Ingested interferon α suppresses Type I diabetes in non-obese diabetic mice

Abstract

Many key features of human Type I diabetes are reflected in the non-obese diabetic (NOD) mouse model. These include the development of insulitis, with infiltration of lymphocytes that are selectively cytotoxic to the insulin producing beta cells into the pancreatic islets of Langerhans, the dependence of disease pathogenesis by T cells, and the transmission of Type I diabetes by haematopoietic cells in bone marrow [1±5].Experimental autoimmune encephalomyelitis (EAE) is an animal model for the presumed autoimmune disease multiple sclerosis. We have previously shown that ingested type 1 interferon (IFN) inhibits chronic relapsing EAE, inhibits the adoptive transfer of EAE by T cells, decreases both antigen-specific and mitogen-induced pro-inflammatory cytokine secretion and decreases serum soluble intercellular adhesion molecule 1 (sICAM-1) levels, a marker for subclinical disease activity, in multiple sclerosis without the absorption of ingested IFN [6±8].The NOD mouse [9±11] model is mechanistically analogous to the EAE animal model because both are presumed to be mediated by a T cell subset, and depend on restriction elements and inflammatory cy- Diabetologia (1998) Summary Type I diabetes mellitus is a chronic disorder that results from autoimmune destruction of the insulin-producing pancreatic beta cell. The nonobese diabetic mouse is a model of the human autoimmune disease Type I diabetes [1±3]. We have previously shown that ingested type 1 interferon inhibits chronic relapsing experimental autoimmune encephalomyelitis and the adoptive transfer of experimental autoimmune encephalomyelites by T cells, and decreases both antigen-specific and mitogen-induced pro-inflammatory cytokine secretion in this disorder. We therefore tried to determine whether ingested murine interferon a inhibits insulinitis and suppresses Type I diabetes mellitus in non-obese diabetic mice. Murine interferon a, given daily, decreased islet inflammation and suppressed diabetes. It increased the concanavalin A and ionomycin plus myristic acid palmitic ester-induced production of interleukin 4 and 10 and interferon g-secretion in spleen cells from treated mice. Adoptive transfer of unstimulated splenocytes secreting interleukin 4 and interleukin 10 from fed interferon a donors suppressed spontaneous diabetes mellitus in recipients. The protective effect of adoptively transferred unstimulated splenocytes shows the presence of ingested interferon a-activated regulatory splenic cell populations that may work via increased interleukin 4 or interleukin 10 production. Ingested interferon a administered during vulnerable periods in at-risk populations may potentially provide a continuous, convenient, non-toxic and effective treatment for Type I diabetes. [Diabetologia (1998) 41: 1227±1232]Keywords Non-obese diabetic mouse, ingested interferon a, interleukin 4, interleukin 10, adoptive transfer

Interferon-α initiates type 1 diabetes in nonobese diabetic mice

“…Previous studies have shown that oral IFN-␣ treatment of NOD mice 5 week or older significantly suppressed the development of insulitis and diabetes (15,16). By 5 weeks of age, however, the principal autoimmune responses have already been established in the PLNs (1).…”

“…Additionally, IFN regulatory factor 1-deficient NOD mice failed to develop insulitis and diabetes (14). However, some studies have shown that oral treatment of prediabetic NOD mice with IFN-␣ suppressed insulitis and diabetes (15,16). Thus, the role that IFN-␣ plays in the pathogenesis of T1D in NOD mice is controversial.…”

Induction of oral tolerance to prevent diabetes with transgenic plants requires glutamic acid decarboxylase (GAD) and IL-4

“…Recently, oral IFN-␣ has been studied in type I diabetes. IFN-␣ delivered orally suppressed disease and increased mitogen-induced IL-4 and IL-10 production in spleen cells from treated mice, raising the possibility that the protective effect may involve induction of protective Th2 cytokines (12). In early uncontrolled clinical trials with oral IFN-␣, newly diagnosed type I diabetic patients showed some preservation in beta cell function over time (34).…”

“…Consistent with this concept, attenuated expression of IL-4 has been suggested to contribute to autoimmune diabetes (10) whereas overexpression of IL-4 in pancreas has prevented insulitis and diabetes in NOD mice (11). Cytokines can resist gastrointestinal degradation and retain biological effect when administered orally because oral IFN-␣ can attenuate autoimmune diabetes by a non-antigen-specific mechanism (12). IL-4 is unlikely to induce neutralizing antibody responses, being an endogenous protein, but would not be an ideal candidate as a mucosal adjuvant to enhance responses with coadministered antigen unless its function was maintained after oral delivery.…”

Oral administration of interferon-β suppresses experimental autoimmune uveoretinitis

“…Oral type I IFNs have been reported to reduce the severity of inflammation in several animal models of autoimmune disease such as experimental autoimmune encephalomyelitis (EAE) in mice [7,8] and rats [9], non-obese diabetic (NOD) mice [11] and collagen-induced arthritis [36]. Oral administration of type I IFNs have also been shown to be effective in patients with multiple sclerosis [10], rheumatoid arthritis, insulin-dependent diabetes mellitus [6] and Sjög-ren's syndrome [31].…”