Distinct murine chronic graft-versus-host disease models enable the delineation of the diverging and converging contributors to fibrotic scleroderma 2250854

Abstract

Abstract Introduction Chronic graft-versus-host disease (cGVHD) is a debilitating complication of allogenic hematopoietic stem cell transplantation (alloHSTC) characterized by immune dysregulation, autoimmunity, and fibrosis. Particularly devastating is scleroderma (Scl), a systemic sclerotic disease that targets the skin causing stiffness and delayed wound healing. Despite FDA approved therapies, complete responses in Scl-cGVHD are rare, highlighting an unmet need for more targeted therapies. Methods To delineate the inflammatory and profibrotic mechanisms underlying Scl disease, we used two distinct murine alloHSCT model in which hosts were lethally irradiated and given bone marrow (BM) ± T cells to induce cGVHD. We compared multiple minor antigen mismatch, B10.D2 into Balb/c to a semi-allogeneic, parent-into-F1 C57BL/6 (B6) into (B6D2) F1 models. Results Mice developed scleroderma signs at different rates facilitating the study of overlapping and diverging fibrosis mechanisms. Mice in the B10.D2into Balb/c model had visible skin lesions by d19 with immune cell infiltration seen as early as d3. In contrast, mice in the parent-into-F1 model had comparatively delayed Scl onset with visible lesions appearing ∼d35. In the B10.D2 into Balb/c model, a 20-fold increase in the frequency of IFNg producing CD4 conventional T cells (Tcon) as compared to BM controls was apparent by d21 (p = 0.0119) with very little IL-17 production (< 0.04% IL-17+ of Foxp3-CD4+ Tcon). Conversely, mice in the parent-into-F1 Scl-GVHD model had a strong signature of IL-17 production, with 60% of CD4 Tcon producing IL-17 at d21 (p = 0.0395). To begin to uncover Scl mechanisms, Scl and BM control skin biopsies (d3, 6, 9, 13 and 21; n = 3 mice/group/time) in the B10.D2into BALB/c model are being analyzed by Nanostring GeoMx along with multiplex immunofluorescence of skin from both models and will be presented. Conclusion Together, our data highlight the need for comprehensive studies of cGVHD/Scl models to develop improved translational therapeutics. Funding Source National Institutes of Health (grants P01 HL158505, P01 AI056299, and R37AI34495) Topic Categories Transplantation Immunology (TRAN)