The lack of adequate in vivo models to study manipulation of the interactions of lymphoid cells in the human immune response greatly retards the development of new treatment regimens for transplant immunosuppression. Use of new immunosuppressive reagents for human transplantation presents a quixotic dilemma. Ideally, these should be used first as isolated single agents in phase I trials. Practical considerations, however, mandate continued standard immunosuppression such that the effect of any added new agent is often difficult to delineate. This is especially evident in the testing of monoclonal antilymphocyte antibodies. In vitro models have been used, but it is never clear if in vitro lymphocyte reactivity truly reflects the array of cellular interactions which take place to effect graft rejection in vivo. Primate models have also been employed to test reagents intended for human use. Indeed, primate lymphocytes express many antigenic markers cross-reactive with antihuman MAb, but the effect of these reagents on primates and humans are not always equivalent. In addition, research using primates is laborious and expensive. Recently it has been shown that mice from an inbred strain expressing a severe combined immune deficiency (SCID) can be reconstituted with mature human peripheral blood lymphocytes such that they can respond to antigenic challenge with a human antibody response. The research proposal in this application is an attempt to develop an in vivo model of human transplant immunity using the SCID mouse. This model will be employed for preclinical testing for efficacy of immunosuppressive reagents which appear promising for clinical application. It will be employed both to look at the ability of these reagents to inhibit a primary immune response and to examine their effect on a secondary in vivo response as a means of studying the problem of immune manipulation in a presensitized recipient.
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