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.
Currently, allogeneic hematopoietic stem cell transplantation (HSCT) remains as the only curative therapy for the treatment of hematological malignancies. However, its success is dependent on the induction of an immunologically mediated reaction known as graft vs tumor (GVT), which can be complicated by the initiation of adverse events such as graft versus host disease (GVHD) post-transplant. Increasingly, preclinical testing to find therapies to modulate GVHD while maintaining GVT have come under scrutiny for their inaccuracies in predicting patient outcomes in human clinical trials. In this grant application we propose that the discrepancy between preclinical testing and clinical outcomes is, at least in part, due to the vast majority of preclinical testing making use of lean specific-pathogen-free (SPF) animal models which may not be reflective of the real world clinical experience. The CDC currently estimates that more than two-thirds of US adults are either overweight or obese, and therefore we are proposing that the pre-existing inflammatory profiles present obesity are directly correlative to increased risk for GVHD pathogenesis and reduced GVT responses. Accounting for this phenotype in both murine and non-human primate models, we will demonstrate that addition of intervention therapeutics can limit GVHD pathogenesis while maintaining GVT responses within obese models.
| Aguilar, Ethan G; Murphy, William J (2018) Obesity induced T cell dysfunction and implications for cancer immunotherapy. Curr Opin Immunol 51:181-186 |
