Tissue transplantation immunosuppression

The protein phosphatase calcineurin was of particular interest since it mediates the immunosuppressive effect of the pharmaceuticals cyclosporin and FK506, often used in organ and tissue transplantations. The biochemical point of application of both pharmaceuticals was unclear for a long time. In initial experiments, it was found that cyclosporin and FK506 bind specifically to two proteins known as cyclophilin and FK506 binding protein, respectively. Both proteins function as peptidyl prolyl cis/trans isome-rases (review Fischer, 1994). 

Sirolimus is used for tissue transplantation where its major advantage over calci-neurin inhibitors is that it is not nephrotoxic. Chronic renal failure in transplant patients who have taken calcineurin inhibitors for the long term can be prevented by the administration of sirolimus. Steroid-free immunosuppression can be achieved by administering sirolimus alone or in combination with mycophenolate mofetil and cyclosporine or tacrolimus. Since impaired wound healing is one of its potential side effects, some transplant centers use sirolimus only after several weeks of surgery. 

Originally developed for chemotherapy, azathioprine is used today mainly as an immunosuppressive agent and rarely as an antineoplastic drug. It was introduced as an immunosuppressive agent by a British pioneer of tissue transplantation, Roy Caine. Azathioprine was used to prevent rejection after tissue transplantation as a replacement for 6-mercaptopurine because it was less toxic. In addition to tissue transplantation, it is also used for rheumatoid arthritis and Crohn s disease. Azathioprine is a prodrug which in the body is converted to its active metabolites 6-mercaptopurine and 6-thioinosinic acid. Until the discovery of cyclosporine, azathioprine in combination with steroids was the standard treatment to prevent rejection after tissue transplantation. 

The monoclonal antibodies used as immunosuppressive agents in tissue transplantation include muromonoab-CD3, daclizumab and basiliximab. Muromonoab-CD3 binds to a specific site on CD3 receptors and interferes with the ability of the TCR to bind the antigen and also inhibits CD3 receptor-dependent signal transduction mechanisms, all of which result in immune suppression. Both daclizumab and basiliximab are monoclonal antibodies directed against IL-2 receptors and consequently inhibit IL-2-dependent responses after tissue transplantation, resulting in immune suppression. The monoclonal antibodies used as immunosuppressive agents are described in detail in Chapter 5. 

Daclizumab is used for the prophylaxis of acute rejection in patients receiving kidney transplants. A dose of 1 mg/kg is sufficient to completely block all the IL-2 receptors. It is administered in five doses at a 2-week interval where its elimination half-life is about 20 days. A combination of several other immunosuppressive agents including cyclosporine (or tacrolimus, rapamycin), mycophenolate mofetil and corticosteroids can be used with daclizumab. When it is used in combination with tacrolimus, the doses of tacrolimus are reduced. After tissue transplantation, the addition of daclizumab to the standard immunosuppressive regimen produces reduction in tissue rejection up to 50%. Daclizumab can cause hypersensitivity reactions, but it does not cause cytokine-release syndrome. There is a low incidence of... 

Basiliximab is used for the prophylaxis of acute rejection for patients undergoing kidney transplantation where it is employed in combination with other standard immunosuppressive therapy regimens. After tissue transplantation, its addition to the standard immunosuppressive regimen results in inhibiting tissue rejection up to approximately 30%. Both daclizumab and basiliximab have similar effects on the expression of IL-2a and -(3 chains. 

The loss of bone mineral after organ and tissue transplant associated with immunosuppressive therapy follows a delayed time course. The long-term effects of immunosuppressive therapy on bone density have been determined in 25 cardiac transplant patients (SEDA-20, 375) (219). As expected, there was bone loss in the spine during the first year, but this was not maintained during the second and third years after transplantation, despite continuing maintenance immunosuppression with prednisolone. Only four patients, all of whom were hypogonadal, continued to lose bone. 

This chapter addresses immunosuppressive drugs, or immunosuppressants, that are currently available to prevent the rejection of transplants or to treat specific diseases caused by an autoimmune response. Clearly, these drugs must be used very cautiously because too much suppression of the immune system will increase a patient s susceptibility to infection from foreign pathogens. Likewise, these drugs are rather toxic and often cause a number of adverse effects to the kidneys, lungs, musculoskeletal system, and other tissues. Nonetheless, immunosuppressive agents are often life-... 

Oxisuran 96, (methylsulfinyl)methyl-2-pyridyl ketone, is a synthetic immunosuppressive drug used in organ and tissue transplants to suppress cell-mediated... 

Diseases in which immunosuppression may be useful include tissue transplantation, inflammatory bowel disease, rheumatoid arthritis, chronic active hepatitis, systemic lupus erythematosus, glomerulonephritis, nephrotic syndrome, some haemolytic anaemias and thrombocytopenias, uveitis, myasthenia gravis, polyarteritis, polymyositis, systemic sclerosis, Behcet s syndrome. 

DOC organ or tissue transplantation (+/- mycophenolate +/- steroids +/- cytotoxic drugs). Tacrolimus has been used alternatively to cyclosporine in renal and liver transplants. Mycophenolate, an inhibitor of de novo synthesis of purines, has adjunctive immunosuppressant actions, permitting dose reductions of cyclosporine to limit toxicity. 

Organ or tissue transplantation Immune globulin Adjunctive immunosuppression... 

The fungal-derived cyclic peptide cyclosporine (cyclosporin A) was found some years ago to be an immunosuppressive agent in organ and tissue transplant surgery. Another compound with this same type of use and that also acts by the inhibition of T-cell activation is the macrolide tacrolimus (FK-506), from Streptomyces tsukubaensis (2). 

Organ transplants and cellular and free tissue transplants are subject to cellular rejection. In allotransplantation, cellular rejection is controlled by conventional immunosuppressive therapy, but there is concern that, for several reasons, cellular rejection may be especially severe in xenotransplants. First, the great variety of antigenic proteins in a xenograft may lead to recruitment of a diverse set of xenoreactive T-cells. Second, the... 

Azathioprine, 6-(l-methyl-4-nitro-imidazole-5-yl)-thiopurine (see Figure 1), is an immunosuppressive agent [1,2], which is widely used in clinical treatment of autoimmune disorders as weU as in prevention of graft rejection or graft-versus-host disease in organ and tissue transplantation [3-10], Azathioprine acts on several activities in cellular immunity processes. It inhibits lymphocyte activation [11], lymphocyte differentiation [12], in-vitro lymphocyte stimulation [13,14], in-vitro mixed lymphocyte reaction [15] and it reduces the activity of natural killer lymphocytes [16,17],... 

Tissue/organ transplantation in which the donor is not genetically identical to the recipient (i.e. in cases other than identical twins). The recipient will mount an immune response against the transplanted tissue, culminating in tissue rejection unless immunosuppressive agents are administered. 

The islet cells transplanted into humans are obtained from pancreatic tissue of deceased human donors (Figure 8.9). Implantation of these cells in recipients displaying a competent immune system would, at best, be of transient therapeutic benefit. The ensuing immune response would quickly destroy the foreign cells. Studies conducted thus far in humans have utilized diabetic patients who have received kidney transplants, as these are already subject to immunosuppressive therapy. However, a major stumbling block to the widespread adoption of this therapeutic approach is, predictably, the requirement to induce concurrent immune suppression. 

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