Ionizing radiation (IR) is one of the most widely used pre-conditioning regimens for allogeneic bone marrow transplantation (BMT). Unfortunately, IR also promotes the development of acute graft-vs.-host disease (aGVHD), presumably in part by activating host cells to produce the inflammatory cytokines TNF-alpha, IL-1 and IL-6. The applicant's recent studies show that exposure of mice to total body IR induces tissue-specific activation of NFkappaB. The activation of NFkappaB has a temporal relationship to the increases in TNF-alpha, IL-1 and IL-6 mRNA expression in the spleen, mesenteric lymph nodes (LN) and bone marrow (BM), and to the appearance of increased serum levels of these cytokines. It has been well established that NFkappaB plays a central role in regulating TNF-alpha, IL-1 and IL-6 production at the level of gene transcription. Therefore, the applicant hypothesizes that (a) the activation of NFkappaB induced by IR pre-conditioning plays an important role in the development of aGVHD by inducing TNF-alpha, IL-1 and IL-6 production and (b) inhibiting NFkappaB activation may offer a novel approach for the prophylaxis of aGVHD. To test this hypothesis, he will determine: (a) in vivo which immune cells are responsible for IR-induced TNF-alpha, IL-1 and IL-6 production and whether IR-induced NFkappaB activation and production of these cytokines are related in a temporal and spatial fashion at the cellular level; (b) whether in vivo the activation of NFkappaB has a cause-effect relationship to IR-induced production of TNF-alpha, IL-1 and IL-6; and (c) if so, whether in vivo inhibition of IR-induced activation of NFkappaB reduces aGVHD or affects donor cell engraftment and the reconstitution of hematopoietic and immune function in murine model systems. These studies will provide new insight into the cellular and molecular mechanisms whereby IR augments the pathology of aGVHD and may lead to the development of new strategies for the prophylaxis of human aGVHD associated with IR and BMT. Thus, this would make IR pre-conditioning and BMT a more safe and effective treatment for human hematological malignant diseases.
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