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 nave T cells and there are no current efforts to improve the efficacy of induction therapies in targeting donor-reactive T cell memory. Our previous studies in a mouse model of cardiac transplantation using rabbit anti-murine thymoglobulin (mATG) showed that recovering memory CD8 T cells are the primary effector mechanism mediating allograft rejection in mATG treated recipients. Preliminary experiments showed that help from depletion-resistant memory CD4 T cells is required for memory CD8 T cell recovery following antibody-mediated depletion and identified B cells as critical mediators of this help. Limiting CD4 T cell help delays memory CD8 T cell reconstitution markedly enhances the efficacy of mATG induction therapy in sensitized recipients and is associated with the increase in T and B cells with regulatory phenotypes. 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 improving allograft outcome in high risk recipients. We hypothesize that following antibody-mediated lymphoablation, residual memory CD4 T cells interact with B cells through TCR/MHC class II and CD40/CD154 and induce Beff cell activation to produce inflammatory cytokines such as TNF?. Subsequently, cognate B cell/CD8 T cell interactions and B cell derived cytokines facilitate homeostatic CD8 T cell expansion. Interference with helper signals will increase Breg/Beff and Treg/Teff cell ratios and effectively inhibit memory CD8 T cell recovery and the development of pathogenic anti-donor responses. We will test this hypothesis in three Specific Aims:
Aim 1. To determine the mechanisms through which B cells mediate memory CD8 T cell reconstitution following antibody-mediated lymphoablation.
Aim 2. To test whether blocking CD4 T cell help increases the efficacy of mATG induction therapy in sensitized heart allograft recipients.
Aim 3. To test the contribution of regulatory T cells to allograft prolongatin 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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI113142-03
Application #
9388957
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2015-12-10
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Benichou, Gilles; Gonzalez, Bruno; Marino, Jose et al. (2017) Role of Memory T Cells in Allograft Rejection and Tolerance. Front Immunol 8:170
Ayasoufi, Katayoun; Kohei, Naoki; Nicosia, Michael et al. (2017) Aquaporin 4 blockade improves survival of murine heart allografts subjected to prolonged cold ischemia. Am J Transplant :
Ayasoufi, K; Fan, R; Valujskikh, A (2017) Depletion-Resistant CD4 T Cells Enhance Thymopoiesis During Lymphopenia. Am J Transplant 17:2008-2019
Ayasoufi, Katayoun; Fan, Ran; Fairchild, Robert L et al. (2016) CD4 T Cell Help via B Cells Is Required for Lymphopenia-Induced CD8 T Cell Proliferation. J Immunol 196:3180-90