6 Month Project Update
This project focuses on using HLA-A2 CAR Tregs to protect HLA-A2-expressing human pancreatic islets from rejection in a humanized model of T1D, which this DRC grant was instrumental in setting up in my laboratory at MUSC. This model involves treating immunodeficient NSG mice with streptozotocin (STZ) to eliminate their endogenous beta cells, transplanting (HLA-A2-expressing) human islets into the kidney capsule of these mice, and then infuse them human immune cells. Initially, we sought to induce rejection of transplanted HLA-A2-expressing human islets with peripheral blood mononuclear cells (PBMCs) from HLA-A2 negative human blood donors. Unfortunately, however, we failed to see robust rejection of transplanted HLA-A2-expressing islets and, if enough time (over one month) was given, animals also started suffering from unwanted xenogeneic graft-vs-host disease (GvHD). We thus switched from using PBMCs to using HLA-A2 CAR T cells, which quickly (one week) recognize and destroy transplanted HLA-A2-expressing islets, as I have published before (Muller, Ferreira et al, Front Immunol 2021 PMID: 34616392). Of note, another group has independently made the same observation on PBMC vs. HLA-A2 CAR T and published it recently (Elis et al, Transplantation 2023 PMID: 37528526).
Ongoing and immediate future experiments are focused on testing the capacity of HLA-2 CAR Tregs to protect HLA-A2-expressing human islets from HLA-A2 CAR T cell-mediated rejection in NSG mice (Aim 1). This DRC grant has also been important in helping to set up and enhance human CAR Treg and CAR T cell generation and testing in my laboratory at MUSC, including assessing the impact of CAR signaling modulation in CAR Treg function (Aim 2). I expect to publish 2-3 research articles in 2024 acknowledging DRC support (one of which was submitted in December 2023).
