Donor CD4⁺ T and B Cells in Transplants Induce Autoimmune-Like Chronic Graft Versus Host Disease.

Chronic graft-vs-host disease (GVHD) is a major morbidity and mortality of long-term survivors of allogeneic hematopoietic cell transplantation (HCT). Chronic GVHD can have features of an autoimmune collagen-vascular disease with clinical manifestations similar to autoimmune scleroderma and systemic lupus erythematosus (SLE). However, the pathogenesis of chronic GVHD is poorly understood. It is unclear how autoreactive T and B cells are generated in chronic GVHD recipients. We have recently developed a new autoimmune-like chronic GVHD model by transplantation of donor DBA/2 (H-2^d) spleen cells into MHC-matched but minor antigen-mismatched sublethally irradiated BALB/c (H-2^d) recipients, as well as athymic BALB/c nu/nu and adult thymectomized BALB/c recipients. Both euthymic and athymic BALB/c recipients developed high-levels of serum IgG autoantibodies, sclerodermatous skin damage and glomerulonephritis. Disease induction required both donor CD25⁻CD4⁺ T and B cells in transplants. In contrast, donor CD25⁺CD4⁺ T regulatory (Treg) cells prevented the disease induction. These results indicate that host thymus is not required for induction of autoimmune-like chronic GVHD, and that quiescent autoreactive T and B cells in transplants from non-autoimmune donors may be activated and expanded to cause autoimmune-like chronic GVHD in allogeneic recipients, and donor Treg cells can suppress this process.