Ldha-dependent t-cell effector programs in heart transplantation

The National Institute of Allergy and Infectious Diseases (NIAID) awarded The Methodist Hospital Research Institute a $300,000 Project Grant under the Allergy and Infectious Diseases Research program (CFDA 93.855) on August 7, 2025, for completion by July 31, 2026. This award supports investigative research on lactate dehydrogenase A (LDHA)-dependent T-cell effector programs in heart transplantation. The research will produce scientific knowledge and methodological advances addressing T cell-mediated rejection in transplant recipients through three coordinated research aims: (1) investigating whether LDHA increases cytosolic acetyl-CoA levels to promote histone acetylation at effector gene loci, (2) exploring whether LDHA-mediated lactate production enhances histone lactylation and NAD+/NADH ratios supporting effector gene expression, and (3) evaluating whether selective LDHA inhibition using FX11 can induce heart transplant tolerance in preclinical models.

The project will generate research outputs including mechanistic insights into how LDHA regulates effector T-cell differentiation through metabolic-epigenetic pathways, empirical data on the efficacy of LDHA inhibition as a therapeutic strategy, and potential innovative therapeutic approaches for improving transplant outcomes without immunosuppression. These deliverables advance NIAID's mission to support biomedical research addressing critical disease mechanisms and developing novel treatment strategies, with work to be conducted at The Methodist Hospital Research Institute's facilities in Houston, Texas.

Abstract

This proposal addresses the significant challenge of t cell-mediated rejection in heart transplantation by investigating the role of lactate dehydrogenase a (ldha) in t-cell effector differentiation. Effector t cells play a critical role in rejecting transplanted hearts. Our recent studies have revealed a novel framework in which naive alloreactive t cells activate, expand as effector precursor t (TEP) cells, and then differentiate into effector t cells that attack the heart allograft. This differentiation process requires precise effector gene expression, which we hypothesize is regulated by ldha through metabolic- epigenetic pathways. Ldha is a key enzyme in aerobic glycolysis, converting pyruvate to lactate, a process more active in effector t cells compared to TEP cells. In mice with t cell-specific ldha deletion, alloreactive TEP cells still proliferate but fail to differentiate into effector cells, resulting in heart allograft tolerance without the need for immunosuppression. This discovery highlights ldha as a critical regulator of effector t- cell function. The proposal tests the hypothesis that ldha regulates effector gene expression through two metabolic-epigenetic pathways: aim 1 investigates whether ldha increases cytosolic acetyl-COA levels, promoting histone acetylation at effector gene loci. Aim 2 explores whether ldha-mediated lactate production enhances histone lactylation and increases the NAD+/nadh ratio, supporting effector gene expression. Aim 3 evaluates whether inhibiting ldha with the selective inhibitor FX11 can induce heart transplant tolerance, mimicking the effects of genetic ldha deletion. This study will provide new insights into how ldha regulates effector t-cell differentiation and offer innovative therapeutic strategies for improving transplant outcomes.