Induction of Antigen-Specific Tolerance in T Cell Mediated Diseases

Abstract

The development of novel approaches to control unwanted immune responses represents an ambitious goal in the management of a number of clinical conditions, including autoimmunity, autoinflammatory diseases, allergies and replacement therapies, in which the T cell response to self or non-harmful antigens threatens the physiological function of tissues and organs. Current treatments for these conditions rely on the use of non-specific immunosuppressive agents and supportive therapies, which may efficiently dampen inflammation and compensate for organ dysfunction, but they require lifelong treatments not devoid of side effects. These limitations induced researchers to undertake the development of definitive and specific solutions to these disorders: the underlying principle of the novel approaches relies on the idea that empowering the tolerogenic arm of the immune system would restore the immune homeostasis and control the disease. Researchers effort resulted in the development of cell-free strategies, including gene vaccination, protein-based approaches and nanoparticles, and an increasing number of clinical trials tested the ability of adoptive transfer of regulatory cells, including T and myeloid cells. Here we will provide an overview of the most promising approaches currently under development, and we will discuss their potential advantages and limitations. The field is teaching us that the success of these strategies depends primarily on our ability to dampen antigen-specific responses without impairing protective immunity, and to manipulate directly or indirectly the immunomodulatory properties of antigen presenting cells, the ultimate in vivo mediators of tolerance.

Regulatory Cell Therapy in Organ Transplantation: Achievements and Open Questions

“…MRC-based therapy represents an emerging approach on the context of SOT to taper general immunosuppression and to promote transplantation tolerance ( 77 ). Thus far, single administration of MRCs have been applied to transplanted patients; however, based on the assumption that tolDC promote tolerance via multiple mechanisms of immunomodulation, including the generation of a tolerogenic microenvironment that leads to a self-sustained tolerogenic process ( 78 ), possible multiple rounds of MRC administration may be more effective in dampening allogeneic T cell responses and in promoting allo-specific Tregs.…”

Targeting Lymphoid Tissues to Promote Immune Tolerance

“…[30,31] As for tolerogenic therapies of autoimmune diseases, a variety of novel strategies have also been developed, including biomaterials-based, cell-based, and microbe-based approaches. [2,18] They offer attractive advantages, such as facilitating the targeting of specific tissues and cells, protecting cargo from enzymatic degradation, providing the delivery of multiple reagents, extending circulation time, and changing delivery kinetics.…”

“…Panel B was reproduced under the terms of the Creative Commons CC‐BY 4.0 license. [ 2 ] Copyright 2020, The Authors, published by Frontiers Media S.A. Panels C,D were reproduced with permission.…”

“…Tolerogenic therapy for autoimmune diseases aims to induce or reestablish an unresponsiveness state against autoantigens, which may deplete or silence antigen-specific immune cells and trigger the differentiation of regulatory T (Treg) cells, while leaving the remainder of immune system intact. [1,2] This strategy gives birth to a new form of vaccine, the tolerogenic vaccine, which works opposite to traditional vaccines to some extent. Traditional vaccines are usually designed as an immune amplifier to stimulate immune response with the help of adjuvant agents, resulting in the promotion of costimulatory molecules (CD80, CD86, etc.)…”

“…Copyright 2020, Springer Nature. Panel B was reproduced under the terms of the Creative Commons CC-BY 4.0 license [2]. Copyright 2020, The Authors, published by Frontiers Media S.A.…”