INTERLEUKIN-1 OR TUMOR-NECROSIS-FACTOR-ALPHA ANTAGONISTS DO NOT INHIBIT GRAFT-VERSUS-HOST DISEASE INDUCED ACROSS THE MAJOR HISTOCOMPATIBILITY BARRIER IN MICE

We show that while interleukin-1 and tumor necrosis factor-alpha antag onists are partially able to inhibit graft-versus-host disease (GVHD) when bone marrow (BM) transplantation is performed in irradiated recip ients of minor antigen-disparate donor BM, these same antagonists do n ot inhibit GVHD when donor BM is fully MHC disparate. This failure in MHC-disparate recipients occurs despite the presence of interleukin-1 and tumor necrosis factor-alpha mRNA in tissues of GVHD mice measured by in situ hybridization and despite escalation of antagonist dosages far beyond those used in previous reports. These findings indicate tha t a relationship may exist between cytokines that amplify GVHD and tar get antigens that elicit GVHD. Moreover, when GVHD inhibition was obse rved in the minor model, it was transient, which suggests that it may be important to target more than one cytokine to effectively inhibit G VHD. These findings suggest that caution is in order in clinical GVHD studies based entirely on anti-proinflammatory cytokine treatment.