A human skin explant model for predicting graft-versus-host disease following bone marrow transplantation

Graft-versus-host disease (GVHD) is the most serious complication following bone marrow transplantation, with an incidence of 40-60%. The disease can be fatal in 50% of cases, even in patients receiving marrow from an HLA ide ntical sibling. Several assays have been developed to try to predict the de velopment of GVHD, including mixed lymphocyte culture reaction, cytotoxic T lymphocyte precursor, and helper T lymphocyte precursor frequency assays. This review describes an in vitro skin explant model which has been used si nce 1988 for both predicting acute GVHD in HLA identical sibling bone marro w transplantation and studying the pathophysiology of the disease. The mode l involves sensitising donor lymphocytes in vitro in a primary mixed lympho cyte reaction and then evaluating the secondary response on patient skin bi opsies by grading the graft-versus-host reactivity (grades I-IV) histopatho logically. From analysis of collective data the model is a clear predictor of GVHD and superior to the other assays widely used, with a correlation of 82% with clinical outcome. The skin explant model allows the investigator to study the pathogenesis of GVHD. The cytokines TNF alpha and IFN gamma ar e shown to be important mediators of cellular damage in graft-versus-host r eactions. Recent work has also involved using the model to study the allore activity of cord blood. The model is currently being assessed in several bo ne marrow transplantation centres in Europe on different patient groups inc luding those who receive marrow from haploidentical and matched unrelated d onors.