Ways Forward for Tolerance-Inducing Cellular Therapies- an AFACTT Perspective

Abstract

Clinical studies with cellular therapies using tolerance-inducing cells, such as tolerogenic antigen-presenting cells (tolAPC) and regulatory T cells (Treg) for the prevention of transplant rejection and the treatment of autoimmune diseases have been expanding the last decade. In this perspective, we will summarize the current perspectives of the clinical application of both tolAPC and Treg, and will address future directions and the importance of immunomonitoring in clinical studies that will result in progress in the field.

Induction of Antigen-Specific Tolerance in T Cell Mediated Diseases

“…The increasing knowledge on the biology of Tregs, on their mode of action and their ability to control autoimmune responses when adoptively transferred in vivo in pre-clinical models of autoimmunity allowed the growth of a number of clinical trials to investigate the safety and feasibility of the approach ( 42 , 101 ). The literature on Treg cell therapy is extensive and will not be reviewed here in depth.…”

“…Tregs were first used in clinical trials to treat patients with graft vs. host disease (GvHD) after hematopoietic stem cell transplantation (HSCT). Results demonstrated that Tregs are safe, with some concern about the occurrence of mild to moderate infections ( 101 ). Treg therapy is currently applied to reduce dependency on immunosuppressive drugs in patients after organ transplantation ( 101 , 102 ).…”

“…Results demonstrated that Tregs are safe, with some concern about the occurrence of mild to moderate infections ( 101 ). Treg therapy is currently applied to reduce dependency on immunosuppressive drugs in patients after organ transplantation ( 101 , 102 ). In the context of autoimmune diseases both FOXP3 + Tregs and Tr1 cells have been tested in clinical trials ( Table 1 ).…”

“…Despite these encouraging results, phase II/III clinical trials are needed to address several open issues and to allow comparison to current available treatments. Indeed, a number of open questions remain before tolDC-based therapies can be routinely used to treat or cure autoimmune diseases ( 101 , 116 ). A variety of routes for tolDC administration have been tested in the past, including intradermal, intraperitoneal, intravenous and intra-articular ( 121 ).…”

“…As for any Ag-specific approach for tolerance induction, an additional major hurdle in developing an effective tolDC-based therapy is the selection of the Ag critical for a given disease. As in the case of peptide-based approaches, the use of broad spectrum disease-related peptides has been postulated to overcome this limitation [reviewed in ( 101 )]. Interestingly, in the context of T1D the identification of neoepitopes opened new perspectives in the field.…”