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 leukocyte 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 and no donor bone marrow. All of these are substantial deviations from the common human transplant situations. The applicant's long term goal is to understand the mechanisms of initiation and pathogenesis of cGVHD. To this end, he has further explored the lethal irradiation, MHC-matched B1O.D2 to BALB that was originally reported to have features resembling cGVHD or scleroderma. This model, little worked on over the last 10 yrs., may be the only known realistic model of cGVHD, although it is unclear why a chronic rather than acute syndrome ensues. One clue may be that unlike most aGVHD situations, CD4 cells rather than CD8 cells play a dominant role. Thus, the B10.D2 to BALB/c model is also an excellent one for understanding the role of CD4 cells in cGVHD. In this application the applicant plans to use this model to test key hypotheses about the initiation, maintenance and pathogenesis of cGVHD. He proposes to: 1) Determine the mechanism of antigen presentation for initiation and host tissue recognition and destruction; 2) Test the hypothesis that cGVHD is a Th2 cytokine dominated alloimmune response; 3) Test the hypothesis that host factors including genetic background and residual host T cells modulate cGVHD.
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