Rapid CommunicationIL-18 binding protein fusion construct delays the development of diabetes in adoptive transfer and cyclophosphamide-induced diabetes in NOD mouse
Introduction
Type 1 diabetes mellitus (T1D) is a multifactorial syndrome clinically characterized by hyperglycemia that is due to the loss of insulin-producing beta cells [1], [2]. The pancreatic beta cells are thought to be selectively attacked and destroyed by autoreactive T cells and macrophages that mount a delayed type hypersensitive (DTH) response against multiple beta cell autoantigens [1], [2]. It has been suggested that the genetic predisposition to develop T1D may contribute to the preferential production in “high risk” individuals of large amounts of type 1 pro-inflammatory cytokines such as IL-1, IL-2, IL-12, IL-18, IFN-γ, and TNF-α that stimulate cellular effectors of DTH responses (T cells, macrophages, NK cells) [2]. Particular attention has been focused on the role of IL-1 beta, TNF-alpha, and IFN-γ as these cytokines are also capable of directly influencing beta cell function and viability in vitro [1], [2].
It has been proposed that during autoimmune diabetogenesis the endogenous cytokine network may be skewed towards an up-regulated type 1 pro-inflammatory cytokine profile along with (or secondary to) a reduced type 2 anti-inflammatory cytokine profile. This accords with clinical studies conducted in prediabetic individuals and newly diagnosed T1D patients as well as in rodent models of the disease such as the NOD mouse, the mouse made diabetic with multiple low doses of streptozotocin (MLDSZ), and the diabetes-prone BB rat [1], [2].
IL-18 is a type 1 pro-inflammatory cytokine produced by different cell types including macrophages, keratinocytes, Kupffer cells, and osteoblasts (reviewed in Ref. [3]) that share structural similarities with the IL-1 family of cytokines. Synergistically with IL-12, IL-18 stimulates the production of IFN-γ from T lymphocytes and the polarization of these cells toward a Th1 phenotype. The important role of IL-18 in the pathogenesis of type 1 cytokine-dependent autoimmune diseases has been highlighted by the beneficial effects of specific IL-18 inhibitors (the IL-18 binding protein [bp] and anti-IL-18 monoclonal antibody) in preclinical models of inflammatory bowel diseases [4], rheumatoid arthritis [5], immuno-inflammatory hepatitis [6], and Guillain Barrè syndrome [7]. Conversely, exogenously administered IL-18 exacerbates the course of type II collagen-induced arthritis [8] and systemic lupus erythematosus-like syndrome in mice [9].
That IL-18 may also play an important pathogenic role in T1D accords with most, but not all, lines of clinical and experimental evidence. Accordingly, while we have shown that augmented blood levels of IL-18 can be found in individuals at high risk for developing T1D [10], others have found that IL-18 (but not IL-18bp) gene promoter polymorphisms may occur in patients with T1D [11], [12], [13]. In particular, studying the single nucleotide polymorphisms of the promoter of IL-18 at positions −137 and −607, which are thought to regulate the activity of the IL-18 gene, the genotype distribution was found to significantly differ between patients with type 1 diabetes and control subjects [11].
Concordant data have also been obtained on the essential role of IL-18 in MLDSZ-induced diabetes [14], [15]. Studies in NOD mouse have shown that increased IL-18 expression occurs in islets during advanced stages of insulitis, and this correlated with elevated transcripts for IFN-γ and the IL-18 receptor [16]. In addition, the murine IL-18 gene maps to the Idd2 susceptibility locus, suggesting a potential role in predisposition to autoimmunity [17]. However, in spite of these data pointing to a central role for endogenous IL-18 in the development of autoimmune diabetes, treatment with IL-18 has been shown to either prevent [18] or accelerate [19] the onset of the disease in these mice.
Hence, we have tested the effects of a specific inhibitor of IL-18, the IL-18 BP:Fc Ig, in two models of accelerated diabetes in the NOD mouse, one induced by cyclophosphamide (CY) and the other by adoptive transfer of diabetogenic cells from syngeneic donors.
The results show that in both models a short prophylactic treatment with IL-18BP:FcIg resulted in a significant protection against development of the disease.
Section snippets
Animals
Studies on CY-induced diabetes were carried out in the animal house of the Department of Biomedical Sciences, University of Catania, on 10–14-week-old female NOD mice obtained from Charles River (Calco, Italy). The animals were kept under standard laboratory conditions (non-specific pathogen free), with free access to food and water, and they were allowed to adapt at least 1 week to their environment before starting the study. Studies on adoptively-transferred diabetes were carried out on NOD
IL-18 bp:FcIg delays adoptive transfer of T1D
Fig. 1 (A and B) clearly shows that daily treatment for 2 weeks with 150 μg of IL-18 bp:FcIg delays the onset of diabetes in both irradiated male NOD and female NOD-SCID mice. Since IL-18 bp:FcIg was administered only for 2 weeks, it is not clear whether the failure to generate a long-lasting effect was due to the short course of the treatment. To avoid a neutralizing antibody response against IL-18bp:Fc Ig, diabetogenic splenocytes were depleted of B cells and transferred into NOD-SCID
Discussion
The development of autoimmune diabetes can be accelerated in NOD mice by challenge with one or two large doses of CY or by adoptive transfer of spleen cells from diabetic mice to euglycemic lymphopenic syngeneic recipients. Both CY-induced and adoptively-transferred diabetes are characterized by high incidence, rapid onset of the disease with a well-defined kinetics. Previous studies by us and others have shown that IFN-γ [21] and IL-1 [22], [23] are essential mediators of these accelerated
Acknowledgments
We would like to thank Chris Bland for his technical assistance. We are also grateful to The Wellcome Trust and Diabetes UK for their support. This work was partly supported from 60% research funds from the University of Catania to Prof. Ferdinando Nicoletti.
