Immune Mechanisms and Therapeutic Strategies in Transplantation
(738) Distinct murine chronic graft-versus-host disease models enable the delineation of the diverging and converging contributors to fibrotic scleroderma
Postdoctoral Fellow Univ. of Minnesota, Twin Cities Minneapolis, Minnesota, United States
Disclosure(s):
Christina Hartigan, PhD: No financial relationships to disclose
Introduction/Rationale: 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.
