Graft rejection prevention

The development of drugs that block Calcineuiin phosphatase activity has allowed successful prevention of graft rejection. Due to the key role that NFAT has in T-cell activation, these inhibitors behave as potent immunosuppressors. Nevertheless, the important roles that NFAT proteins have in other tissues suggest that exploring the use of similar drugs in other pathological contexts may be clinically and therapeutically relevant. 

Diamino-1,2,4-thiadiazoles of type (361) have been patented for use in the treatment of hypertension <82EUP44266), while 5-amino-1,2,4-thiadiazoles such as (362) are claimed to be useful for treating autoimmune diseases and in the prevention of graft rejection. Compounds of type (362) also have antirheumatic properties and are, in particular, useful in the treatment of rheumatoid arthritis and immune diseases such as systemic lupus <91EUP455356). 

Muromonab is a mouse monoclonal antibody against the CD3 receptor of T-lymphocytes. Its activity is based on inhibition of interactions between antigen-presenting cells and T-cells. By preventing antigen presentation it suppresses T-cell activation and proliferation. The indication for muromonab is the treatment of acute graft rejection after kidney, liver and hart transplantations. Its adverse effects consist of those symptoms that are initiated by the release of cytokines and lymphokines as a result of the reaction of muromonab with CD3 positive T-lymphocytes. These symptoms may vary from a mild flu-like syndrome to serious cardiac, pulmonale and neurological reactions. 

The drugs like azathioprine and cyclosporine A are used chiefly to prevent transplant rejection and in the treatment of autoimmune diseases. They are used to prevent graft rejection after kidney, liver, lung, pancreas transplant or bone marrow transplantation. 

It is a cyclic polypeptide with 11 amino acids. It selectively inhibits T-lymphocytes proliferation, IL-2 and other cytokine production. It is the most effective drug for prevention and treatment of graft rejection reaction. It is used in cardiac, hepatic, renal, bone marrow transplantation and as second line drug in rheumatoid arthritis, inflammatory bowel disease, dermato-myositis, bronchial asthma and certain other autoimmune diseases. 

Combined administration of azathioprine and allopurinol may result in severe pancytopenia. The dose of Azathioprine should be reduced by two-thirds when given with allopurinol. Azathioprine rarely causes liver dysfunction, frequently manifested by an isolated rise in ALT and bilirubin. With the introduction of mycophenolate mofetil, azathioprine may be relegated to a second-line anti metabolite for the prevention of graft rejection. 

Muromonoab-CD3 is used for the treatment of acute organ transplant rejection. It is effective in preventing graft rejection after kidney, heart or liver transplantation. Muromonoab-CD3 is effective in patients who after acute cardiac or liver allograft rejection do not respond to steroid therapy. It is administered intravenously and with a dose of 5 mg/day, a general concentration range of 400-1500 ng/ml can be achieved. A serum concentration of 600-1150 ng/ml in renal transplant patients produces desirable immunosuppressive effects. The levels of CD3 expression, their production and antibodies to the drug determine its rate of clearance. In the absence of antibodies to muromonoab-CD3, its half-life is about 18 h. 

Bellgrau D, Gold D, Selawry H, Moore J, et al. 1995. A role for CD95 hgand in preventing graft rejection. Nature. 377 630-632. 

M. Moran, et al., Prevention of acute graft rejection by the prostaglandin El analogue misoprostol in renal transplant recipients treated with cyclosporine and prednisone. N. Engl. J. Med. 322 1183-1188, 1990. 

Cyclosporin was isolated from the fungus Tolypocladium infiatum. Its immunosuppressive activity was discovered in 1976 [4]. Although since then many analogs have been prepared and investigated, cyclosporin A (CsA, Sandimmune, 17) remains the most effective cyclic peptide and is the major immunosuppressant dmg to prevent graft rejection after transplant surgery. 

Voclosporin (ISA-247, R1524) 88 (Isotechnika) is being evaluated in a Phase III trial for the treatment of psoriasis,250 as well as a Phase III trial by Lux Biosciences as for the treatment of uveitis (coded as LX211, Luveniq ).251,252 In addition, voclosporin 88 has completed a Phase lib trial for the prevention of kidney graft rejection. Voclosporin 88253,254 is a slightly more potent but less toxic semi-synthetic derivative of the fungal-derived immunosuppressant cyclosporin A 89, which has the same mechanism of calcineurin inhibition. Cyclosporin A 89 was first isolated from Tolypocladium inflatum by workers at Sandoz and its structure was published in 1976.255,256... 

Ohlen, C., Kling, G., Hoglund, P., Hansson, M., Scangos, G., and Bieberich, C. et al. (1989). Prevention of allogeneic bone marrow graft rejection by H-2 transgene in donor mice. Science 246(4930), 666-668. 

Cyclophosphamide is a prodrug which is converted into active metabolites in the liver. Urotoxic side effects must be anticipated they can be suppressed by the additional administration of sodium-2 mercaptoethanesulphonate. This alkylating substance has a strong immunosuppressive effect therefore, it is occasionally used to prevent graft rejection or (at a low dosage) in autoimmune hepatitis, (s. p. 686)... 

Ciclosporin eye-drops have been used after keratoplasty, in high-risk cases, to prevent graft rejection and to treat severe vernal conjunctivitis, keratoconjunctivitis sicca, and various immune-related comeal disorders. Despite its severe adverse effects after systemic use, topical ciclosporin can generally be used without serious adverse reactions (44,45). 

Inolimomab Prevention ot graft rejection Keliximab Rheumatoid arthritis Muromonab Prevention ot acute renal allograft rejection Natalizumab Acute relapse in multiple sclerosis Crohn s disease... 

Kreis H, Cisterne JM, Land W, Wramner L, Squiffiet JP, Abramowicz D, Campistoi JM, Moraies JM, Grinyo JM, Mourad G, Berthoux FC, Brattstrom C, Lebranchu Y, Viaitei P. Siroiimus in association with mycophenoiate mofetii induction for the prevention of acute graft rejection in renai aiiograft recipients.Transpiantation 2000 69 1252-1260. 

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