Graft-versus-host disease: The influence of type 1 and type 2 T cell cytokines

Abstract

G RAFT-VERSUS-HOST DISEASE (GVHD) has been associated with the infusion of unirradiated cellular blood products. ~ Manifestations of GVHD usually occur several weeks after the transfusion, and include rash, diarrhea, fever, liver abnormalities, and eventually pancytopenia. There is an extremely high fatality rate for transfusion-associated GVHD. 2 Transfusion from HLA homozygous donors into HLA heterozygous recipients who share one HLA haplotype with the donor are at particular risk for this complication. The development of GVHD in this setting is almost invariably fatal, despite therapy with high-dose corticosteroids and cyclosporine. GVHD is initiated by alloreactive donor T cells recognizing foreign major histocompatibility complex (MHC) antigens and/or minor histocompatibility antigens (minor HA) of the host. The subsequent induction of inflammatory effector mechanisms ultimately culminates in a complex syndrome in which specific host tissues, including the skin, liver, lung, gastrointestinal tract, and the immune system itself, are severely damaged. There is now substantial evidence to implicate the inappropriate production of cytokines, which are the central regulatory molecules of the immune system, as a primary cause for the induction and maintenance of experimental and clinical GVHD. 3-5 Dysregulation of complex cytokine networks occurring at different steps in the sequence is thought to be responsible for the manifestations of this disease. Because of the central role of cytokines in the pathophysiology of GVHD, advances in the understanding of cytokine networks should enable us to optimize preventive and therapeutic strategies. As will be discussed later in more detail, several protocols that include the intervention in cytokinemediated processes during the effector phase of GVHD have been initiated with varying success. The nature of the cytokine cascade makes it difficult to intervene in GVHD once clinical signs appear. Recent breakthroughs in the understanding of T-cell cytokine networks, particularly with the emergence of the Thl/Th2 paradigm, may provide valuable new tools for the directed intervention in