Allogeneic stem cell transplantation (alloSCT) is a potentially curative therapy for hematologic malignancies and inherited hematopoietic stem cell disorders. Graft vs. host disease (GVHD) is a major cause of morbidity and mortality in alloSCT. Strategies to reduce GVHD are limited because they can adversely affect: graft vs tumor, stem cell engraftment, and immune reconstitution. Thus, a better understanding of GVHD is needed GVHD has two manifestations, acute and chronic. Acute GVHD (aGVHD) is relatively well-studied and treated. By comparison, chronic GVHD (cGVHD) is less well understood. Nonetheless, cGVHD is becoming an increasing problem due to longer survival of recipients, better therapy of aGVHD, the use of peripheral blood stem cells (PBSC), treatment of older patients with nonmyeloablative alloSCT, and delayed leukocytc infusions (DLI). Murine models of aGVHD involving lethal irradiation, and crossing only minor histocompatibility Ags (miHAs) as in the most common human transplant situation, have been invaluable. However, the same has not generally been true of cGVHD. The most commonly used models are parent into Fl transplants (P to F1) and use huge doses of donor spleen cells and little or no host irradiation. All of these are substantial deviations from the common human transplant situations. Our long term goal is to understand the mechanisms of initiation and pathogenesis of cGVHD. To this end, we have further explored the lethal irradiation, MHC-matched BIO.D2 to BALB which was originally reported to have features resembling cGVHD or scleroderma. This model, little worked on over the last 10yrs., may be the only known realistic model of cGVMD, although it is unclear why a chronic rather than acute syndrome ensues. In this proposal we plan to use this model to test key hypotheses about the initiation, maintenance and pathogenesis of cGVHD. We propose to use this model to: 1) Determine whether CD4 mediated injury requires cognate interactions wit target tissues; 2) test the hypothesis that cGVHD is a T2 cytokine dominated alloimmune response. These studies should form the basis of a more comprehensive investigation of this system.
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