Targeting Allograft Inflammation with CAR Tregs in Transplantation

Engineering HLA-DQ–specific CAR Tregs to selectively suppress anti-donor immune responses at sites of graft inflammation, this project seeks a more precise, durable alternative to broad immunosuppression in transplantation.
Ongoing Other Adaptive Immunity Animal Models Biological & Mechanistic Experimental Platforms & Models Immune Tolerance In Vitro Models Precision Medicine T Cell Biology Therapeutic Development Translational & Clinical

Funding Year: 2024

Project Overview

Organ transplantation is often limited by immune rejection, requiring lifelong use of generalized immunosuppressive drugs that carry significant side effects. Regulatory T cells (Tregs), which naturally suppress immune responses, offer a promising alternative as a cell-based therapy. This project focuses on engineering chimeric antigen receptor (CAR) Tregs to specifically target HLA-DQ molecules—key drivers of chronic rejection that are highly expressed at sites of graft inflammation. While CAR Tregs have been experimentally tested against HLA-A2 antigens as proof of concept, HLA-DQ represents the most clinically prevalent driver of chronic rejection, making it a more impactful therapeutic target. By designing CAR Tregs that home to inflamed tissues and selectively suppress anti-donor immune responses, the study aims to develop a patentable, HLA-DQ–specific CAR Treg with optimal stability and suppressive function. The project follows a three-year workflow spanning in vitro development and optimization, in vivo preclinical testing, and FDA consultation prior to early-phase clinical trials.

Impact & Innovation

Precision immune control for transplant medicine.

 

This project engineers HLA-DQ–specific CAR Tregs to home to inflamed graft tissue and selectively suppress rejection — a targeted alternative to the broad immunosuppression that limits transplant care today.

  • Aims to develop a patentable HLA-DQ–specific CAR Treg with reactivity across multiple alleles, maximizing translational breadth while minimizing general immunosuppression
  • Generates insights into CAR Treg biology with relevance to autoimmune diseases beyond transplantation
  • Advances the Consortium’s From Mechanistic Insight to Translation pillar through a defined three-year workflow culminating in FDA consultation ahead of early-phase clinical trials
Research Approach

A framework designed for discovery

This project combines cellular engineering, immunology, and translational research to develop and optimize HLA-DQ–specific CAR Tregs. By systematically testing how receptor design and inflammatory environments affect Treg behavior, the study aims to define the key parameters required for effective and stable immune suppression in transplant settings.

Engineering CAR Tregs with HLA-DQ–specific receptors, in vitro functional assays to evaluate suppressive activity, and preclinical in vivo models to assess efficacy, stability, and trafficking to sites of inflammation.

A large library of anti–HLA-DQ single-chain variable fragment (scFv) sequences, in vitro cell-based assays of Treg function and stability, and preclinical transplant models to evaluate immune responses under varying antigen density and inflammatory conditions.

Optimization of CAR Treg design by defining how receptor avidity, antigen expression, and inflammatory signals influence suppressive function and stability. The goal is to develop a clinically viable, patentable CAR Treg therapy, advancing from in vitro optimization to preclinical testing and preparation for early-phase clinical trials.

Investigators & Institutions

Powering the science

Principal Investigators

Marlena Habal, MD, Colton Consortium Member

Assistant Professor, Department of Medicine, NYU Grossman School of Medicine / NYU Langone Health

Mark Yarmarkovich, PhD, Colton Consortium Member

Assistant Professor, Department of Pathology, NYU Grossman School of Medicine / NYU Langone Health

Colton Centers & Institutions

Judith & Stewart Colton Center for Autoimmunity at NYU Langone Health

NYU Grossman School of Medicine