The focus of this application is on GvHD and on donor/recipient disparities, other than those associated with MHC, that may influence its severity, especially when MHC-matched unrelated donors are used. Recent improvements in bone marrow transplant techniques have resulted in a renewed interest in the use of matched unrelated """"""""alternative"""""""" donors to treat those patients who lack a suitable sibling. It has been recognized, however, that in using alternative donors the risk of fatal GvHD is increased, even with the application of the techniques that have otherwise proved beneficial in HLA-matched sibling transplant. Likewise, it has also been observed that the probable causes for this increased risk may lie in non-MHC (i.e., non-HLA) disparities, some of which may be controllable. Retrospective analyses of the clinical data have suggested that these disparities may involve donor/recipient sex-match, age factors, and, especially, previous allosensitization of the donor to minor histocompatibility antigens either through pregnancy or transfusion. However, whether or not any or all of these factors do in fact affect GvHD has not yet been proven in a controlled prospective study. Moreover, there is some controversy among the clinical groups as to the relative importance of these factors and whether they act independently or in an inter-related fashion. This application has been designed to address that controversy, and especially the allosensitization hypothesis, by using a preclinical model in which the relevant variables can be tightly controlled. That model consists of specific unrelated donor and recipient mouse strains, matched at the MHC, but with well-defined differences in their minor histocompatibility antigens. Using the model, each of the factors suggested by the clinical analyses as being a possible potentiating risk factor for GvHD will be systematically addressed; their relative significance will be evaluated; assessment will be made as to whether they act separately or interdependently; and the possibility that donor allosensitization may be a prime mechanism for GvHD intensification will be examined. Concurrently, the potential for using in vitro T-cell colony-forming techniques to detect allosensitization will be explored. Finally, the possibility of using selective T-depletion techniques to manipulate the donor cells and reduce the intensity of the allosensitization will also be examined.
