Tolerogenic Antigen-Presenting Cells – Modulating Unwanted Immune Response at Their Core

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Newcastle University

Catharien Hilkens

Newcastle University

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Conventional treatments for autoimmune diseases and prevention of allograft rejection comprise immunosuppressive small molecule drugs and, increasingly, potent biologic agents. Whilst often highly effective, these treatments are associated with short-and long-term toxicities, which can have major effects on the quality of life.

Whilst tolerogenic therapies have been studied in animal models for at least three decades, their translation to the clinic has been slow. However, increasing knowledge of the immune mechanisms and pathways that are dysregulated in autoimmune disease, and active in transplant rejection, has increased the tractability of such approaches. Nonetheless, these will still be associated with the potential for harm, at least in the short term.

In this volume we focus on the potential of cellular tolerogenic therapies, in particular focussing on those cells that control the immune response via antigen presentation. The concept behind cellular therapies is that they repair, or reinforce, natural tolerogenic mechanisms. In this way they should be safer than conventional synthetic or biological drugs. By manipulating the processes at the very core of immune responses, tolerogenic antigen-presenting cell therapies have the potential to reinforce natural immunoregulatory processes, and to downregulate unwanted responses- truly ‘resetting’ the immune system.

There are a number of different approaches to developing tolerogenic antigen-presenting cell therapy. Firstly, there is variation in the methodologies used to generate these cells, and therefore in their mode of action. Secondly, some but not all cell products are loaded with putative autoantigen(s); and if they are loaded the choice of autoantigen varies. Thirdly, the choice of cell dose, route and frequency of administration (both in in experimental models and clinical trials) adds another layer of complexity. In the following articles we have tried to capture the breadth of approaches currently in development for modulating unwanted immune responses at their core.

Conventional treatments for autoimmune diseases and prevention of allograft rejection comprise immunosuppressive small molecule drugs and, increasingly, potent biologic agents. Whilst often highly effective, these treatments are associated with short-and long-term toxicities, which can have major effects on the quality of life.

Whilst tolerogenic therapies have been studied in animal models for at least three decades, their translation to the clinic has been slow. However, increasing knowledge of the immune mechanisms and pathways that are dysregulated in autoimmune disease, and active in transplant rejection, has increased the tractability of such approaches. Nonetheless, these will still be associated with the potential for harm, at least in the short term.

In this volume we focus on the potential of cellular tolerogenic therapies, in particular focussing on those cells that control the immune response via antigen presentation. The concept behind cellular therapies is that they repair, or reinforce, natural tolerogenic mechanisms. In this way they should be safer than conventional synthetic or biological drugs. By manipulating the processes at the very core of immune responses, tolerogenic antigen-presenting cell therapies have the potential to reinforce natural immunoregulatory processes, and to downregulate unwanted responses- truly ‘resetting’ the immune system.

There are a number of different approaches to developing tolerogenic antigen-presenting cell therapy. Firstly, there is variation in the methodologies used to generate these cells, and therefore in their mode of action. Secondly, some but not all cell products are loaded with putative autoantigen(s); and if they are loaded the choice of autoantigen varies. Thirdly, the choice of cell dose, route and frequency of administration (both in in experimental models and clinical trials) adds another layer of complexity. In the following articles we have tried to capture the breadth of approaches currently in development for modulating unwanted immune responses at their core.

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Newcastle University

Catharien Hilkens

Newcastle University

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Frontiers in Immunology

Immunological Tolerance and Regulation

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