Alloreactive memory T cells present a serious hurdle in clinical transplantation. Antibody-mediated depletion is widely used as induction therapy in sensitized transplant recipients to overcome the deleterious effects of preexisting donor-reactive immunity. However, memory T cells are less susceptible to depletion than na?ve T cells and there are no current efforts to improve the efficacy of induction therapies in targeting pre-existing donor-reactive T cell memory. Our previous studies in a mouse model of cardiac transplantation using rabbit anti-murine thymoglobulin (mATG) showed that memory T cells are a dominant component of anti-donor immune responses following lymphoablation and that recovering memory CD8 T cells are the primary effector mechanism mediating allograft rejection in mATG treated recipients. Preliminary experiments identified two groups of signals driving memory CD8 T cell recovery following antibody-mediated depletion: help from CD4 T cells mediated through B cells and post-transplant inflammation. The goal of the proposed study is to determine the mechanisms of memory T cell reconstitution following antibody mediated depletion and to use this information to develop strategies inhibiting memory T cell recovery and improving allograft outcome in high risk recipients. We hypothesize that 1) interference with helper and pro-inflammatory signals will effectively inhibit memory CD8 T cell recovery and increase the Treg/Teff cell ratio to impede the development of pathogenic anti-donor responses, and 2) these clinically feasible strategies will improve the efficacy of lymphocyte depleting induction therapies in high risk recipients containing alloreactive memory T cells and receiving cadaveric donor organs with prolonged ischemia time. We will test this hypothesis in three Specific Aims:
Aim 1. To determine cellular and molecular requirements for memory T cell reconstitution following antibody - mediated lymphoablation.
Aim 2. To test the effects of post-transplant inflammation on memory T cell recovery and functions in ATG treated recipients.
Aim 3. To test the contribution of regulatory T cells to allograft prolongation by lymphoablative strategies. We anticipate that the approaches developed in these studies will specifically target pre-existing donor-reactive memory T cells and will improve the efficacy of lymphoablation in sensitized transplant patients.
Induction therapy with anti-lymphocyte antibodies to deplete recipient immune cells is often used to condition high-risk transplant patients. Despite this treatment, donor-reactive memory T cells often return quickly and put the graft and the patient at risk for rejection. The proposed studies will use a mouse heart transplant model to define the mechanism driving the recovery of recipient immune cells and transplant rejection following lymphocyte depletion. This work will develop novel strategies to improve the efficacy of induction therapy and to achieve better outcomes in sensitized transplant patients.