Bone Marrow Graft-Versus-Host Disease in Major Histocompatibility Complex-Matched Murine Reduced Intensity Allogeneic Hemopoietic Cell Transplantation.

Background: Most clinical allogeneic hemopoietic cell transplants (alloHCT) are now performed using reduced intensity conditioning (RIC) instead of myeloablative (MAC) conditioning, however, the biology underlying this treatment remains incompletely understood. Methods: We investigated a murine model of major histocompatibility complex (MHC)-matched multiple minor histocompatibility antigen mismatched alloHCT, using bone marrow (BM) cells and splenocytes from B6 (H-2b) donor mice transplanted into BALB.B (H-2b) recipients after RIC therapy with fludarabine 100 mg/kg/day for 5 days, cyclophosphamide 60 mg/kg/day for 2 days, and total body irradiation (TBI). Results: The lowest TBI dose capable of achieving complete donor chimerism in this mouse strain combination was 325 cGy given as a single fraction. Mice given RIC had a reduced incidence and delayed onset of GVHD and significantly prolonged survival compared to MAC (TBI 850 cGy, plus cyclophosphamide 60 mg/kg/day for 2 days) transplanted recipients. Compared to syngeneic controls, RIC mice with GVHD showed evidence of BM suppression, with anemia, reduced BM cellularity, and profound reduction in BM B cell lymphopoiesis, associated with damage to the endosteal BM niche. This was associated with an increase in BM CD8+ effector T cells in RIC mice, and elevated blood and BM plasma levels of Th1 cytokines. Increasing doses of splenocytes resulted in increased incidence of GVHD in RIC mice. Conclusion: We demonstrate that the BM is a major target organ of GVHD in an informative clinically relevant RIC mouse MHC-matched alloHCT model by a process that appears to be driven by CD8+ effector T cells. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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