Monoclonal antibody blocking the recognition of an insulin peptide–MHC complex modulates type 1 diabetes

Zhang, Li; Crawford, Frances; Yu, Liping; Michels, Aaron; Nakayama, Maki; Davidson, Howard W.; Kappler, John W.; Eisenbarth, George S.

doi:10.1073/pnas.1323436111

Cited by 59 publications

(81 citation statements)

References 59 publications

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“…Therefore, because of its superagonist properties, the potential exists to use the insulin B22E mimotope as a tolerogenic vaccine in those at risk for T1D. In other studies, antibodies specific for the register 3 B:9-23/IA g7 complex inhibit T-cell responses in vitro and delay T1D onset in vivo in NOD mice (31,32), opening another potential avenue for antigen-specific therapy. Our results also raise the possibility that individuals with a β57D + -containing DQ allele may have the ability to produce a regulatory response to the insulin epitope.…”

Section: Discussionmentioning

confidence: 99%

Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

Nakayama

McDaniel

Fitzgerald-Miller

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9-23) mimotopes engineered to bind the mouse MHCII molecule, IA g7 , in an unfavorable position or register. Because of the similarities between IA g7 and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9-23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-γ response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9-23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulinspecific therapies to prevent diabetes onset.T ype 1 diabetes (T1D), the autoimmune form of diabetes, results from T cell-mediated destruction of insulin-producing β-cells within pancreatic islets (1). The disease is dramatically increasing in incidence, doubling in the last two decades (2, 3), and now predictable with the measurement of antibodies directed against insulin and other proteins found in β-cells (4). Major efforts at disease prevention have been undertaken using preparations of insulin (s.c., oral, and intranasal) to induce tolerance and delay the onset of clinical symptoms (5-7). Measuring insulin-specific T-cell responses from the peripheral blood has been challenging but would allow for assessment of therapeutic response, which has been a major obstacle in these trials. In our study, we sought to detect peripheral T-cell responses to insulin in T1D patients and nondiabetic controls using a modified insulin B-chain peptide.Insulin is a major self-antigen for both T and B cells in murine and human T1D, with insulin B-chain amino acids 9-23 (B:9-23) being a key epitope presented by major histocompatibility complex class II (MHCII) molecules to CD4 T cells targeting pancreatic β-cells (8-10). There is strong evidence from the nonobese diabetic (NOD) mouse model of spontaneous autoimmune diabetes that the NOD MHCII molecule, IA g7 , is required for development of T1D and that pathogenic CD4 T cells recognize insulin B:9-23 presented in an unfavorable position or register (Reg3) in the IA g7 peptide binding groove (9, 11,...

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Section: Discussionmentioning

confidence: 99%

Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

Nakayama

McDaniel

Fitzgerald-Miller

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…The NOD (J001976) mouse colony, which was the same colony used in most of the other published studies (71)(72)(73), was purchased from The Jackson Laboratory and maintained in a strict specific pathogen-free (SPF) barrier facility at the Model Animal Research Center of Nanjing University. Both male and female NOD mice were tested regularly (at least every 3 months) for microbiological screening when housed at the barrier facility.…”

Section: Methodsmentioning

confidence: 99%

ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity

Bi¹,

Li²,

Liu³

et al. 2017

Journal of Clinical Investigation

108

105

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“…The interaction between the components of the trimolecular complex (CD4 + T cell receptors, self-peptide, and MHC class II molecules) plays a pivotal role in autoimmune disease pathogenesis. The development of therapies targeting various components of the trimolecular complex for the prevention of type 1 diabetes is actively being pursued (Michels, 2013; Zhang et al, 2014). …”

Section: Genetic Susceptibilitymentioning

confidence: 99%

Immunogenetics of type 1 diabetes mellitus

Morran

Vonberg

Khadra

et al. 2015

Molecular Aspects of Medicine

120

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Type 1 diabetes mellitus (T1DM) is an autoimmune disease arising through a complex interaction of both genetic and immunologic factors. Similar to the majority of autoimmune diseases, T1DM usually has a relapsing remitting disease course with autoantibody and T cellular responses to islet autoantigens, which precede the clinical onset of the disease process. The immunological diagnosis of autoimmune diseases relies primarily on the detection of autoantibodies in the serum of T1DM patients. Although their pathogenic significance remains uncertain, they have the practical advantage of serving as surrogate biomarkers for predicting the clinical onset of T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects, (i.e. HLA) and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3) or DRB1*04-DQB1*0302 (DR4)]. In addition, HLA alleles such as DQB1*0602 are associated with dominant protection from T1DM in multiple populations.A discordance rate of greater than 50% between monozygotic twins indicates a potential involvement of environmental factors on disease development. Viral infections may play a role in the chain of events leading to disease, albeit conclusive evidence linking infections with T1DM remains to be firmly established. Two syndromes have been described in which an immunemediated form of diabetes occurs as the result of a single gene defect. These syndromes are termed autoimmune polyglandular syndrome type I (APS-I) or autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy (APECED), and X-linked poyendocrinopathy, immune dysfunction and diarrhea (XPID). These two syndromes are unique models to understand the mechanisms involved in the loss of tolerance to self-antigens in autoimmune diabetes and its associated organ-specific autoimmune disorders. A growing number of animal models of these diseases have greatly helped elucidate the immunologic mechanisms leading to autoimmune diabetes.

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Monoclonal antibody blocking the recognition of an insulin peptide–MHC complex modulates type 1 diabetes

Cited by 59 publications

References 59 publications

Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity

Immunogenetics of type 1 diabetes mellitus

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