It has been claimed that limb transplants are a justifiable goal (1). The ultimate goal of our proposed studies is to lay the experimental foundation for the clinical application of Cyclosporine (CyA) and composite tissue allografts (CTAs) (and in particular, limb allografts) for the correction of severe and to date untreatable problems in reconstructive surgery. The possibility of indefinitely surviving CTAs opens a new realm of afflictions and disfigurements that could be effectively, functionally, and completely treated. Now with the advent of CyA, a novel and selective immunosuppressent, the concept of CTA use in reconstructive surgery is close to becoming reality. The rat limb offers a unique model to study each individual tissue (skin, muscle, bone, vessels, nerves, and connective tissue) within a vascularized CTA in a well defined histocompatibility system. We have already observed that CTAs treated with CyA show unique rejection processes. In addition we have succeeded in obtaining long-term CTA survival (hind limbs) using a single short-term course of CyA. Moreover, preliminary reports indicate CyA combined with methods already established for the induction of active enhancement are additive in their effect. Thus, a lower dose of CyA and shortening duration of its administration may lead to indefinite CTA survival. To achieve our ultimate goal of clinically exploiting CyA and CTAs much further research is required. Specifically we will investigate the following: (1) Methods to reduce the minimally effective dose of CyA but still achieve indefinite CTA survival through the use of active enhancement regimens (multiple nonspecific blood administrations, donor macrophages, and donor skin cells) combined with strong and moderate CyA treatments; (2) A new model for limb transplantation will be established which consist of a hind quarter allograft designed to be weight bearing and fully functional; (3) Rejection processes within individual tissues of the CTAs (limbs) and methods to quantitate such rejection processes for possible clinical application through the determination of various biochemical, thermal, fluorometric, and histopathological parameters; (4) Immune functions within CTA recipients; (5) Possible toxic side effects of CyA administration, and (6) Immunosuppressive mechanisms of CyA through the determination of lymphocytic changes in cAMP and cGMP.
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