Mucosal Tolerance to Prevent Type 1 Diabetes: Can the Outcome Be Improved in Humans?

MediCity Research Laboratory, University of Turku and National Public Health Institute, Tykistökatu 6, FIN-20520 Turku, Finland.
The Review of Diabetic Studies 02/2004; 1(3):113-21. DOI: 10.1900/RDS.2004.1.113
Source: PubMed


The results of trials in which autoantigens have been fed to individuals affected by autoimmune diseases - multiple sclerosis, rheumatoid arthritis and type 1 diabetes - have been disappointing in terms of clinical improvement. This is in striking contrast to the results in experimental rodent models of these diseases. The outcome of the recent DPT-1 trial testing oral insulin in individuals at risk of type 1 diabetes was also disappointing, in contrast to the effects of oral insulin in the non-obese diabetic (NOD) mouse model of type 1 diabetes. However, it is premature to conclude that mucosal tolerance works only in in-bred rodents and not in humans with autoimmune disease. Except for oral insulin in DPT-1, the human trials were performed in individuals with end-stage disease when this form of immune regulation might not be expected to be effective. Importantly, in no trial was an immune response to the autoantigen documented, to demonstrate that the dose was at least bioavailable. Furthermore, mucosal autoantigen administration is a 'double-edged sword' and in rodents can lead not only to regulatory and protective immunity but also to pathogenic, tissue-destructive immunity and exacerbation of autoimmune disease. When suppression of autoimmune disease is observed it may be because autoantigen was administered under conditions which minimize induction of pathogenic immunity. Thus, clinical protocols for mucosal autoantigen administration may need to be modified to favor induction of regulatory immunity. In this short review, we discuss recent studies in autoimmune diabetes-prone NOD mice indicating that with novel modifications mucosal autoantigen administration could be harnessed to prevent type 1 diabetes in humans.

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Available from: Leonard Charles Harrison, Mar 03, 2014
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    • "GAD65/alum failed to show a protective effect [10], [36]–[38]. Also in other autoimmune diseases, human trials with oral autoantigens have not led to satisfactory outcomes - (reviewed in [39]. "
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    ABSTRACT: Induction of long-term tolerance to β-cell autoantigens has been investigated both in animal models and in human type 1 diabetes (T1D) in order to prevent the disease. As regards external compounds, the dietary plant protein fraction has been associated with high penetrance of the disease, whereas gluten-free diets prevent T1D in animal models. Herewith we investigated whether intranasal (i.n.) administration of gliadin or gluten may arrest the diabetogenic process. I.n. administration of gliadin to 4-week-old NOD mice significantly reduced the diabetes incidence. Similarly, the insulitis was lowered. Intranasal gliadin also rescued a fraction of prediabetic 13-week-old NOD mice from progressing to clinical onset of diabetes compared to OVA-treated controls. Vaccination with i.n. gliadin led to an induction of CD4+Foxp3+ T cells and even more significant induction of γδ T cells in mucosal, but not in non-mucosal lymphoid compartments. This prevention strategy was characterized by an increased proportion of IL-10 and a decreased proportion of IL-2, IL-4 and IFN-γ-positive CD4+Foxp3+ T cells, and IFN-γ-positive γδ T cells, preferentially in mucosal lymphoid organs. In conclusion, i.n. vaccination with gliadin, an environmental antigen with possible etiological influence in T1D, may represent a novel, safer strategy for prevention or even early cure of T1D.
    PLoS ONE 04/2014; 9(4):e94530. DOI:10.1371/journal.pone.0094530 · 3.23 Impact Factor
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    • "Ingestion of antigen, including the putative RA autoantigen collagen II [24], has been shown to induce inhibition of both T and B cell responses in a specific manner [25] [26]. Remission of disease in animal models of RA [27], multiple sclerosis [28], and type I diabetes [29], has been reported by oral administration of autoantigens. Anterior chamber associated immune deviation (ACAID) is a phenomena in which local implantation of antigen results in a systemic immune modulation towards the antigen. "
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    ABSTRACT: Since the days of Medawar, the goal of therapeutic tolerogenesis has been a "Holy Grail" for immunologists. While knowledge of cellular and molecular mechanisms of this process has been increasing at an exponential rate, clinical progress has been minimal. To provide a mechanistic background of tolerogenesis, we overview common processes in the naturally occurring examples of: pregnancy, cancer, oral tolerance and anterior chamber associated immune deviation. The case is made that an easily accessible byproduct of plastic surgery, the adipose stromal vascular fraction, contains elements directly capable of promoting tolerogenesis such as T regulatory cells and inhibitory macrophages. The high content of mesenchymal and hematopoietic stem cells from this source provides the possibility of trophic/regenerative potential, which would augment tolerogenic processes by decreasing ongoing inflammation. We discuss the application of this autologous cell source in the context of rheumatoid arthritis, concluding with some practical examples of its applications.
    Cellular Immunology 01/2010; 264(1):7-17. DOI:10.1016/j.cellimm.2010.04.002 · 1.92 Impact Factor
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    • "Based on experimental data, there are compelling reasons to pursue mucosal tolerance as a therapy for patients with a variety of autoimmune diseases. The results of clinical studies to date, however, have been disappointing [20,21]. While there are many potential explanations for the failure of mucosal tolerance in clinical trials, there is concern that mucosal administration of antigen can, at least in some instances, lead to detrimental autoimmunity. "
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    ABSTRACT: An inflammatory insult following middle cerebral artery occlusion (MCAO) is associated with a predisposition to develop a deleterious autoimmune response to the brain antigen myelin basic protein (MBP). Induction of immunologic tolerance to brain antigens prior to MCAO prevents this deleterious autoimmune response and is associated with better functional outcome early after stroke. In this study, we sought to determine the long term immunologic consequences of experimental stroke and induction of mucosal tolerance. Male Lewis rats were tolerized to MBP or ovalbumin (OVA) by intranasal administration prior to MCAO and administration of lipopolysaccharide (LPS). Neurological outcome was assessed at set points after MCAO and animals sacrificed at 3 months; the immune response to MBP in brain and spleen was determined using ELISPOT assay and degree of cellular inflammatory brain infiltrate assessed by immunocytochemistry. Animals that developed a pro-inflammatory (TH1) response to MBP experienced worse outcome, while those that developed a regulatory response (TREG) experienced better outcome. A TREG response in spleen was also associated with decreased inflammation and an increase in the number of FoxP3 positive cells in brain. In this study, tolerization to MBP prior to MCAO was associated with a tendency to develop a TH1 response to MBP by 3 months after MCAO. These data show that induction of immunological tolerance to MBP is associated with improved outcome after stroke. This study, however, raises concern about the potential for inadvertent induction of detrimental autoimmunity through mucosal administration of antigen.
    Experimental and Translational Stroke Medicine 10/2009; 1(1):3. DOI:10.1186/2040-7378-1-3
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