Pathogenesis of acute graft-versus-host disease: Cytokines and cellular effectors

The pathogenesis of acute graft versus host disease (GVHD) is multistep pro cess. This review considers acute GVHD in three sequential steps: condition ing regimen, donor T cell activation, and effector mechanisms. In step one, the conditioning regimen simultaneously damages and activates host tissues , amplifying antigen presentation to allogeneic donor T cells. In step two, donor T cells, activated by host alloantigens, proliferate and secrete a v ariety of cytokines. Type 1 cytokines (interleukin-2 and interferon-gamma) are critical for acute GVHD, but several regulatory mechanisms of tissue da mage include inflammatory cytokines and cytolytic cellular effecters. The g astrointestinal (GI) tract is a principal target organ because damage to th e GI mucosa can release inflammatory mediators such as endotoxin that ampli fy systemic disease. The inflammatory processes of acute GVHD can be consid ered as a distortion of the cellular responses to viral and bacterial infec tions. Cell-mediated toxicity is critical to other GVHD target organs, part icularly the liver, where Fas-mediated injury predominates. The cytolytic p athways (e.g., perforin) clearly intensify acute GVHD, although they are no t necessary for systemic disease in several model systems. Many of these in sights come from animal models using mutant mouse strains that can clarify the role of individual proteins or cell types in the disease process. These insights should allow the testing of new classes of drugs and inhibitors i n clinical bone marrow transplantation.