Potential and limitations of regulatory T-cell therapy in solid organ transplantation

Abstract

Over the past few years, the therapeutic potential of Treg has been highlighted in the field of autoimmune diseases and after allogeneic transplantation. The first hurdle for the therapeutic use of Treg is their insufficient numbers in non-manipulated individuals, in particular when facing strong immune activation and expanding effector cells, such as in response to an allograft. Here we review current approaches being explored for Treg expansion in the perspective of clinical therapeutic protocols. We describe different Treg subsets that could be suitable for clinical application, as well as discuss factors such as the required dose of Treg, their antigen-specificity and in vivo stability, that have to be considered for optimal Treg-based immunotherapy in transplantation. Since Treg may not be sufficient as stand-alone therapy for solid organ transplantation in humans, we draw attention to possible hurdles and combination therapy with immunomodulatory drugs that could possibly improve the in vivo efficacy of Treg.

Keywords::

• alloantibody
• allorecognition
• graft rejection
• immunosuppression
• immunotherapy
• memory T cell
• Treg
• transplantation

Financial & competing interests disclosure

This work was supported by the Fondation Pierre Mercier pour la Science, Fondation Medi-CAL Futur and Fondation Lausannoise pour la Transplantation d’Organes (to D Golshayan), as well as an unrestricted grant from Astellas (to D Golshayan and M Pascual). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Newer therapeutic approaches are needed in clinical solid organ transplantation to improve patient and graft long-term outcome across immunological barriers.

• Extensive experimental data have shown that the induction and maintenance of peripheral transplantation tolerance is predominantly mediated by donor-specific Treg.

• Because of the low natural frequency of thymic-derived Treg in the human peripheral blood, various strategies are explored for Treg expansion or induction in the perspective of clinical transplantation: ex vivo expansion of thymic-derived Treg; in vitro conversion of naïve T cells into iTreg; in vitro induction and expansion of Treg type 1 cells ; and in vivo expansion of pre-existing peripheral Treg populations.

• For optimal clinical safety and efficacy in solid organ transplantation, expanded Treg are required to be of high purity, to be specific for donor antigens as well as to remain stable in vivo and maintain their suppressive function.

• The development of strategies aiming at expanding Treg in vivo would overcome some of the limitations associated with in vitro manipulations.

• Because of the strength of the alloresponse in a clinical setting, Treg may not have sufficient potency as a stand-alone therapy and therefore should be combined with Treg-supportive immunomodulatory drugs.

• In order to develop clinically relevant Treg-based therapies for solid organ transplantation, it is necessary to elaborate new experimental models that reflect better the human T- and B-cell repertoire.

Notes