# Designing induction therapies to target memory T cells in high risk recipients

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $396,250

## Abstract

   
DESCRIPTION (provided by applicant): 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 naïve 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 TNFα. 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.

## Key facts

- **NIH application ID:** 9820710
- **Project number:** 5R01AI113142-05
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Anna Valujskikh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2015-12-10 → 2021-09-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9820710

## Citation

> US National Institutes of Health, RePORTER application 9820710, Designing induction therapies to target memory T cells in high risk recipients (5R01AI113142-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9820710. Licensed CC0.

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