Multispecies Comparison of the Impact of Obesity on GVHD/GVT

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We propose to build upon exciting preliminary data to modulate graft-versus-host disease (GVHD) and graft- versus-tumor (GVT) effects following allogeneic hematopoietic stem cell transplantation (HSCT) by understanding the role of obesity in the two processes. Currently, the vast majority of both HSCT and preclinical tumor studies involve the use of lean specific-pathogen-free (SPF) inbred mice. Obesity is a dynamic process that has been well defined to be immunomodulatory, and characteristically contains a “meta- inflammatory” environment, defined as a state of low-grade, chronic, self-sustaining inflammation. As cytokine storms from inflammatory cytokines play a critical component in GVHD pathophysiology, this grant application seeks to delineate the effects obesity as a pre-existing inflammatory condition on GVHD pathogenesis and GVT responses. Additionally recent investigation into the effects of obesity on commensal microbiome ecology and colonization of the gut have shed light onto the relationship between microbial diversity and immunopathology. Our application proposes the following three aims using a combination of mouse and non- human primate studies due to the unique ability to obtain obese non-human primates at UC Davis: 1) Evaluate the impact of obesity on the induction of inflammatory responses and pathology in response to conditioning regimens, and its effect on immune reconstitution post-autologous/syngeneic HSCT using mouse and non- human primate models, 2) to determine the impact of obesity on GVHD pathogenesis using murine and non- human primate models following allogeneic HSCT, and 3) to determine the effects of obesity on tumor progression and using the pharmacological and microbiological interventions affecting GVHD in the second aim, will determine effects on GVT.