Graft-versus-host-disease (GVHD) remains a major cause of post-transplant morbidity and mortality in recipients of an allogeneic hematopoietic stem cell transplantation (HSCT). The gut is not only a primary GVHD target organ, but is also the source of endotoxin and inflammatory cytokines, which can amplify the development of GVHD in the intestines and elsewhere. AIIoreactive donor T cells play a pivotal role in GVHD and graft-versus-tumor (GVT) activity after an allogeneic HSCT. T cell trafficking has an important role in the T cell immune response and T cell mediated diseases, and is mostly regulated by integrins and chemokines. The central hypotheses of this proposal are that: (1) integrins and chemokine ligands and receptors, which are required for T cell trafficking to the normal or inflamed intestines, are important in the development of acute intestinal GVHD, and (2) inhibition of these integrins and chemokines can ameliorate the development of acute intestinal and systemic GVHD while sparing GVT activity by alloreactive T cells in all other tissues. Based upon preliminary data including a kinetic analysis of gene expression (using DNA micro-arrays) during intestinal GVHD, the following proteins were selected for further study in mouse models for allogeneic HSCT: the alpha-4/beta-7 integrin, the chemokine receptors CCR2 and CCR9, and the chemokine CCL25. To study the effects of inhibition of these molecules on the development of intestinal and systemic GVHD and GVT activity, mice deficient for beta-7, CCR2 and CCR9, neutralizing antibodies for alpha-4/beta-7, beta-7 and CCL25 will be used. Subsequently, the effects of these inhibitory strategies will be assessed by non-invasive imaging techniques (bioluminescence imaging, PET and CT scanning) in combination with immunofluorescence microscopy using genetically labeled donor T cells. These studies will contribute to a better mechanistic understanding of intestinal GVHD and provide preclinical data for new strategies to treat or prevent intestinal GVHD, while sparing GVT activity. ? ?
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