Cyclosporine immune response

Cyclosporine (Sandimmune) is a potent inhibitor of antibody- and cell-mediated immune responses and is the immunosuppressant of choice for the prevention of transplant rejection. It also has application in the treatment of autoimmune diseases. 

Glucocorticoids are also used in conjunction with antineoplastic agents in regimens for the management of malignant diseases. They are also given to reduce immune responses after organ transplantation, often in conjunction with azathioprine or cyclosporin. 

Another class of transcription-modulating drugs is the immunosuppressants such as cyclosporin A (CsA), which inhibit T cell activation and proliferation, events playing a central role in the immune response and therefore in the inflammatory process. CsA blocks transcriptional induction of cytokines by inhibiting the phosphatase calcineurin, and by the subsequent inhibition of the activation of NF-AT and NF-AT-dependent activation genes. 

NFATc, and as a result, the transport of NFATc to the nucleus is prevented and consequently its association with NFATn does not proceed (Fig. 4.1). The association of NFATc with NFATn is essential for the initiation of IL-2 production, which is achieved through binding of NFATc-NFATn to the promoter of the IL-2 gene. As a result, IL-2 production is inhibited, which is necessary for the optimal function of the immune response. Cyclosporine does not inhibit cytokine-induced transduction mechanisms and also has no effect on antigen recognition by T cells in the context of MHC molecules. 

Because of the autoimmune basis of rheumatoid arthritis, various other drugs that affect the immune response are used on a limited basis. For instance, cyclosporine (Sandimmune), an immunosuppressant agent that is used to prevent rejection of organ transplants (see Chapter 37), is sometimes used to treat... 

Mechanism of Action. Cyclosporine and tacrolimus (see below) are known as calcineurin inhibitors because they inhibit a specific protein (calcineurin) in lymphoid tissues. This inhibition ultimately suppresses the production of IL-2, a cytokine that plays a critical role in immune response by promoting the growth and proliferation of activated T lymphocytes and other immune cells, such as NK. cells (see Fig. 37—1).5,52 Thus, cyclosporine is one of the premier immunosuppressants because of its relative selectivity for T cells and its inhibition of a key mediator of the immune response (IL-2).41 This relatively specific inhibition is often advantageous when compared with other nonse-lective drugs such as azathioprine, cyclophosphamide, and glucocorticoids that inhibit virtually all the cells and chemical mediators involved in the immune response. 

Clinical Use. Mycophenolate mofetil (CellCept) is primarily used to prevent or treat organ rejection following cardiac and renal transplantation. This drug is typically combined with other immunosuppressants (cyclosporine, glucocorticoids) to provide optimal immunosuppression in patients receiving these transplant types.39,40,70 Mycophenolate mofetil may also be useful in suppressing the immune response associated with autoimmune conditions such as systemic lupus erythematosus.2... 

Mechanism of Action. Tacrolimus acts like cyclosporine by binding to a specific protein (calcineurin) in lymphoid tissues and inhibiting the production of key immune mediators such as IL-2.5 IL-2 plays a critical role in the immune response because this substance promotes the growth and proliferation of activated T... 

The most important activity of cyclosporin A consists clearly in the marked suppression of antibody formation and cell-mediated immune response [4, 5]. In addition, the metabolite exhibits antiphlogistic effects, restricted to chronic inflammation processes, as well as antifungal and antiparasitic activities. Whether these different biological activities are inter-related or represent separate mechanisms is still an open question. Considering immunosuppression, early observations revealed that cyclosporin A acts selectively on lymphocytes, mainly on T cells, affecting rather the inductive phase than the proliferative phase of lymphoid cell populations. Apparently, cyclosporin A inhibits primary T-helper cell activation and blocks the formation of... 

The initial success with sirolimus has led to the search of sirolimus analogs, Among these are everolimus (a new macrocylic triene derivative), ABT 578, and other antiimmunosuppressive compounds such as mycophenolic acid, cyclosporine, and tacrolimus, which inhibit proliferation via GI arrest and reduce the immune response. Data from animal experiments suggest that oral everolimus administered for one month effectively inhibits NIH (37) however, human trials have not been conducted. 

Immunosuppressant (-)-FK-S06 (2). This 23-membered lactone-lactam resembles cyclosporin A, a macrocyclic polypeptide, in that they both inhibit immune responses to transplantation, but FK-506 seems to be more active. The total synthesis of (- )-FK-506 has been achieved by a process research group at Merck.1 The cyclization to a carboxamide was carried out with Mukaiyama s reagent (1) under high dilution in 81% yield. The most unusual feature of 2 is the presence of a three-keto sequence at C8, C9, and C,(l (hemiketal). 

The potent immune supression that results reveals how crucial the activity of this transcription factor is to the development of an immune response. Without drugs such as cyclosporin, organ transplantation would be extremely difficult because transplanted tissue expresses a wide range of foreign antigens, which causes the immune system to reject the new tissue. 

With the discovery and development of cyclosporine, a new era in immunopharmacology was born. Cyclosporine was the first agent to affect a specific cell line of the body s immune defenses. It is suppressive mainly to T cells, in condast to the cytotoxic agents, which affect all cell lines at the same time. Cyclosporine is the forerunner of a group of immunosuppressants that are acdve against specific components of the immune response. 

Tacrolimus is a macrolide antibiotic produced by the soil fungus Streptomyces tsukubaensis. It is one hundred times more potent than cyclosporine in vitro, but is equally as toxic if not more so. It suppresses both humoral and cell-media ted immune responses. Although chemically distinct from cyclosporine it elicits similar immunosuppressant effects. 

This active substance suppresses the release of interleukin 1 from monocytes and the synthesis of interleukins 2, 3 and 4 as well as of TNF-a from T helper cells T cell proliferation, macrophage stimulation and B cell activation are inhibited. Even at an early stage of the immune reaction, this leads to the suppression of both humoral and cellular immune responses. The body s bacterial defence is still not significantly influenced, as the phagocytic activity of the RES is barely inhibited by cyclosporine. Bioavailability is about 35% following oral application it is almost completely metabolized in the body and eliminated predominantly via the bile. Clin-... 

Cyclosporine Nephropathy, reversible immune response suppression (essential aid to organ transplantation) Rat, monkey Yes... 

The main target for the modern immunosuppressants such as cyclosporin and tacrolimus is inhibition of cytokine gene transcription in a highly selective manner in the helper T-lymphocyte populations. The consequence of this is to inhibit helper T-cell auto-activation and helper T-cell co-activation of cytotoxic T lymphocytes and of B lymphocytes, and thus considerably damp down cell-mediated and humoral immune responses to the graft. 

Immunosuppressants are drugs capable of suppressing immune responses. They are used to treat autoimmune disease, aUergy, multiple myeloma, and chronic nephritis, and in organ transplantation. For example, immunosuppressants that are used to provide maintenance immunosuppression in solid organ and bone marrow transplant patients include cyclosporine, everoHmus (Ever), mycophe-nolic acid (MPA), Siro, and Tac (Figure 33-13). 

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