Altered Treg Differentiation in ALD: A Novel Role for Anaphylatoxins C3a and C5a

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PROJECT SUMMARY The Candidate is a postdoctoral fellow and young investigator dedicated to developing an academic career focused on the identification and characterization of molecular mechanisms stemming from ethanol-induced inflammation, contributing to impaired liver tolerance and tissue injury. With a strong background in oxidative stress and innate immunity related to ethanol-induced liver injury, the candidate has developed particular expertise in the use of mouse models to conduct the proposed studies. Use of these model systems has revealed and important role for complement, and anaphylatoxins in mediating liver inflammation and injury caused by ethanol. Moreover, we hypothesize that altered Treg homeostasis is a causative event for impaired resolution of inflammation and injury. The Candidate's recent and current work has provided her with the opportunity to develop her own research program and begin her transition to independence. The Career Development Plan described in the proposal outlines 2-years of mentored training with includes technical skills training in addition to career development activities designed to promote the successful transition to independence. A 3-year program of independent scientific and career development after successful recruitment as an Assistant Professor position is also outlined. The Candidate's Mentor has a proven track- record of excellent scientific productivity and successful mentorship and can provide the Candidate with a solid research environment in her lab at the Lerner Research Institute at the Cleveland Clinic. Research plan: Alcoholic liver disease (ALD) is remains a major socioeconomic burden. For decades, rates of morbidity and mortality have remained constant and the long-term prognosis for patients remains poor. ALD is multifactorial, mediated in part by the innate immune system. Complement, a component of innate immunity, is also implicated in the development of ALD and is becoming an attractive therapeutic target. Our early studies have identified that aberrant, uncontrolled complement activation contributes to tissue injury; however, complement is also required for liver healing. These studies provided the foundation for our current proposal: cell-specific complement therapies are a required alternative to current inhibitory therapies, which can be used as a novel treatment for ALD. Regulatory T cells (Treg) are key contributors to the resolution phase of inflammation and maintain immunological tolerance via secretion of a myriad of immunosuppressive and pro-resolving cytokines. Peripheral Treg are reduced in patients with advanced ALD, but the mechanism by which ethanol alters T cell homeostasis has not been investigated.  It is our working hypothesis that sustained complement activation due to ethanol leads to abnormal regulation of Treg in the liver, thus contributing to liver inflammation and tissue injury. In three specific aims, we will characterize ethanol-mediated Treg differentiation in the liver following Gao-Binge feeding in mice, explore the ability of adoptively transferred ex vivo differentiated iTreg to resolve liver inflammation and diminish liver injury in ethanol-fed mice, and assess the ability of extracellular vesicles to stimulate ex vivo differentiation of naïve CD4+ T cells to iTreg and Th17 subtypes. We expect the results of these aims will provide a strong foundation for future mechanistic studies and clinical interventions for ethanol- induced inflammation and tissue injury.