Biology of graft-vs.-host disease

Abstract

Graft-vs.-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation, which is an important approach for the treatment of various diseases. In experimental animal models, lethal GVHD can be induced in major histocompatibility complex (MHC)-matched strain combinations that differ in their expression of multiple minor histocompatibility antigens. It has been shown that T cell subset populations expressing the CD8+ phenotype play an important role in the development of GVHD directed to the minor histocompatibility antigens. Moreover, highly purified preparations of these cells are capable of mediating GVHD without apparent help from mature donor-derived CD4+ T cells. CD4+ T cells can also mediate GVHD, but only in certain strain combinations. The pathogenesis of GVHD is similar, whether it is mediated by CD4+ or CD8+ T cells, with the exception that CD4+ cells may be responsible for more gastrointestinal injury. The ability of T cells to respond to minor histocompatibility antigens is further complicated by the phenomenon of immunodominance, which causes T cells to focus on a limited number of antigens out of the larger available pool. Immunodominance does occur in GVHD, but it seems to involve a different pattern of responses than those observed for the generation of cytotoxic T lymphocytes in vitro. Understanding these immunologic interactions is an important step toward the ultimate goal of developing a new approach for bone marrow transplantation, one that will avoid GVHD while retaining enough immunity to counter leukemic relapse and opportunistic infections.