeutics by avoiding the dangerous side effects of general immunosuppressive therapy, while alleviating the stringent demands of antigen-specific tolerance induction. SCIIT aims to achieve this by targeting receptor-ligand interactions that provide signals that are critical for the survival, activation, and function of T-cells in the periphery.
抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』
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