Modeling chronic Graft-vs-Host disease in MHC-matched mouse strains: genetics, graft composition and tissue targets

ABSTRACT Graft-vs-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplantation. Acute GVHD results from direct damage by donor T cells, while the biology of chronic GVHD (cGVHD) with its autoimmune-like manifestations remains poorly understood – mainly due to the paucity of representative preclinical models. We examined over an extended time period seven MHC-matched, minor antigen mismatched mouse models for development of cGVHD. Development and manifestations of cGVHD were determined by a combination of MHC-allele type and recipient strain, with BALB recipients being the most susceptible. The C57BL/6 into BALB.B combination most closely modeled the human syndrome. In this strain combination moderate acute GVHD was observed and BALB.B survivors developed overt cGVHD at 6-12 months affecting eyes, skin and liver. Naive CD4+ cells caused this syndrome as no significant pathology was induced by grafts composed of purified hematopoietic stem cells (HSC) or HSC plus memory CD4+ or CD8+ cells. Furthermore, co-transferred naive and memory CD4+ T cells demonstrated differential homing patterns and locations of persistence. No clear association with donor TH17 cells and the phenotype of acute or chronic GVHD was observed in this model. Donor CD4+ cells caused injury to medullary thymic epithelial cells, a key population responsible for negative T-cell selection, suggesting that impaired thymic selection was an underlying cause of the cGVHD syndrome. In conclusion, we report for the first time that the C57BL/6 into BALB.B combination is a representative model of cGVHD that evolves from immunological events during the early post-transplant period.