INTERLEUKIN-1 IS A CRITICAL EFFECTOR MOLECULE DURING CYTOKINE DYSREGULATION IN GRAFT VERSUS HOST DISEASE TO MINOR HISTOCOMPATIBILITY ANTIGENS1

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Abstract

Cytokines are believed to cause a number of inflammatory diseases. We have investigated the role of 3 inflammatory cytokines, IL-1, IL-2, and TNFα, during graft-versus-host disease (GVHD), a paradigm disease of cytokine dysregulation in vivo. Measuring cytokine mRNA transcripts with a quantitative polymerase chain reaction technique, we demonstrate that IL-1 transcript levels are increased several hundred-fold in GVHD target organs, whereas TNFα transcripts increase only 4-to 6-fold. Kinetic studies during the first month after transplant unexpectedly show that GVHD never induces IL-2 transcripts in the skin and only induces IL-2 transcripts in the spleen during the first week, whereas levels of IL-1 transcripts continue to increase throughout the entire 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 role of IL-1 as an effector molecule of GVHD and suggesting new therapeutic strategies for this disorder.

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