INTERLEUKIN-1 IS A CRITICAL EFFECTOR MOLECULE DURING CYTOKINE DYSREGULATION IN GRAFT-VERSUS-HOST DISEASE TO MINOR HISTOCOMPATIBILITY ANTIGENS

Cytokines are believed to cause a number of inflammatory diseases. We have investigated the role of 3 inflammatory cytokines, IL-1, IL-2, an d TNF alpha, during graft-versus-host disease (GVHD), a paradigm disea se of cytokine dysregulation in vivo. Measuring cytokine mRNA transcri pts with a quantitative polymerase chain reaction technique, we demons trate that IL-1 transcript levels are increased several hundred-fold i n GVHD target organs, whereas TNF alpha transcripts increase only 4- t o 6-fold. Kinetic studies during the first month after transplant unex pectedly show that GVHD never induces IL-2 transcripts in the skin and only induces IL-2 transcripts in the spleen during the first week, wh ereas levels of IL-1 transcripts continue to increase throughout the e ntire 4 weeks. Administration of an IL-1 receptor antagonist after the termination of the IL-2 response and after the establishment of GVHD significantly increases long-term survival, confirming the central rol e of IL-1 as an effector molecule of GVHD and suggesting new therapeut ic strategies for this disorder.