It is firmly established that aGVHD is initiated by T-cell recognition of antigenic foreignness and ex vivo depletion of T-cells has been the most effective method to reduce its incidence and severity. The proposed studies are to test 2 hyptheses: 1) The IL-23p19/IL-17 cytokine axis plays a major role in the inflammatory reactions characteristic of aGVHD by regulating the expression of key cytokine genes that may promote or inhibit aGVHD. 2) The IL -23p19/1L-17 cytokine axis interacts closely but not completely with the TNF1, IL-12, and IL-6 cascade to amplify the pathology of aGVHD. Three objectives are designed to address these They are derived from our observation that BALB/c mice transplanted with bone marrow (BM) plus T- containing spleens (SCs) from mutant mice deficient in the p19 dimer of the IL-23 p19/p40 heterodimer develop aGVHD less frequently and less severely than BALB/c transplanted with normal wild type C57BL/6 BM + SCs. IL-17 mRNA and serum cytokine produced by CD8 Th17 cells are elevated in BALB/c mice transplanted with both WT and p19 deficient cells but to significantly higher levels in the WT animals. Induction of Th17 producing IL-17 in the p19-/- mice was shown to be derived from TGF2, IL-6 and IL23p19 induced by total body irradiation of the host BALB/c animals. The first objective is to determine the effect on the induction of aGVHD by isolated T and other cells in the donor inoculum. The second objective is to determine the role of the products of Th17 cells in the pathogenesis of aGVHD. The third objective is to determine the relative roles of the IL-23/IL17-21-22 cascade versus the TNF1-IL-12-IL-6 cascade in the pathology of aGVHD. Use of target mutant animals deficient in IL-23p19, RORgamma t (critical for Th17 cell development) and TNF1 provide unique models in which to dissect the components of aGVHD pathology.
Relevance to VA Mission: Every day large numbers of unfortunate veterans present with new cancers. In addition to the leukemias, myelodysplasia and multiple myeloma, other cancers could be amenable to stem cell transplantation. Admittedly, there are some cancers that probably would not benefit from this therapy but the ability to achieve a revitalized immune system could be an important addition to their care. However, as stated above, the current risk of developing transplant related toxicities, GVHD and overwhelming infection are too great to offer stem cell transplantation to patents with a wider variety of cancers. The proposed studies are to investigate a new approach to minimize GVHD