Bioengineered T Cell Therapies for Precision Immunotherapy in Renal Transplantation, Autoimmune Relapse, and Sensitization

Abstract Patients with end-stage renal disease (ESRD) undergoing dialysis experience higher mortality rates, increased healthcare costs, and reduced quality of life compared to those receiving allogeneic renal transplantation (RT). Although RT provides proven survival and functional benefits, long-term graft outcomes remain limited by the ongoing risk of immune-mediated rejection—even in cases with donor-recipient histocompatibility, except for rare syngeneic (identical twin) transplants. Additionally, the recurrence of primary autoimmune glomerular diseases, which commonly contribute to ESRD pathogenesis, continues to pose a clinical challenge for maintaining stable allograft function and optimizing long-term outcomes. While immunosuppressive therapy remains crucial to the prevention of allograft rejection and autoimmune relapse, its use is frequently associated with clinically significant complications, including nephrotoxicity, opportunistic infections, new-onset diabetes after transplantation (NODAT), and an elevated risk of malignancy. Chimeric Antigen Receptor (CAR) regulatory T cells (Tregs) are emerging as a potential alternative to polyclonal or antigen-specific Tregs, offering advantages such as reduced cell dosing requirements and HLA-independence. These features may help overcome limitations posed by HLA allele variability in genetically diverse populations. However, the concurrent use of immunosuppressive agents to prevent autoimmune relapse—particularly in conditions such as focal segmental glomerulosclerosis (FSGS), lupus nephritis (LN), and IgA nephropathy (IgAN)—poses challenges to the therapeutic efficacy and safety profile of CAR Tregs. Furthermore, CAR Tregs have demonstrated potential in attenuating anti-HLA-A2 IgG donor-specific antibodies (DSAs) in naïve preclinical models, their efficacy in sensitized recipients remains insufficiently established. This review explores the challenges and therapeutic potential of dual CARs and bicistronic CARs in Tregs, alongside chimeric HLA antibody receptor (CHAR) T cell strategies, to concurrently address RT rejection and autoimmune relapse through CAR Tregs, and allo-sensitization through CHAR T cells. Emphasis is placed on optimizing CAR construct design, selecting appropriate target antigens, expanding eligibility criteria, and integrating CAR Treg therapy with CHAR T cell–based desensitization protocols. These approaches collectively aim to improve transplant outcomes, reduce relapse rates, minimize reliance on conventional immunosuppressants, and ensure the safety and efficacy of CAR Treg and CHAR T cell therapies.