The long-range objective of this proposal is to understand the immunological pathways responsible for the rejection of xenografts and to develop new therapeutic strategies to prevent this reaction. In the current application, the investigators have chosen to focus on the humoral components of the xenograft reaction in rhesus monkeys as preliminary work they have conducted in humans has demonstrated that antibody responses to xenografts are encoded by a restricted population of germline Ig genes. The applicants have recently hypothesized that xenoreactive antibodies and natural antibodies that mediate rapid immune responses to infectious agents are structurally and functionally related and are both produced by B cells independent of a requirement for T cell help. The investigators' immediate objective for this application, which is the next step in the attainment of their long-range goal, is to validate the use of rhesus monkeys as an experimental model for testing new approaches and treatment strategies for preventing these early phases of the humoral xenograft rejection in patients. The use of Old World primates is currently of limited scientific value as there is almost no direct information available on the nature of the host immune reaction in these species to pig xenografts.
The specific aims of the proposal include a direct comparison of the Ig genes responsible for encoding the xenoantibody response, establishing if identical populations of antibodies are used to mediate rejection of isolated cells and vascularized organ grafts, and which subsets of B cells are used to produce new xenoantibodies. NHPs represent a final and obligatory step in the application of new treatment strategies to human clinical trials and the work described in this proposal directly addresses the usefulness of this experimental model. Understanding the basis for the mechanisms responsible for xenograft rejection in NHPs is critical for: 1) the use of this experimental model as a testing platform for new drug candidates to prevent xenograft rejection prior to their introduction into patients; 2) the development of new therapeutic strategies to prolong xenograft survival that would be impossible to test directly in patients, and 3) the generation of new fundamental information of the nature of the xenograft response in primates.
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