Research Project
10129519
This is a competitive renewal application to continue our work deciphering the molecular and cellular facets of host immunity in high-risk corneal grafts, performed in inflamed host beds and distinguished by their rapid rejection. Over the past 4 funded cycles, this project has led to over 100 scientific articles spanning important areas of transplant immunity, including characterization of corneal antigen-presenting cell (APC) populations and the mechanisms of their trafficking, regulation of hemangiogenesis and lymphangiogenesis, mechanisms of T cell activation and homing, and the function of regulatory T cells (Treg) in promoting immune quiescence and allotolerance. In the last 4 years, we have made significant progress, showing how the microenvironment of a graft can regulate Treg phenotype: in the physiologic state, which is largely maintained in the low-risk graft setting, Foxp3hi Treg express an array of membrane-associated inhibitory factors (CTLA-4, PD-L1) and secreted anti-inflammatory cytokines (IL-10, TGF?) that promote immune tolerance and graft cytoprotection. This homeostasis is lost in the high-risk setting, leading to Treg dysfunction and potential generation of a subset of Treg (`ex-Treg') that express pro-inflammatory cytokines that cause tissue damage. In the current proposal, we aim to better understand the cross-regulation of APC and Treg in different graft settings. Our overarching hypothesis is that the high-risk graft is characterized by an ocular microenvironment that abrogates the capacity of Treg to suppress graft site APC maturation (Aim 1), while these mature APC will in turn promote Treg dysfunction in the draining lymph node, the critical site of host T cell sensitization and expansion (Aim 2). We then aim to exploit functional host Treg by administering them locally to high-risk host beds to assess their anti-angiogenic functions (Aim 3). Our aims are novel, addressing important gaps in our knowledge: Aim 1, investigating the differential capacity of Treg derived from the ocular surface of HR vs. LR graft recipients in regulating APC maturation is the first study in the field of transplantation evaluating regulation of APCs by Tregs at the graft site. Aim 2 will address a major gap in our knowledge about how APC secretory function can influence Treg phenotype and function. Aim 3 includes the first studies characterizing the mechanisms by which Treg exert anti-angiogenic function in transplantation, a novel and potentially feasible therapeutic strategy in the HR transplant setting. Our study design relies on the core expertise and extensive experience of our lab studying the immunology of corneal transplantation. The overall health relevance of this research is that corneal grafting is the number one form of transplantation performed in the US. While most high-risk transplants get rejected, there has been no significant change in their management for 60+ years. The long-term objective of our project is to develop new strategies to promote graft acceptance without the use of systemic immunosuppressive regimens that place grafted recipients at significant risk of serious morbidities.
