Research
Keep up to date with our research projects here!
Reprogramming hypofunction in memory T cells to achieve transplantation tolerance
Alloreactive memory T cells are key mediators of acute and chronic graft rejection and represent a potent barrier to transplantation tolerance in the clinic. Remarkably, pregnancy is able to reprogram memory T cells to hypofunctional states that persisted post-partum, and that manifest as restored susceptibility to co-stimulation blockade-mediated transplantation tolerance. We are investigating the mechanisms of this novel reprogramming, using classical cellular in conjunction with high-dimensional multi-omics approaches.
Main Collaborator: Marisa Alegre (UChicago)
Desensitizing humoral responses to increase access to transplantation
Pregnancy is an immunological paradox that results in fetus-specific T cell tolerance, but simultaneously, humoral sensitization and fetus-specific antibody production. The presence of these pregnancy-induced antibodies contributes to a sex disparity in access to clinical transplantation. We study the mechanisms of B cell sensitization and explore mechanisms to reverse this sensitization in mouse models. Furthermore, we collaborate with transplant physicians to translate these findings to desensitizing transplant candidates. The long-term goal of this project is to improve access to transplantation in historically-disadvantaged multiparous women, as well as to optimize their post-transplant outcomes through the prevention and reversal of pregnancy-induced humoral sensitization.
Main Collaborators: Marlena Habal (NYU), Piotr Witkowski (UChicago)
Autoreactive B cells and antibodies in antibody-mediated rejection
Antibody-mediated rejection is a major contributor to graft loss in the clinic, with donor HLA being the major target of these antibodies. Yet, the majority of transplanted organs diagnosed with antibody-mediated rejection are not associated with donor HLA antibodies. Our investigation into the specificity of B cells infiltrating kidney biopsies from the clinic diagnosed with antibody-mediated rejection determined that these B cells were not donor-HLA reactive, but unexpectedly, they were predominantly autoreactive. This bedside-to-bench project aims to understand the immunobiology of autoreactive antibody production and their role in antibody-mediated rejection. We use mouse models of kidney transplant rejection, and collaborate with our clinical partners on this translational project.
Main Collaborators: Marcus Clark (UChicago), Anat Tambur (Northwestern U), Amishi Desai (Northwestern U).
Redefining clinical rejection with highly multiplexed spatial profiling
This project is a collaboration led by the Clark team, that aims to better define the immune architecture in clinical kidney biopsies diagnosed with T cell-mediated rejection and antibody-mediated rejection, or viral infection. We use the CODEX-Phenocycler platform to stain and visualize up to 50 different immune and kidney cell markers, and are developing bioinformatics pipelines based on neural network spatial analysis. Ultimately this project aims to improve the diagnosis of rejection. We will also use this information to develop more clinically-relevant mouse models to study mechanisms of kidney rejection, with the eventual goal of identifying therapies for individualized treatment of rejection in the clinic.
Main Collaborators: Marcus Clark (Medicine, UChicago), Tony Chang (Pathology, UChicago), Angie Perez Gutierrez (Surgery, UChicago)
Nanoparticle adjuvant-free vaccines
We observed that infections can precipitate graft rejection, so we have extended our research into the prevention of infections through vaccination, with the hypothesis that this strategy can stabilize graft acceptance. We embarked on a 10-year collaborative project to develop self-assembling nanofibers as adjuvant-free vaccines capable of eliciting protective antibody and T cell immune responses with minimal inflammation, even when delivered intranasally. We are currently conducting mechanistic investigations with these nanofibers appended with T cell epitopes, and using mouse models or human organoid cultures, to define their effects on dendritic cells and T cells. We aspire that these investigations will lead to a new framework for designing safe and efficaciously inhaled needle-free vaccines to protect against respiratory infections.
Main Collaborators: Joel Collier (Duke U), Anne Sperling (UVA)
