Classical dendritic cells (CDC1) govern cardiac allograft tolerance

The National Institute of Allergy and Infectious Diseases awarded The Washington University $113,595 on January 16, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to support research on classical dendritic cells and cardiac allograft tolerance.

The research uses single-cell RNA sequencing to investigate how co-stimulation blockade—specifically CTLA-4 Ig and anti-CD40L neutralizing antibodies—modulates immune responses in transplanted hearts compared to traditional immunosuppression with cyclosporine. The project employs a fully HLA-mismatched mouse heart transplantation model (BALB/c donor to B6 recipient) to identify immune cell populations and mechanisms responsible for inducing and maintaining donor organ tolerance. Preliminary analysis has identified a marked increase in classical dendritic cells (CDC1s and CDC2s) in mice receiving co-stimulation blockade, with these cells expressing high levels of negative regulators of T-cell activation. This work addresses significant gaps in understanding how blocking B7-CD28 and CD40-CD40L costimulatory pathways confers allograft tolerance, an approach that has demonstrated promising results in human renal transplant studies and sustained graft survival in nonhuman primate models.

Performance occurs at The Washington University Office of Sponsored Research Services in St. Louis, Missouri, with an ultimate completion date of July 31, 2029.

Abstract

Acute and chronic rejection continue to represent serious challenges in transplant medicine. Current medical regimens focus on suppressing t-cell responses, lack effectiveness for some patients and impose significant risks of infection and malignancy. Recent studies have suggested that inhibition of CO-stimulation pathways between antigen presenting cells (dendritic cells, macrophages, b-cells) and t-cells may serve as an effective strategy to prevent rejection by promoting allograft tolerance as opposed to simply suppressing immune responses. This concept has garnered excitement across the transplant community and demonstrated promising results in human renal transplant studies. A commonly used approach is inhibition of B7-CD28 and CD40-CD40L costimulatory pathways. Blocking these pathways leads to prolonged allograft survival in fully HLA-mismatched mouse heart transplantation models and non-human primates. There are important gaps in knowledge pertaining to mechanisms by which CO-stimulation blockade modulates the recipient immune responses and confers donor organ tolerance. The precise immune cell populations and mechanisms responsible for induction and maintenance of donor organ tolerance remain incompletely understood. We have leveraged single cell RNA sequencing to dissect how traditional immunosuppression (cyclosporine) and CO-stimulation blockade (ctla-4 IG, anti-CD40L neutralizing antibodies) differentially impact the immune landscape of the transplanted heart using a fully HLA-mismatched mouse model (balb/c donor heart à B6 recipient). Analysis of these datasets demonstrated striking differences between these treatment regimens. Mice that received CO-stimulation blockade displayed a marked increase in the abundance of classical dendritic cells (CDC1S and CDC2S). Compared to the cyclosporine treated group, these cells expressed high levels of negative regulators of t-cell stimulation including PD-L1. Using recipient mice that lack either CDC1S or CDC2S, we found that CDC1S are absolutely required for CO-stimulation blockade to confer long-term allograft survival and prevent recipient immune responses against the transplanted donor heart. This proposal seeks to elucidate mechanisms by which CDC1S prevent allograft rejection and inflammation. The proposed experiments will identify chemokine pathways responsible for CDC1 trafficking and delineate effector mechanisms by which CDC1S suppress effector t-cells.