Calcineurin Blockers

The introduction of cyclosporin and later FK506 resulted in spectacular improvements in the outcome of all forms of organ transplanta tion [72]. Registry studies would suggest that it has had no effect on the outcome of corneal transplantation because it has found little place in this context. This is because side effects are common when it is used in immunosuppressive doses and some of the complications are life threatening. Furthermore graft rejection still commonly occurs in high-risk patients even when the drug is used optimally.

Cyclosporin is a cyclic endecapeptide produced as a metabolite of a fungus. In vivo experiments indicate that it interferes with the development of cell-mediated responses such as allograft immunity, delayed cutaneous hyper-sensitivity, graft versus host disease and T-cell-dependent antibody production. Cyclosporin appears to block resting lymphocytes in G0 or G1 phase of the cell cycle and inhibits antigen-triggered release of lymphokines including IL-2. Cyclosporin seems to affect only lymphocytes, and in particular does not suppress haemopoiesis and has no effect on phago-cytic cells, making infection a less common complication than is seen with antiproliferative agents.

FK506 is a macrolide lactone with potent im-munosuppressive activity. At a cellular level it inhibits the formation of cytotoxic lymphocytes that are crucial contributors to the allograft response. It also suppresses T-cell activation and T-helper-cell-dependent B-cell proliferation, as well as lymphokine production, including IL-2, and the IL-2 receptor. At a molecular level the effects of the drug are related to binding to a cyto-solic protein (FKPB) and a combination of this drug-protein complex, calcium, calmodulin and calcineurin, which inhibits the phosphatase activity of calcineurin [83].

Despite the specificity of these drugs for the lymphoproliferative system the side effects are considerable when used systemically in im-munosuppressive doses - and the topical preparations of the drug have not been conclusively proved to be effective.

Systemic administration of cyclosporin has been advocated for the prevention of allograft rejection in high-risk cases. There is considerable in vivo work demonstrating a beneficial effect in animal models of corneal transplantation [84-86]. There is also evidence of effect claimed from a number of controlled [87, 88] and uncontrolled clinical studies [89] - and other studies challenging the benefits of this approach [90-92]. What is broadly accepted is that the complications from systemically administered cyclosporin are frequent and often serious [93]. This limits the usefulness of the drug in the clinical context of corneal transplantation.

Was this article helpful?

0 0
How To Deal With Rosacea and Eczema

How To Deal With Rosacea and Eczema

Rosacea and Eczema are two skin conditions that are fairly commonly found throughout the world. Each of them is characterized by different features, and can be both discomfiting as well as result in undesirable appearance features. In a nutshell, theyre problems that many would want to deal with.

Get My Free Ebook

Post a comment