Tolerogenic therapies in transplantation

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Abstract

Since the concept of immunologic tolerance was discovered in the 1940s, the pursuit of tolerance induction in human transplantation has led to a rapid development of pharmacologic and biologic agents. Short-term graft survival remains an all-time high, but successful withdrawal of immunosuppression to achieve operational tolerance rarely occurs outside of liver transplantation. Collaborative efforts through the NIH sponsored Immune Tolerance Network and the European Commission sponsored Reprogramming the Immune System for Establishment of Tolerance consortia have afforded researchers opportunity to evaluate the safety and efficacy of tolerogenic strategies, investigate mechanisms of tolerance, and identify molecular and genetic markers that distinguish the tolerance phenotype. In this article, we review traditional and novel approaches to inducing tolerance for organ transplantation, with an emphasis on their translation into clinical trials.

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The inhibitory cytokine IL-35 contributes to regulatory T-cell function.

Lauren W. Collison, Creg J Workman, Timothy T Kuo … (2007)

Regulatory T (T(reg)) cells are a critical sub-population of CD4+ T cells that are essential for maintaining self tolerance and preventing autoimmunity, for limiting chronic inflammatory diseases, such as asthma and inflammatory bowel disease, and for regulating homeostatic lymphocyte expansion. However, they also suppress natural immune responses to parasites and viruses as well as anti-tumour immunity induced by therapeutic vaccines. Although the manipulation of T(reg) function is an important goal of immunotherapy, the molecules that mediate their suppressive activity remain largely unknown. Here we demonstrate that Epstein-Barr-virus-induced gene 3 (Ebi3, which encodes IL-27beta) and interleukin-12 alpha (Il12a, which encodes IL-12alpha/p35) are highly expressed by mouse Foxp3+ (forkhead box P3) T(reg) cells but not by resting or activated effector CD4+ T (T(eff)) cells, and that an Ebi3-IL-12alpha heterodimer is constitutively secreted by T(reg) but not T(eff) cells. Both Ebi3 and Il12a messenger RNA are markedly upregulated in T(reg) cells co-cultured with T(eff) cells, thereby boosting Ebi3 and IL-12alpha production in trans. T(reg)-cell restriction of this cytokine occurs because Ebi3 is a downstream target of Foxp3, a transcription factor that is required for T(reg)-cell development and function. Ebi3-/- and Il12a-/- T(reg) cells have significantly reduced regulatory activity in vitro and fail to control homeostatic proliferation and to cure inflammatory bowel disease in vivo. Because these phenotypic characteristics are distinct from those of other IL-12 family members, this novel Ebi3-IL-12alpha heterodimeric cytokine has been designated interleukin-35 (IL-35). Ectopic expression of IL-35 confers regulatory activity on naive T cells, whereas recombinant IL-35 suppresses T-cell proliferation. Taken together, these data identify IL-35 as a novel inhibitory cytokine that may be specifically produced by T(reg) cells and is required for maximal suppressive activity.

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Interleukin-2 and regulatory T cells in graft-versus-host disease.

John Koreth, Ken-ichi Matsuoka, Haesook T. Kim … (2011)

