Interleukin-1 Antagonism: A Sturdy Companion for Immune Tolerance Induction in Type 1 Diabetes?

  1. Thomas Mandrup-Poulsen
  1. Immuno-endocrinology Laboratory, Section for Endocrinological Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  1. Corresponding author: Thomas Mandrup-Poulsen, tmpo{at}sund.ku.dk.

Intervention trials testing immunomodulatory monotherapies in type 1 diabetes have generally been disappointing (1). Possible explanations include suboptimal pharmacokinetics/dynamics or inappropriate dosing/timing of the interventions and heterogeneity of study populations. However, considering that β-cell destruction in type 1 diabetes involves complex cooperation between the innate and adaptive immune systems (2), evolutionarily designed to provide foolproof protection of the host with redundant backup systems against environmental threats, we have been naïve in our belief that monotherapies would cure type 1 diabetes.

Although combination therapy for type 1 diabetes may increase efficacy and safety, clinical testing of drug combinations is a daunting enterprise. How do we decide on rational and safe combinations, doses, timing, and in which patients? How do we obtain regulatory approval, funding, and sufficient statistical power with the limited number of available patients? Is there solid preclinical evidence favoring a certain combination?

Animal models of type 1 diabetes have been rightly mocked for unjustified promise for prevention (3,4). However, few animal studies have shown reversal of overt diabetes (5), and therefore it is worth paying attention to these studies because of their relevance to the treatment not of at-risk patients, but of patients with disease of recent onset. In this issue, Pagni et al. (6) report one of these rare studies using transgenic mice with β-cell−specific expression of lymphocytic choriomeningitis virus in which diabetes is induced acutely by infecting the mice with the virus and thereby triggering an autoimmune response against the β-cells that express viral antigens. Interestingly, they report that intraperitoneal injection once weekly for 4 weeks with antibody against the key innate immune mediator interleukin-1β (IL-1β) potentiated the partial reversal of diabetes obtained by tolerizing immunization with the β-cell antigen GAD65, given as intramuscular DNA plasmid injections on days 0, 4, and 11 after disease onset.

Pagni et al. confirms the markedly potentiating effect of IL-1 antagonism on the partial reversal of autoimmune diabetes in the NOD mouse model obtained by administration of a deliberately suboptimal dose of a nondepleting antibody against the common T lymphocyte marker cluster of differentiation (CD) 3, which induces immune tolerance in recipient mice (7). In both studies, IL-1 antagonism alone caused no or insignificant reversal. The novelty of the study by Pagni et al. is that IL-1 antagonism potentiated β-cell antigen−specific tolerance induction. One strength of the article is its careful data analysis. Subjective stratification on baseline glucose using 400 mg/dL as surrogate threshold for β-cell function revealed that efficacy of the combination therapy was restricted to animals with glycemia below that threshold. More imaginatively, when analyzing noncured animals, combination therapy conferred milder and nonprogressive hyperglycemia.

A weakness of the studies by Pagni et al. (6) and Ablamunits et al. (7) is their lack of clear understanding of the mechanism of action by which IL-1 antagonism potentiates tolerance induction. IL-1 is believed to counteract immune-tolerance mainly by reducing differentiation of adaptive regulatory T cells, by costimulating antigen-specific proinflammatory T-cell helper (Th)1 and Th17 cell activation (811) and by stimulating target tissue immune infiltration by chemokine induction (8,12,13). Consistent comparisons between placebo-, mono-, and combination-arms allowed Ablamunits et al. (7) to propose that IL-1 antagonism synergizes with the anti-CD3−mediated increase in regulatory T cells and a Th1 to Th2 conversion by upregulating anti-inflammatory IL-10 production, possibly inducing a pro- to anti-inflammatory shift in the splenic CD11b/c+ macrophage/dendritic cell phenotype. Although the number of these cells was unaffected, the proportion of CD11b/c+ cells with an anti-inflammatory phenotype evidenced by the expression of arginase-1, an enzyme that breaks down L-arginine to urea, was increased by IL-1 antagonism alone and in combination. This may promote immune tolerance by preventing autoantigen presentation. This may also protect target β-cells from direct IL-1−mediated damage because IL-1 potently induces expression of β-cell inducible nitric oxide synthase (iNOS), an enzyme that generates toxic nitric oxide (NO) from conversion of L-arginine to -citrulline, and also reduces β-cell arginase-1 expression (1416). IL-1 antagonism thus would effectively block NO production by preventing iNOS expression and the availability of its substrate. This effect may explain the stunning rapidity of disease reversal observed (100% cure using IL-1β antibody and increased pancreatic insulin contents within 1 week post therapy), as it would be dependent on restoration of β-cell function, with restoration of mass expected to occur much later.

In the study by Pagni et al., the mechanisms of action underlying IL-1 antibody synergy with GAD tolerance induction are more difficult to tease apart because placebo and IL-1 antibody monotherapy comparisons are only carried out in a limited number of investigations. The contribution of GAD immunization was to reduce islet immune infiltration, likely by modestly increasing regulatory T cells and reducing splenic cytotoxic T-cell activity determined by their tumor necrosis factor (TNF) and interferon-γ production. IL-1 antibody alone had no effects on these parameters, but did synergize with GAD immunization in reducing pancreatic lymph node helper T cell IL-2 and cytotoxic T-cell TNF production. More strikingly, IL-1 antibody reduced the number of islet CD11b+/high and cytotoxic T cells. The CD11b+/high cells were not further phenotyped, in particular regarding arginase expression.

Thus, the mechanistic studies, incomplete as they are, suggest that IL-1 antagonism contributes to the tolerizing synergy primarily by reducing recruitment and/or activation of islet CD11b+/high macrophages, whereas anti-CD3 antibody or islet antigen immunization contributes mainly by T-cell regulation, jointly leading to reduced intraislet inflammation and expression of cytotoxic inflammatory mediators (Fig. 1).

Figure 1

Model of the mechanisms by which IL-1 antagonism (anti-IL-1) and GAD “vaccination” each contribute to synergize in tolerance induction in type 1 diabetes of recent onset. IL-1 antagonism reduces the recruitment and/or activation of islet CD11b+/high/Arg-1neg proinflammatory M1 macrophages. GAD vaccination induces regulatory T cells (Treg), leading to reduced activation and recruitment of cytotoxic T cells. Jointly M1- and T-cell regulation reduces intraislet inflammation and expression of β-cell cytotoxic inflammatory mediators IL-1, TNF-α, interferon-γ (IFN), and NO. Arg-1, arginase-1; Tc, cytotoxic T cell.

The studies by Pagni et al. (6) and Ablamunits et al. (7) have considerable clinical relevance as human trials have demonstrated that anti-CD3 therapy (17) or DNA plasmid-conveyed antigen-specific proinsulin tolerization (18) each transiently or partially improved β-cell function in recent-onset type 1 diabetic patients, and that although IL-1 antagonism as monotherapy was ineffective, it was safe (19). Therefore, there is now both a preclinical and clinical rationale to warrant human trials of the combination of IL-1 antagonism with antigen-specific or nonspecific adaptive immune modulations in type 1 diabetes of recent onset.

Article Information

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Footnotes

  • See accompanying article, p. 2015.

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References

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