The potential for Treg-enhancing therapies in transplantation

Abstract

Summary Since the discovery of regulatory T cells (Tregs) as crucial regulators of immune tolerance against self-antigens, these cells have become a promising tool for the induction of donor-specific tolerance in transplantation medicine. The therapeutic potential of increasing in vivo Treg numbers for a favorable Treg to Teff cell ratio has already been demonstrated in several sophisticated pre-clinical models and clinical pilot trials. In addition to improving cell quantity, enhancing Treg function utilizing engineering techniques led to encouraging results in models of autoimmunity and transplantation. Here we aim to discuss the most promising approaches for Treg-enhancing therapies, starting with adoptive transfer approaches and ex vivo expansion cultures (polyclonal vs. antigen-specific), followed by selective in vivo stimulation methods. Furthermore, we address next generation concepts for Treg function enhancement (CARs, TRUCKs, BARs) as well as the advantages and caveats inherit to each approach. Finally, this review will discuss the clinical experience with Treg therapy in ongoing and already published clinical trials, however, data on long-term results and efficacy is still very limited and many questions that might complicate clinical translation remain open. Here, we discuss the hurdles for clinical translation and elaborate on current Treg based therapeutic options as well as their potencies for improving long-term graft survival in transplantation.

Treg in inborn errors of immunity: gaps, knowns and future perspectives

“…However, antigen-specific Tregs are present in very low numbers in blood, and the expansion protocol needed for their use as ACT is very challenging ( 38 ). Therefore, polyclonal Treg could be a more feasible approach although it could generate more side effects due to bystander suppression ( 143 ).…”

“…These transduced cells gather in target tissues expressing the specific antigen, exerting their function directly or by bystander suppression. Importantly, they are MHC restricted so matching MHC between donor and recipient is needed ( 143 ). This technique has demonstrated remarkable potential in mouse models of multiple sclerosis and hemophilia, exhibiting promising results ( 37 ).…”

Immune modulation in transplant medicine: a comprehensive review of cell therapy applications and future directions

“…T regs have become crucial in the field of SOT, presenting new therapeutic possibilities for enhancing graft acceptance and decreasing the need for immunosuppressive medications ( 64 , 65 ). Investigations into Foxp3 + CD4 + CD25 + splenic nT regs have shown the critical importance of ex vivo expansion modifications in preserving Foxp3 + expression in SOT ( 66 ).…”

“…Further, CAR-T regs have been shown to secrete anti-inflammatory cytokines that promote immunotolerance ( 35 ). Research has shown promising potential in engineering CAR-T regs to further exploit key pathways, such as TGF-β and IL-2 to improve the cellular stamina and therapeutic effectiveness of CAR-T regs ( 64 , 82 , 90 ).…”

A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes

“…Infusion of polyclonal expT regs has been shown to be safe and feasible across multiple disease settings [reviewed in (1,4)] and efficacious in maintaining transplant tolerance (8). However, less is known about efficacy of expT regs to treat complex autoimmune diseases where autoantigens are targeted and there may be chronic inflammation in the host (9), intrinsic defects in T regs (10)(11)(12)(13)(14), and greater heterogeneity in disease stage and progression rate.…”