Dysfunction of regulatory T (Treg) cells has been detected in diverse inflammatory disorders, including chronic graft-versus-host disease (GVHD). Interleukin-2 is critical for Treg cell growth, survival, and activity. We hypothesized that low-dose interleukin-2 could preferentially enhance Treg cells in vivo and suppress clinical manifestations of chronic GVHD. In this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous interleukin-2 (0.3×10(6), 1×10(6), or 3×10(6) IU per square meter of body-surface area) for 8 weeks. The end points were safety and clinical and immunologic response. After a 4-week hiatus, patients with a response could receive interleukin-2 for an extended period. A total of 29 patients were enrolled. None had progression of chronic GVHD or relapse of a hematologic cancer. The maximum tolerated dose of interleukin-2 was 1×10(6) IU per square meter. The highest dose level induced unacceptable constitutional symptoms. Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites. The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than eight times the baseline value (P<0.001), without affecting CD4+ conventional T (Tcon) cells. The Treg:Tcon ratio increased to a median of more than five times the baseline value (P<0.001). The Treg cell count and Treg:Tcon ratio remained elevated at 8 weeks (P<0.001 for both comparisons with baseline values), then declined when the patients were not receiving interleukin-2. The increased numbers of Treg cells expressed the transcription factor forkhead box P3 (FOXP3) and could inhibit autologous Tcon cells. Immunologic and clinical responses were sustained in patients who received interleukin-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60% (range, 25 to 100). Daily low-dose interleukin-2 was safely administered in patients with active chronic GVHD that was refractory to glucocorticoid therapy. Administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic GVHD in a substantial proportion of patients. (Funded by a Dana-Farber Dunkin' Donuts Rising Star award and others; ClinicalTrials.gov number, NCT00529035.).

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Mesenchymal stem cells: mechanisms of inflammation.

Nora Singer, Arnold I. Caplan (2011)

In adults, human mesenchymal stem cells (hMSCs) are found in vivo at low frequency and are defined by their capacity to differentiate into bone, cartilage, and adipose tissue, depending on the stimuli and culture conditions under which they are expanded. Although MSCs were initially hypothesized to be the panacea for regenerating tissues, MSCs appear to be more important in therapeutics to regulate the immune response invoked in settings such as tissue injury, transplantation, and autoimmunity. MSCs have been used therapeutically in clinical trials and subsequently in practice to treat graft-versus-host disease following bone marrow transplantation. Reports of successful immune modulation suggest efficacy in a wide range of autoimmune conditions, such as demyelinating neurological disease (multiple sclerosis), systemic lupus erythematosus, and Crohn's disease, among others. This review provides background information about hMSCs and also describes their putative mechanisms of action in inflammation. We provide a summary of ongoing clinical trials to allow (a) full comprehension of the range of diseases in which hMSC therapy may be beneficial and (b) identification of gaps in our knowledge about the mechanisms of action of therapeutic MSCs in disease.

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Author and article information

Journal

Journal ID (nlm-ta): Front Immunol

Journal ID (iso-abbrev): Front Immunol

Journal ID (publisher-id): Front. Immun.

Title: Frontiers in Immunology

Publisher: Frontiers Research Foundation

ISSN (Electronic): 1664-3224

Publication date (Electronic): 18 July 2012

Publication date Collection: 2012

Volume: 3

Electronic Location Identifier: 198

Affiliations

simpleDepartment of Surgery, Emory University Hospital, Atlanta, GA, USA

Author notes

Edited by: Stephen Paul Cobbold, University of Oxford, UK

Reviewed by: Stephen Paul Cobbold, University of Oxford, UK Abdelhadi Saoudi, Institut National de Recherche Scientifique, France Anne L. Fletcher, Dana-Farber Cancer Institute, USA

*Correspondence: Stuart J. Knechtle, Department of Surgery, Emory University Hospital, 101 Woodruff Circle, 5105-WMB, Atlanta, GA 30322, USA. e-mail: stuart.knechtle@ 123456emoryhealthcare.org

This article was submitted to Frontiers in Immunological Tolerance, a specialty of Frontiers in Immunology.

Article

DOI: 10.3389/fimmu.2012.00198

PMC ID: 3399382

PubMed ID: 22826708

SO-VID: 1fe1201c-fe73-486a-9c0c-2704d44bed7d

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

History

Date received : 15 April 2012

Date accepted : 22 June 2012

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Figures: 1, Tables: 1, Equations: 0, References: 184, Pages: 14, Words: 0

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Tolerogenic therapies in transplantation

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Regulatory T cell (Treg) therapy

Most cited references 143

The inhibitory cytokine IL-35 contributes to regulatory T-cell function.

Interleukin-2 and regulatory T cells in graft-versus-host disease.

Mesenchymal stem cells: mechanisms of inflammation.

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