Induction of tolerance via T regulatory cells

M. Battaglia

Research output: ThesisDoctoral thesis 2 (Research NOT UU / Graduation UU)

Abstract

T regulatory (Treg) cells are a subset of lymphocytes specifically dedicated to maintain the correct balance between efficient immune responses towards harmful events (such as a viral infections) and tolerogenic responses towards self and non-harmless antigens (such as food antigens). This is a delicate process that needs to be finely tuned. It is clear that Treg cells can be infused in animals and induce tolerance thus leading to, for example, reversal of autoimmunity. However, how much data generated in animals can be successfully translated into humans remains one of the key questions. There are two distinct ways to perform Treg-cell–based therapy: (i) via infusion of ex vivo manipulated Treg cells or (ii) via the direct in vivo induction of Treg cells. Both methods have advantages and disadvantages. Aim of our work was to address some of the still open and key questions to be solved to make Treg-cell therapy in humans a reality. Some of the key issues related to the infusion of ex manipulated Treg cells that need to be addressed - and that were subjects of this thesis - are: (i) the definition of an efficient and safe protocol for the ex vivo manipulation of Treg cells; (ii) the demonstration that that the ex vivo treated Treg cells can promote tolerance in vivo; and (iii) the demonstration that the protocol is equally efficient and safe by using human cells obtained from both healthy donors and patients. We showed that a drug commonly used in the field of transplantation (named rapamycin) can efficiently expand functional Treg cells ex vivo and that these cells, when infused in transplanted mice, protect from graft rejection. In addition, the same protocol is efficacious for the ex vivo manipulation of Treg cells from both healthy donors and patients with autoimmune type 1 diabetes. Some of the important issues that need to be addressed in case of direct in vivo induction of Treg cells - and that were subjects of this thesis- are: (i) the definition of a therapy that allows control of aggressive and unwanted immune responses while permitting induction of functional Treg cells; (ii) the demonstration that such a Treg-cell–permissive therapy is efficient in inducing tolerance in more than one disease animal models; and (iii) the clinical relevance of the findings eventually reported in animals. We showed that two drugs already used in patients (namely, rapamycin and interleuchin-10 (IL-10)) can control unwanted aggressive immune responses and at the same time boost Treg cells that can control allograft rejection and autoimmunity. In addition, we observed that patients with autoimmunity and treated with rapamycin have more functional circulating Treg cells as compared to those isolated before therapy. Overall, we developed an efficient, safe and clinical translatable protocol for the expansion of functional Treg cells and we showed that induction of tolerance via Treg-cells directly in vivo is also feasible and efficient.
Original languageEnglish
Awarding Institution
  • University Medical Center (UMC) Utrecht
Supervisors/Advisors
  • Prakken, Berent, Primary supervisor
  • Roncarolo, M.G., Primary supervisor, External person
Award date18 Nov 2014
Publisher
Publication statusPublished - 18 Nov 2014
Externally publishedYes

Keywords

  • Graft rejection
  • autoimmunity
  • tolerance
  • T regulatory cells
  • rapamycin
  • IL-10

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