# Designing induction therapies to target memory T cells in high risk recipients > **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $482,486 ## Abstract ABSTRACT Antibody-mediated lymphocyte depletion is a common strategy to eliminate donor-reactive T cells in transplant recipients. However, memory T cells are more resistant to depletion and have been associated with acute rejection episodes in transplant recipients treated with polyclonal rabbit anti-thymocyte globulin (ATG) or anti- CD52 mAb. Understanding the mechanisms and composition of T cells reconstituted in lymphopenic transplant recipients is thus critical for the rational use of lymphoablative therapies and for improving their graft-prolonging efficacy. The ultimate goal of our studies is to develop approaches that minimize homeostatic expansion and shift the balance towards thymopoiesis, thus avoiding over-immunosuppression. During the previous funding cycle, we used a murine ATG analog (mATG) in a mouse heart allograft model to establish that homeostatic reconstitution of the entire T cell compartment is driven by depletion-resistant memory CD4+ T cells via B cells and CD40/CD154 pathway. While cognate TCR-pMHC interactions between B cells and T cells were dispensable, we identified posttransplant inflammation and B cell-derived cytokines IL-1β, IL-6 and IL-27 as key factors facilitating homeostatic T cell recovery. Our preliminary data indicate that signaling through pattern recognition receptors TLR4, TLR9 and a Macrophage-inducible C-type lectin (Mincle, or Clec4e) is required to initiate B cell production of proinflammatory cytokines. We further identified innate-like marginal zone (MZ) B cells acting as initial sensors of posttransplant inflammation in lymphopenic recipients. Genetic deficiency or specific depletion of MZ B cells markedly delays T cell reconstitution in mATG treated heart allograft recipients. We hypothesize that inflammation induced by transplantation at the time of lymphoablation promotes rapid T cell reconstitution. DAMPs released by the graft activate B cells to secrete proinflammatory cytokines that further amplify B cell activation and directly enhance T cell proliferation. In particular, MZ B cells activated via C-type lectin receptor Mincle and TLRs act as initial sensors of posttransplant inflammation facilitating proinflammatory functions of follicular B cells. Therefore, the homeostatic recovery of memory T cells and ensuing allograft rejection may be decreased by minimizing DAMPs signaling or by targeting MZ B cell activation and functions. We will test this hypothesis in two Specific Aims: Aim 1. To test the role of MZ B cells as primary sensors of graft tissue injury in lymphopenic recipients. Aim 2. To investigate the mechanisms by which C-type lectin receptor Mincle facilitates B cell proinflammatory functions after mATG lymphoablation. The proposed studies will mechanistically dissect how inflammatory pathways triggered by allograft ischemia/reperfusion injury drive rapid reconstitution of depletion-resistant memory T cells. Based on these insights, we will test the efficacy of several clinicall... ## Key facts - **NIH application ID:** 10492575 - **Project number:** 5R01AI113142-07 - **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU - **Principal Investigator:** Anna Valujskikh - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $482,486 - **Award type:** 5 - **Project period:** 2014-07-15 → 2026-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10492575 ## Citation > US National Institutes of Health, RePORTER application 10492575, Designing induction therapies to target memory T cells in high risk recipients (5R01AI113142-07). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10492575. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*