<i>Idd</i>Loci Synergize to Prolong Islet Allograft Survival Induced by Costimulation Blockade in NOD Mice

Mangada, Julie; Pearson, Todd; Brehm, Michael A.; Wicker, Linda S.; Peterson, Laurence B.; Shultz, Leonard D.; Serreze, David; Rossini, Aldo A.; Greiner, Dale L.

doi:10.2337/db08-0275

Cited by 15 publications

(9 citation statements)

References 53 publications

(70 reference statements)

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“…In vivo transplantation with IFA treatment alone does not result in any statistically significant increase in allograft survival (Fig. 3), confirming the importance of an optimal level of IFN-γ for allograft acceptance (15,19,25). This concept is also supported by the work of Konieczny et al and Markees et al, which reveal that IFN-γ is required for graft acceptance, signifying that our negative vaccination allows for levels of IFN-γ sufficient for allograft acceptance (16,20), while immunosuppressive treatments tend to flatline IFN-γ levels.…”

Section: Discussionsupporting

confidence: 52%

Administration of a Negative Vaccination Induces Hyporesponsiveness to Islet Allografts

et al. 2013

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As a result of less than optimal outcomes the use of islet allografts as a standard insulin replacement therapy is limited to adults with a history of extreme glucose dysregulation and hypoglycemia unawareness. In this study, we examined the use of prophylactic immunotherapy to prevent islet allograft rejection in the absence of antirejection drugs. Our protocol to achieve allograft acceptance used a negative vaccination strategy that is comprised of apoptotic donor cells delivered in Incomplete Freund’s Adjuvant (IFA) 1 week prior to islet transplantation. The goal of this new protocol is to elicit hyporesponsiveness to alloantigen prior to islet transplantation. First, we examined our protocol without islet allograft transplants and determined that the negative vaccination was not globally immunosuppressive or immunostimulatory. Islet allograft experiments using fully MHC-mismatched islet donors and recipients demonstrated that the negative vaccination strategy induced long-term islet allograft acceptance. Upon rechallenge with alloantigen, the negative vaccination protocol successfully achieved hyporesponsiveness. In addition, the microenvironment at the site of the tolerant allograft revealed a decrease in proinflammatory mediators (IFN-γ, TNF-α) and an increase in the anti-inflammatory mediator IL-10, as well as increased expression of the master regulator of T-regulatory cells, FOXP3. Our data suggest that pretreating allograft recipients with apoptotic donor alloantigen delivered in IFA induced long-term islet allograft acceptance and glycemic control by introducing alloantigen to the recipient immune system in a nonimmunostimulatory manner prior to transplant.

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Section: Discussionsupporting

confidence: 52%

Administration of a Negative Vaccination Induces Hyporesponsiveness to Islet Allografts

et al. 2013

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“…Interestingly, in the islet cell–vaccinated group, there was an increase in the TH1-dependent cytokine IFN- γ , which also peaked at the 13-week time point. Recent work has demonstrated the need for IFN- γ in order for regulatory T cells to exert their functions [39, 40]. Therefore, the production of IFN- γ in the negatively vaccinated mice may play an important role in facilitating the formation of immune tolerance through controlling regulatory T cell function.…”

Section: Discussionmentioning

confidence: 99%

A multivalent vaccine for type 1 diabetes skews T cell subsets to Th2 phenotype in NOD mice

et al. 2011

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Previous studies by our group, using an experimental autoimmune thyroiditis (EAT) model in Strain 13 inbred guinea pigs, resulted in T cell-mediated delayed hypersensitivity; however, autoantibodies proved not to be cytotoxic to thyroid epithelial cells in the presence or absence of complement proteins. Albeit, T cell-mediated lymphocyte cytotoxicity began to diminish sharply concomitantly with increasing titers of circulating autoantibodies, indicating a skewing of the self-reactive response and amelioration of the EAT. Furthermore, immunization of guinea pigs with thyroglobulin in incomplete Freund’s adjuvant (IFA) generated a high titer of antithyroglobulin antibodies and proved to inhibit thyroiditis. These observations indicated that the shift in the immune response from Th1 to Th2 and the production of antibodies were likely responsible for ameliorating EAT. Based upon these results, we extrapolated our studies to design a multivalent vaccine, which shows promise in preventing/reversing T1D in NOD mice. A small pilot study was conducted in which a total of 34 mice, 20 non-immunized controls and 14 immunized with syngeneic islet lysate, were monitored for mean day to diabetes for a total of 28 weeks. Immunization of NOD animals with syngeneic islet lysates resulted in a significant delay in diabetes onset (P < 0.001) as compared to non-immunized controls. To further assess the vaccine’s efficacy, robustness, and delay of disease, a large-scale experiment was conducted and monitored for 32 weeks using 106 mice, 64 non-immunized controls and 42 immunized with syngeneic islet lysate. At the end of the study, 90% of the non-immunized group developed diabetes, while less than 25% of the immunized group became diabetic (P < 0.0001). The protective effect, as a result of vaccination, correlated with an increase in the levels of IL-10 and IL-4 cytokines as well as a skewing to Th2-dependent isotype antibodies in serum. Strikingly, adoptive transfer of spleen cells from immunized animals into NOD.scid recipients provided protection against transfer of diabetes by diabetogenic spleen cells. The results of this study provide evidence that vaccination with islet lysate leads to a Th2-dependent skewing of the immune response to islet beta cells as a possible mechanism of protection. This strategy may be implemented as a possible vaccination protocol for arresting and/or preventing T1D in patients.

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“…But, whereas susceptibility in humans relates to the IL2RA gene region, variants in the NOD are in the IL-2 gene (in Idd3) (259,339). Consistent with an indispensible role for proper IL-2 signaling to prevent T1D, several reports have documented the correlation of Idd3 with decreased IL-2 levels leading to impaired tolerance induction and Treg functionality (160,269,272,332,390). Taken together, this degree of similarity between two evolutionary distinct species emphasizes the critical role of the IL-2 pathway in maintaining self-tolerance.…”

Section: H Parallels Between Human Genetics and Genetics Of The Nod mentioning

confidence: 99%

Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies

Belle

Coppieters

Herrath

2011

Physiological Reviews

854

695

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Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D.

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IddLoci Synergize to Prolong Islet Allograft Survival Induced by Costimulation Blockade in NOD Mice

Cited by 15 publications

References 53 publications

Administration of a Negative Vaccination Induces Hyporesponsiveness to Islet Allografts

Administration of a Negative Vaccination Induces Hyporesponsiveness to Islet Allografts

A multivalent vaccine for type 1 diabetes skews T cell subsets to Th2 phenotype in NOD mice

Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies

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