Chimeric anti-HLA antibody receptor engineered human regulatory T cells (CHAR Tregs) suppress alloreactive B cells from pre-sensitized transplant recipients 9218

Description Organ transplantation is a lifesaving procedure. However, many patients on the organ waiting list harbor antibodies and B cells directed against allogeneic human leukocyte antigen (HLA) molecules, often HLA-A2, greatly decreasing their likelihood of receiving a compatible organ. Current strategies to desensitize patients non-specifically target circulating antibodies and B cells, resulting in poor efficacy and complications. Regulatory T cells (Tregs) are a subset of immune cells dedicated to suppressing specific immune responses by interacting with both innate and adaptive immune cells. Here, we modified Tregs with a chimeric anti-HLA antibody receptor (CHAR) consisting of an extracellular HLA-A2 protein fused to a CD28-CD3zeta intracellular signaling domain, driving Treg activation upon recognition of anti-HLA-A2 alloreactive B cells. HLA-A2 CHAR Tregs were stimulated specifically by anti-HLA-A2 antibody-producing cells. with no negative impact on their stability, as measured by FOXP3 and HELIOS expression. Interestingly, HLA-A2 CHAR Tregs were not cytotoxic towards anti-HLA-A2 antibody-producing cells, in contrast with HLA-A2 CHAR CD4+ T effector cells. Importantly, HLA-A2 CHAR Tregs recognized and significantly suppressed IgG antibody production by B cells from HLA-A2 sensitized patients. Altogether, CHAR Tregs represent a new type of engineered Treg aimed at inhibiting alloreactive B cells, providing a targeted therapeutic strategy to desensitize transplant recipients.