The clinical component of this set of Interactive RO1 applications has demonstrated striking anti-tumor responses using a protocol involving the induction of mixed chimerism following HLA matched or mismatched donor BMT. Twenty of 23 evaluable patients have developed mixed chimerism, and 13 of these patients achieved anti-tumor responses, 7 complete (CR) and 6 partial (PR). The morbidity and complexity of the therapy make it clear that studies in a large animal model are needed both to understand the mechanism and to optimize the treatment protocol. Partially inbred miniature swine have been developed in this laboratory as a large animal, preclinical model for studies of transplantation biology and are very similar to man in many parameters related to BMT. They represent the only large animals in which transplantation across defined MHC barriers can be reproducibly performed. The overall objective of this research proposal is therefore to extend our studies of mixed lymphohematopoietic chimerism to miniature swine as a large animal preclinical model. Specifically, we will: 1) Establish mixed chimerism in miniature swine as a large animal model for studies of engraftment and GvHD relevant to the clinical protocol being studied in Project 1; 2) Attempt to convert mixed chimeras to full chimeras without GvHD by administering donor T cells after establishment of chimerism, and determine which donor cell populations are required to achieve such conversion across different histocompatibility barriers; and 3) Attempt to treat severe acute GvHD by administering autologous (i.e. host) mononuclear cells after onset of BMT-induced GvHD and determine which donor cell populations are required to abrogate GvHD. Our preliminary data indicate feasibility of all of these Aims, and suggest that this model may provide important input into the clinical protocol with respect both to conversion of mixed chimeras to fully allogeneic chimeras and to the abrogation of GvHD.
