Allogeneic hematopoietic cell transplantation can cure hematologic malignancies, but its full potential is limited primarily by graft-versus-host disease. Beneficial allo-immune responses target minor histocompatibility antigens (mHA) expressed on hematopoietic tumor cells resulting in beneficial graft- versus-leukemia responses. However, when donor lymphocytes target mHA expressed by normal recipient tissues, patients suffer both acute and chronic GVHD. Our research shows 50% of male transplant patients with female donors develop antibodies against mHA encoded on the Y-chromosome, called H-Y antigens. The development of antibodies against any H-Y correlates with cGVHD development (p<0.0001). This suggests allogeneic B cell responses may contribute to cGVHD pathogenesis, and supports a trial of anti-B cell therapy for cGVHD. Dr. Miklos has completed a phase l/ll trial of rituximab therapy for steroid refractory cGVHD patients. Twenty-one patients were treated with one or two courses of Rituximab (375mg/m2 x 4 weeks), and their overall response rate was 70% with one year of follow-up. Thus, our research has yielded two insights into the pathogenesis of cGVHD. Allogeneic antibody development correlates with the development of cGVHD, and anti-B cell therapy is a promising therapy for patients with cGVHD. Hypothesis: Allogeneic antibody responses contribute to chronic GHVD pathogenesis, and serum collected from cGVHD patients canidentify clinically relevant minor histocompatibility antigens. Our laboratory has developed assays to quantify allogeneic and protective anti-viral antibody responses in relation to clinical outcomes. Our two rituximab trials in the PPG (in this Project and in Project 1) provide unique opportunities to measure these antibody effects in relation to clinical outcomes when depleting donor B cells after allogeneic transplantation. Serologic screening of a 5000 human protein microarray will identify candidate mHA as being recognized by patient sera after HCT but not before. Novel mHA will be confirmed by SNP genotyping of donor/recipient pairs for mHA disparity in relation to allogeneic antibody detection.
Specific Aims : 1 Determine if rituximab added to prednisone therapy for newly diagnosed cGVHD patients provides a steroid-sparing benefit with improved cGVHD control. 2a Using microarray technology, determine the temporal development of H-Y antibody in relation to clinical outcomes, especially cGVHD and disease relapse. 2b Determine if in vivo B cell depletion using rituximab prevents/decreases allogeneic antibody development in relation to cGVHD. 3 Serological Identification of human GVHD minor histocompatibility antigens.
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