Cytokine profile and insulin antibody IgG subclasses in patients with recent onset Type 1 diabetes treated with oral insulin

Abstract

Aims/hypothesis. Tolerance to orally administered antigens may be generated through the induction of T helper cell type 2 and 3 (Th2/Th3) regulatory cells. We previously reported that treatment of recent onset Type 1 diabetes with oral insulin had no effect on residual beta cell function. The aim of this study was to evaluate whether this treatment produces a deviation in the immune response, with polarisation of the cytokine pattern and the induction of a Th2-like antibody response. Methods. Mononuclear cells were collected from a total of 20 patients with Type 1 diabetes before and after 12 months of treatment with oral insulin (n=11) or placebo (n=9). Following stimulation of the cells with insulin or phytohaemagglutinin, levels of Th2 and Th3 cytokines (including TGF-β, IFN-γ, IL-4 and IL-5) in the culture supernatants were assessed by ELISA. In addition, levels of total and specific insulin antibody IgG subclasses were measured by radioimmunoassay in serum samples drawn from 33 patients with Type 1 diabetes before and after 3, 6 and 12 months of therapy with oral insulin (n=18) or placebo (n=15). Results. After 12 months of treatment, the release of TGF-β was significantly higher in patients who received oral insulin compared with those who received placebo (p=0.025 and p=0.006 for lymphocytes challenged with insulin and phytohaemagglutinin respectively). The two groups had similar levels of IL-4 and IL-5 both at baseline and after 12 months of treatment. The release of IFN-γ was markedly reduced in patients treated with oral insulin compared with those who received placebo at the 12-month follow-up. Circulating levels of IgG1 and IgG3 subclasses directed against insulin were significantly lower in the oral insulin group than in the placebo group after 12 months of treatment (p=0.05 for IgG1 and p=0.014 for IgG3). Conclusions/interpretation. The increased TGF-β release observed in patients treated with oral insulin suggests that a regulatory response can be induced in vivo by this treatment. The lower levels of insulin antibody IgG1 and IgG3 subclasses present in patients exposed to oral insulin are consistent with a Th2 deviation of the immune response. The failure of oral insulin treatment to provide any measurable clinical benefit may be due to the timing of treatment initiation.

Oral or Nasal Antigen Induces Regulatory T Cells That Suppress Arthritis and Proliferation of Arthritogenic T Cells in Joint Draining Lymph Nodes

“…Mucosal tolerance has been proposed as a means to induce Ag-specific protection in inflammatory diseases, ranging from autoimmune disease to transplant rejection and allergy (3,4). However, successful translation of prevention of disease in animal models to therapeutic application in human disease proved to be difficult (5)(6)(7)(8)(9)(10)(11). The disappointing outcome of clinical trials can be explained by several facts, such as: the trials were performed in end-stages of disease; the patient populations studied were inherently diverse; and there was a lack of pretreatment screening to determine whether the Ag was immunologically relevant in patients to be treated.…”

Modulating the natural history of type 1 diabetes in children at high genetic risk by mucosal insulin immunization

“…Intranasal insulin has been given to islet autoantibody-positive subjects as young as 2 years of age without side effects [28,29]. Immunologic studies suggested some modulation of immune response to insulin in these studies [28,43]. The INIT I (Intranasal Insulin Trial) in particular showed that administration of intranasal insulin was associated with an overall increase in antibodies and a decrease in T-cell responses to insulin [28], similar to that seen in the mouse model.…”

“…Two studies in patients with new-onset T1DM administering insulin orally at doses ranging from 2.5 to 7.5 mg/d (together with standard insulin replacement therapy) could not demonstrate obvious benefit in preserving residual -cell function [26,27]. However, one of these studies demonstrated increases in the regulatory cytokine TGF- [43]. In a cohort of 372 prediabetic islet cell antibody-and IAApositive relatives of T1DM patients aged 3 to 45 years, no significant beneficial effects were achieved by administering oral insulin, 7.5 mg/d [9•].…”

Evaluation of the natural killer cytotoxicity and the levels of cytokines in rats with type I diabetes mellitus

“…Hayashi et al (1998) also suggested that IFN-γ might play a role in islet inflammation leading to islet cell destruction. Monetini et al (2004) informed that the release of IFN-γ was markedly reduced in patients treated with oral insulin.…”