Inflammatory Cytokine Networks in Gastrointestinal Tract Graft Versus Host Disease

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PROJECT SUMMARY Graft versus host disease (GVHD) is the major complication associated with allogeneic hematopoietic stem cell transplantation (HSCT). Damage to the gastrointestinal (GI) tract from acute GVHD is a particularly serious event leading to significant morbidity and mortality. Proinflammatory cytokines play a critical role in the pathophysiology of intestinal GVHD, in part, by activating donor T cell populations which subsequently induce tissue damage. In preliminary studies, we have identified GM-CSF as a pivotal cytokine which plays an important role in the pathophysiology of acute GVHD in the GI tract. The goal of this proposal is to define the mechanistic pathways by which GM-CSF affects the innate and adaptive arms of the immune system to induce inflammation in this tissue site during GVHD. Our overall hypothesis is that GM-CSF induces a proinflammatory environment in the GI tract, and that this effect is attributable to the recruitment of pathogenic myeloid cell populations and the augmentation of alloreactive donor T cell responses. Studies in Specific Aim 1 will characterize the innate cell populations that are responsive to GM-CSF signaling and define the functional role of specific GM-CSF-responsive cells in mediating damage in the GI tract during acute GVHD. To address this question, we will employ novel Csf2rbfl/fl mice in which the high affinity beta chain of the GM-CSF receptor has flanking lox p sites, which will allow for myeloid cell-specific deletion when bred with appropriate lineage-specific Cre animals. Experiments in Specific Aim 2 will define mechanistic pathways by which GM-CSF affects T cell-mediated inflammatory and regulatory functions in the immune system, and thereby modulates the severity of GVHD in the GI tract. Specifically, we will determine whether GM-CSF elicits IL-23 production by donor-derived APCs in the GI tract, examine whether CD4+ T cell-derived GM-CSF promotes indirect alloantigen presentation by donor-derived APCs in the colon, and define the role of GM- CSF in the reconstitution of the regulatory T cell compartment during GVHD. Studies in Specific Aim 3 will determine whether CD4+ GM-CSF+ T cells represent a stable T cell lineage that is regulated by interleukin 7 (IL-7) signaling. To address this question, we will construct a novel GM-CSF fate reporter mouse that will allow us to fate map immune cell populations that produce GM-CSF and define their response to IL-7. The overall objective of this proposal is to develop new insights into the pathophysiology and regulation of GVHD within the GI tract that will foster the development of clinically relevant strategies to mitigate this complication in allogeneic HSCT recipients and improve outcomes in patients with blood cancers.