Prophylaxis of aGVHD by inhibiting IR-induced NFkB

Ionizing radiation (IR) is one of the most widely used pre-conditioni~g regimens for allogeneic bone man-ow transplantation (BMT). Unfortunately, IR also promotes the development of acute graft-vshost disease (aGVHD), presumably in part by activating host cells to produce the inflammatory cytokines TNFa, IL-I and IL-6. Our recent studies show that exposure of mice to total body IR induces tissuespecific activation of NF-KB. The activation of NF-KB has a temporal and spatial relationship to the increases in TNFa, IL-I and IL-6 mRNA expression in the spleen, mesenteric lymph nodes (LN) and bone marrow (BM), and precedes the ~ppearance of increased serum levels of these cytokines in mice after being exposed to IR. It has been well established that NF-KB plays a central role in regulating TNFa, IL-I and IL-6 production at the level of gene transcription. Therefore, we hypothesize that (a) the activation of NF-'KB induced by [R plays an important role in the development of aGVHD by inducing TNFa, IL-l and IL-6 production and (b) inhibiting NF-KB activation may offer a novel approach for the prophylaxis of aGVHD. To test this hypothesis, we will determine: (a) which immune cells are responsible for IR-induced NF-KB activation and TNFa, [1:1 and IL-6 production in vivo and whether these events are related in a temporal and spatial fashion at the cellular level; (b) whether the activation of NF-KBhas a cause-effect relationship to IR-induced production of TNFa, IL-l and IL-6 ill vivo; and (c) if so, whether ill vivo inhibition of IR-induced activation of NF-KB reduces aGVHD but does not adversely affect 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 o~ aGV~D and may lead to the development of new strategi~~ fo!, the prophylaxIs of human aGYHD. assocIated with IR and BMT. Thus, this would make IR pre-condltlOnmg and BMT a more safe and effectIve treatment for human hematological malignant diseases.