Function and Stability of Expanded Regulatory T cells in Obese Renal Transplant Candidates ABSTRACT More than two-thirds of adults in the United States are currently considered obese. The epidemic is particularly acute in Kentucky (ranked fifth highest state in the US) as well as in Appalachian counties in adjacent states that make up the University of Kentucky Transplant Center?s service area. In 2016, this center evaluated nearly 1,000 patients with end-stage renal disease (ESRD), of which 54.2% had a body mass index (BMI) equal or greater than 30 Kg/m2 (obese status). Obesity is an increasingly common comorbidity in patients with chronic renal diseases. In kidney transplant patients, it has been associated with delayed graft function, acute rejection episodes, and graft loss. Acute cellular rejection occurs through immunologic mechanisms that include the adaptive immune response mediated by T cells. A growing body of evidence recognizes the balance between graft-reactive effector cells and graft-protective suppressor regulatory T cells (Tregs) as the ultimate determinant of long-term allograft survival. Our Transplant Center is developing a novel clinical protocol using expanded autologous Treg infusions to induce tolerance in renal transplant recipients with the ultimate goal of enhancing long-term allograft function, preventing rejection, and reducing the overall toxicity of current immunosuppressive regimens. Circulating Treg cells are reduced in number and function in obese patients. Therefore, the generation of sufficient numbers of clinically competent suppressive Treg cells from these obese patients is especially challenging. In addition, how the obese microenvironment may alter the functional competency of adoptively transferred Treg is not known. In order to characterize the association between obesity-related parameters and the functional integrity of Tregs, this study will (1) optimize the conditions of primary Treg cell expansion isolated from obese potential transplant recipients, and (2) determine the tissue distribution, functional progress, and lineage stability of adoptive transferred Tregs in obese recipients. We hypothesize that the ex-vivo activation and expansion of obese Treg cells will overcome cell-intrinsic alterations and extrinsic pro-inflammatory signals associated with obesity.
In Specific Aim 1, we will measure baseline levels of Treg cells in peripheral blood from obese (BMI ?35) and non-obese (BMI <25) ESRD patients. We will also purify the Treg cells, expand them ex-vivo and verify their cell phenotype, expansion rates, suppressor activity, metabolic profile, and linage stability. We will compare the data generated from obese and non-obese patients and perform a multivariable logistic regression analysis with the parameters collected to determine independent predictors of Treg cell expansion and function.
In Specific Aim 2 we will use a mouse model to evaluate in vivo the functional proficiency of adoptively transferred Treg cells into obese recipients. The results will (1) characterize the population of Treg cells (baseline levels), (2) determine the feasibility of expanding functionally competent and stable Treg cells from obese patients, and (3) establish the in vivo influence of obese environment to the functional status of adoptively transferred Treg cells.
Function and Stability of Expanded Regulatory T cells in Obese Renal Transplant Candidates PROJECT NARRATIVE PUBLIC HEALTH RELEVANCE: This project will characterize the functional competency of Treg cells in obese and develop the optimal conditions for the pre-clinical validation of expanded obese Tregs.
|Gedaly, Roberto; De Stefano, Felice; Turcios, Lilia et al. (2018) mTOR Inhibitor Everolimus in Regulatory T cell Expansion for Clinical Application in Transplantation. Transplantation :|