Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide

Martinez, Nathan R.; Augstein, Petra; Moustakas, Antonis K.; Papadopoulos, George K.; Gregori, Silvia; Adorini, Luciano; Jackson, Daniel M.; Harrison, Leonard C.

doi:10.1172/jci17166

Cited by 55 publications

(59 citation statements)

References 41 publications

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“…This overlap of MHC class I and class II epitopes, called 'combitope', potentially adds significance for immunotherapy. 45,46 Notably, the InsB11-23-extended epitope has very hydrophobic solvent-contact residues (and thus potential TCR contact residues). From peptide extraction studies of DQ2cis, we know that a hydrophobic residue can be present at several positions within the binding core of DQ2cis.…”

Section: Discussionmentioning

confidence: 99%

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

et al. 2011

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Human leukocyte antigen (HLA) class II haplotypes are established risk factors in type 1 diabetes (T1D). The heterozygous DQ2/8 genotype confers the highest risk, whereas the DQ6/8 genotype is protective. We hypothesized that DQ2/8 transmolecules composed of a and b chains from DQ2 and DQ8 express unique b-cell epitopes, whereas DQ6 may interfere with peptide binding to DQ8. Here we show that a single insulin epitope (InsB13-21) within the T1D prototype antigenic InsB6-22 peptide can bind to both cis-and trans-dimers, although these molecules display different peptide binding patterns. DQ6 binds a distinct insulin epitope (InsB6-14). The phenotype of DQ8-restricted T cells from a T1D patient changed from proinflammatory to anti-inflammatory in the presence of DQ6. Our data provide new insights into both susceptible and protective mechanism of DQ, where protecting HLA molecules bind autoantigens in a different (competing) binding register leading to 'epitope stealing', thereby inducing a regulatory, rather than a pathogenic immune response.

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Section: Discussionmentioning

confidence: 99%

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

et al. 2011

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“…Several studies have shown that prevention of diabetes can be achieved in animal models by the down-regulation of autoreactive T cells after administration of immunodominant peptides derived from the major ␤ cell antigens. Prevention of diabetes in animal models has been achieved through oral, intranasal, i.v., or s.c. administration of B9 peptide from the insulin B chain (39), peptide B24-C36 from proinsulin (7,40), peptides from glutamic acid decarboxylase 65 (41)(42)(43), or peptides from the heat-shock protein hsp60 (44,45). However, the short half-life of peptides in the circulation and the need for repeated administrations are some of the limitations of peptide therapy.…”

Section: Discussionmentioning

confidence: 99%

Autoreactive CD8 T cells associated with β cell destruction in type 1 diabetes

Pinkse

Tysma

Bergen

et al. 2005

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

260

251

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Type 1 diabetes is a T cell-mediated autoimmune disease, and insulin is an important target of the autoimmune response associated with ␤ cell destruction. The mechanism of destruction is still unknown. Here, we provide evidence for CD8 T cell autoreactivity associated with recurrent autoimmunity and loss of ␤ cell function in type 1 diabetic islet transplant recipients. We first identified an insulin B chain peptide (insB10-18) with extraordinary binding affinity to HLA-A2(*0201) that is expressed by the majority of type 1 diabetes patients. We next demonstrated that this peptide is naturally processed by both constitutive and immuno proteasomes and translocated to the endoplasmic reticulum by the peptide transporter TAP1 to allow binding to HLA-A2 in the endoplasmic reticulum and cell surface presentation. Peripheral blood mononuclear cells from a healthy donor were primed in vitro with this peptide, and CD8 T cells were isolated that specifically recognize target cells expressing the insulin B chain peptide. HLA-A2 insB10-18 tetramer staining revealed a strong association between detection of autoreactive CD8 T cells and recurrent autoimmunity after islet transplantation and graft failure in type 1 diabetic patients. We demonstrate that CD8 T cell autoreactivity is associated with ␤ cell destruction in type 1 diabetes in humans.insulin ͉ islet transplantation ͉ cytotoxic T lymphocyte ͉ tetramer

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“…In contrast, the weak binding segment (encompassing the 1-11 residue) escapes negative selection. Of note, a peptide from mouse proinsulin, B24-C36 has been reported to bind to soluble I-A g7 with relatively good binding affinity (39).…”

Section: Discussionmentioning

confidence: 99%

The Insulin-Specific T Cells of Nonobese Diabetic Mice Recognize a Weak MHC-Binding Segment in More Than One Form

Levisetti

Suri

Petzold

et al. 2007

The Journal of Immunology

108

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Several naturally occurring anti-insulin CD4 T cells were isolated from islet infiltrates of NOD mice. In accordance with the results of others, these T cells recognized the segment of the β-chain from residues 9–23. Peptides encompassing the B:(9–23) sequence bound weakly to I-Ag7 in two main contiguous registers in which two residues at the carboxyl end, P20Gly and P21Glu, influenced binding and T cell reactivity. Naturally occurring insulin-reactive T cells exhibited differing reactivities with the carboxyl-terminal amino acids, although various single residue changes in either the flanks or the core segments affected T cell responses. The insulin peptides represent another example of a weak MHC-binding ligand that is highly immunogenic, giving rise to distinct populations of autoimmune T cells.

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Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide

Cited by 55 publications

References 41 publications

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Autoreactive CD8 T cells associated with β cell destruction in type 1 diabetes

The Insulin-Specific T Cells of Nonobese Diabetic Mice Recognize a Weak MHC-Binding Segment in More Than One Form

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