References (27)
IL-18: a TH1-inducing proinflammatory cytokine and new member of the IL-1 family
J. Allergy Clin. Immunol.
(1999)- et al.
Association between IL-18 gene promoter polymorphism and CTLA-4 gene 49 A/G polymorphysm in Japanese patients with type 1 diabetes
J. Autoimmun.
(2004) - et al.
Lack of mediators of innate immunity attenuate the development of autoimmune diabetes in mice
J. Autoimmun.
(2003) - et al.
Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu
Cytokine Growth Factor Rev.
(2001) An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus
Diabetes Metab. Rev.
(1998)- et al.
Choice of death- the signal-transduction of immune-mediated β-cell apoptosis
Diabetologia
(2001) - et al.
Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage
Gut
(2002) - et al.
Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis
J. Clin. Invest.
(2001) - et al.
IL-18 binding protein protects against lipopolysaccharide-induced lethality and prevents the development of Fas/Fas ligand-mediated models of liver disease in mice
J. Immunol.
(2001) - et al.
Neutralizing antibodies to IL-18 ameliorate experimental autoimmune neuritis by counter regulation of autoreactive Th1 responses to peripheral myelin antigen
J. Neuropathol. Exp. Neurol.
(2002)
A proinflammatory role for IL-18 in rheumatoid arthritis
J. Clin. Invest.
A proinflammatory role of IL-18 in the development of spontaneous autoimmune disease
J. Immunol.
Serum levels of the interferon-g-inducing cytokine interleukin-18 are increased in individuals at high risk of developing type 1 diabetes
Diabetologia
Cited by (34)
Vitamin D and type 1 diabetes
2023, Feldman and Pike's Vitamin D: Volume Two: Disease and TherapeuticsInflammatory cytokines and appetite in older hospitalized patients
2021, AppetiteCitation Excerpt :Future studies focusing on IL-18 as a target should consider appetite and weight change to clarify the proposed anorexigenic effect in interventional trials. As an example, IL-18 binding protein (IL-18BP) and Caspase-1 Inhibitor i.e. pralnacasan (Faggioni et al., 2001; Harms, Creer, Lorenzo-Arteaga, Ostlund, & Sarvetnick, 2017; He et al., 2008; Howley & Fearnhead, 2008; Zaccone, Phillips, Conget, Cooke, & Nicoletti, 2005) have been considered as an anti-inflammatory intervention in animal models, specially acting on the IL-18 pathway. In addition, appetite, which is a subjective phenomenon, is different from food intake.
IL-18/IL-18BP and IL-22/IL-22BP: Two interrelated couples with therapeutic potential
2019, Cellular SignallingStandardized bovine colostrum derivative impedes development of type 1 diabetes in rodents
2017, ImmunobiologyCitation Excerpt :According to the results of this study, which demonstrated reduced IL-23 and IL-6 gene expression, it could be speculated that SBCD-mediated interference with Th17 cells is most probably at the level of their propagation and/or differentiation. Also, many attempts have been made in order to lessen the pathogenic Th17/Th1 response and strenghten the anti-inflamatory Th2/Treg immunity (Saksida et al., 2014), including the use of specific inhibitors of IFN-γ (Nicoletti et al., 1997) or IL-18 (Zaccone et al., 2005; Nicoletti et al., 2003) or the administration of type 2 cytokines such as IL-13 (Zaccone et al. 1999). In our work, protection from T1D by SBCD treatment was found to be associated at least partly with a selective decrease of Th1 cells in the spleen, and upregulation of Th2 phenotype.
Increased expression of IL-18 in the serum and islets of type 1 diabetics
2015, Molecular ImmunologyCitation Excerpt :IL-18 activity and resultant IFN-γ production is inhibited by the IL-18 binding protein (IL-18BP) (Kim et al., 2000). Zaccone et al. (2005) reported that an IL-18BP fusion construct delayed diabetes development in NOD mice, and IL-18BP transgenic mice display extended normoglycemia while the transgenic islets are safeguarded against streptozotocin-induced apoptosis (Lewis and Dinarello, 2006). Furthermore, a second cytokine within the IL-1 family, IL-37, can bind to IL-18BP and enhance its IL-18-inhibitory function (Bufler et al., 2002; Dinarello and Bufler, 2013).
Novel T-cell inhibiting peptides delay the onset of Type 1 diabetes in non-obese diabetic mice
2014, Diabetes and MetabolismCitation Excerpt :The problem with both of these is rejection of the graft or islets, and the secondary complications arising from the use of immunosuppressive therapy, such as prednisone, tacrolimus and cyclosporin. Newer approaches and agents such as interleukin (IL)-18 and IL-7Ra inhibitors, have being used and examined with limited success [5,6]. Core peptide (CP; GLRILLLKV) is a novel immunosuppressive peptide that has the potential to treat T1D by inhibiting the activation of T-cells, and thus the T-cell mediated destruction of islets.