Elsevier

Clinical Immunology

Volume 154, Issue 1, September 2014, Pages 84-89
Clinical Immunology

Review
Targeting the IL-17/IFN-γ axis as a potential new clinical therapy for type 1 diabetes

https://doi.org/10.1016/j.clim.2014.06.006Get rights and content

Highlights

  • Review of recent therapeutic clinical trials in T1D

  • Evidence for targeting the IL-17/IFN-γ axis as a clinical therapy for T1D

  • Review of ustekinumab (antibody to p40 subunit of IL-12 and IL-23) use in psoriasis

  • Rationale for a planned pilot study of ustekinumab in subjects with new-onset T1D

Abstract

Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing pancreatic beta cells. There is now mounting evidence that pro-inflammatory pathways, which are mediated by T cells that secrete IL-17 and IFN-γ, play a critical role in the loss of beta cells. These data suggest that blockade of T cells that secrete IL-17 and IFN-γ may halt or reverse disease in subjects with recent-onset T1D. Agents to facilitate this approach are currently in clinical use. Ustekinumab, a humanized monoclonal antibody that targets the shared p40 subunit of IL-12 and IL-23, has been used for the treatment of psoriasis, an indication for which it has proven to be safe and effective. In this review, we summarize the evidence that supports a combined pathogenic role of IL-17 and IFN-γ in the development of T1D, with the aim of providing a rationale for testing agents such as ustekinumab for the treatment of T1D.

Introduction

The destruction of beta cells in T1D is accompanied by infiltration of pancreatic islets by lymphocytes, presumed to be autoreactive, and other mononuclear cells. Allowed to progress, the resulting deficiency in insulin may lead to fatal hyperglycemia. The use of daily injections of exogenous insulin has provided an effective maintenance therapy. However, several severe and potentially life-shortening complications including renal failure and premature cardiovascular disease still occur. Therefore, the discovery and development of a preventive therapy remain important goals.

T1D arises from multiple defects in immune tolerance, particularly in a subset of regulatory T cells phenotypically identified as FOXP3+CD25+CD4+ Tregs. Their dysfunction is a significant contributing factor in the expansion of autoreactive CD4+ and CD8+ T cells. These autoreactive T cells are presumed to target and kill insulin-producing beta cells in humans as they do in animal models. Disruption of this autoimmune process is the major aim of T1D immunotherapy.

Section snippets

Clinical trials involving immune targets in T1D

Studies in 2010 using broad immunosuppression with non-specific agents such as cyclosporine have demonstrated that modulation of the immune system is a strategy that results in beta cell preservation [1], but that broad immunosuppression is associated with untenable side-effects. Alternative immune modulatory approaches have since been explored including novel therapies that might promote enhancement of immune regulatory mechanisms, particularly through the use of the cytokine IL-2. The

A potential synergy between IL-17 and IFN-γ in T1D (rodent studies)

Like many other diseases, before the discovery of IL-17, T1D was thought to be largely mediated by IFN-γ. In a study where a null mutation of the IFN-γ receptor alpha chain was bred into the NOD mouse and a simplified T cell receptor transgenic model of T1D (BDC2.5 TCR tg mice), there was a marked suppression of insulitis. Since T helper cell phenotypes remained unchanged, this delay in disease development was presumed to reflect a defect in the antigen-presenting cells or the pancreatic beta

The role of IL-17 and IFN-γ in T1D (human studies)

IL-17 and IFN-γ are also strongly implicated in the pathogenesis of disease in humans. We previously showed that, in contrast to age-matched healthy controls, peripheral lymphocytes from children with recent-onset T1D have an increased proportion of a subset of FOXP3+ T cells that secretes a substantial amount of IL-17 [26]. These subjects were also observed to have an increased number of IL-17 secreting CD4+ (Th17) and CD8+ T cells (Tc17). These data are supported by a study from Honkanen and

The success of targeting the IL-17 pathway using p40 blockade in psoriasis

Psoriasis is a chronic, autoimmune/autoinflammatory skin disease characterized by inflamed and scaly demarcated skin plaques. A primary feature of disease is rapid keratinocyte proliferation with thickening of the epidermis (termed acanthosis), resulting from the inflammatory process driven by activated T cells in the dermis and epidermis [31]. Initially, the presence of high levels of IFN-γ, TNF-α, and IL-12 in the serum and lesions of psoriasis patients identified this as a Th1-mediated

Proposed use of ustekinumab (p40 blockade) in new-onset T1D

There is a wide variety of pro-inflammatory cytokine targets that may be pursued in terms of clinical trials in T1D, which are extensively discussed in the recent review by Nepom et al. [8]. These include IL-6R, which is being targeted in the upcoming tocilizumab EXTEND trial performed by the immune tolerance network (ITN). Another valid target would be TNF, which has been widely implicated in T1D. However, these cytokines have a much broader effect than IL-12/IL-23 and so generalized immune

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

We acknowledge Dr. Raghu Mirmira for submitting to us his unpublished data for inclusion in this review. We thank Kevin Tsai for creating the figures for the article. We thank Dr. Rusung Tan for editing the article. The authors are all members of the Juvenile Diabetes Research Foundation Canadian Clinical Trial Network. AKM is a recipient of the Michael Smith Foundation for Health Research Post-Doctoral Fellowship award and the JDRF Canadian Clinical Trial Network Post-Doctoral Fellowship award

References (39)

  • M. Battaglia

    Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients

    J. Immunol.

    (2006)
  • N. Marek-Trzonkowska

    Clinical application of regulatory T cells in type 1 diabetes

    Pediatr. Diabetes

    (2013)
  • K.C. Herold

    Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders

    Diabetes

    (2013)
  • E. Bettelli et al.

    T(H)-17 cells in the circle of immunity and autoimmunity

    Nat. Immunol.

    (2007)
  • B. Wang

    Interferon-gamma impacts at multiple points during the progression of autoimmune diabetes

    Proc. Natl. Acad. Sci. U. S. A.

    (1997)
  • J. Joseph

    IL-17 silencing does not protect nonobese diabetic mice from autoimmune diabetes

    J. Immunol.

    (2012)
  • J. van den Brandt

    Type 1 diabetes in BioBreeding rats is critically linked to an imbalance between Th17 and regulatory T cells and an altered TCR repertoire

    J. Immunol.

    (2010)
  • E.P. Mensah-Brown

    IL-23 leads to diabetes induction after subdiabetogenic treatment with multiple low doses of streptozotocin

    Eur. J. Immunol.

    (2006)
  • J.A. Emamaullee

    Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice

    Diabetes

    (2009)
  • Cited by (0)

    View full text