Graft versus host disease (GVHD) remains a major complication of bone marrow transplantation. Inflammatory cytokines are thought to play an important role during GVHD. We have used a murine model of GVHD after allogenic bone marrow transplantation to examine cytokine dysregulation, and we have demonstrated that Interleukin-1 (IL-1) is increased during GVHD. We have shown the importance of IL-1 in GVHD pathophysiology in this model by administering an IL-1 receptor antagonist (IL-1ra) to mice after transplant and reducing both the mortality and the immunosuppression associated with GVHD. We now propose to investigate the relationships between inflammatory cytokines, IL-1ra and GVHD in this murine model, and to extend these findings to other murine models of GVHD. We also propose to investigate the production of inflammatory cytokines during clinical transplantation and to evaluate the effects of IL-1ra in patients with steroid-resistant GVHD.
Our specific aims are: 1) To analyze inflammatory cytokine dysregulation in GVHD target organs in murine models of GVHD to both minor and major histocompatibility antigens. 2) To characterize the effect of IL-1ra administration on both the production of inflammatory cytokines and on the clinical course of GVHD in these murine models. 3) To analyze the production of inflammatory cytokines after clinical bone marrow transplantation, both before and during treatment for acute GVHD. 4) To evaluate the safety and efficiency of IL-1ra for steroid-resistant acute GVHD and to evaluate its effect on the production of inflammatory cytokines.
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| Renteria, Anne S; Levine, John E; Ferrara, James L M (2016) Therapeutic targets and emerging treatment options in gastrointestinal acute graft-versus-host disease. Expert Opin Orphan Drugs 4:469-484 |
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