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- Title
Suppression of Type 1 Diabetes in NOD Mice by Bifunctional Peptide Inhibitor: Modulation of the Immunological Synapse Formation.
- Authors
Murray, Joseph S.; Oney, Sabah; Page, Jennifer E.; Kratochvil-Stava, Angela; Yongbo Hu; Makagiansar, Irwan T.; Brown, John C.; Kobayashi, Naoki; Siahaan, Teruna J.
- Abstract
The aim of this work was to design and utilize a bifunctional peptide inhibitor called glutamic acid decarboxylase–bifunctional peptide inhibitor to suppress the progression of type 1 diabetes in non-obese diabetic mice. The hypothesis is that glutamic acid decarboxylase–bifunctional peptide inhibitor binds simultaneously to major histocompatibility complex-II and intercellular adhesion molecule type 1 on antigen-presenting cell and inhibits the immunological synapse formation during T-cell–antigen-presenting cell interactions. Glutamic acid decarboxylase–bifunctional peptide inhibitor was composed of a major epitope of the type 1 diabetes-associated antigen, glutamic acid decarboxylase 65 kDa, covalently linked to a peptide derived from CD11a of lymphocyte function-associated antigen-1. The suppression of insulitis and type 1 diabetes was evaluated using non-obese diabetic and non-obese diabetic severe combined immunodeficiency mice. Glutamic acid decarboxylase–bifunctional peptide inhibitor had the capacity to suppress invasive insulitis in non-obese diabetic mice. CD4+ T-cells isolated from glutamic acid decarboxylase–bifunctional peptide inhibitor treated mice also suppressed insulitis and hyperglycemia when transferred with diabetogenic non-obese diabetic spleen cells into non-obese diabetic severe combined immunodeficiency recipients. As predicted, the glutamic acid decarboxylase–bifunctional peptide inhibitor cross-linked a significant fraction of major histocompatibility complex class-II molecules to intercellular adhesion molecule type 1 molecules on the surface of live antigen-presenting cell. Intravenous injection of the glutamic acid decarboxylase–bifunctional peptide inhibitor elicited interleukin-4-producing T-cells in non-obese diabetic mice primed against the glutamic acid decarboxylase-epitope peptide. Together, the results indicate that glutamic acid decarboxylase–bifunctional peptide inhibitor induces interleukin-4-producing regulatory cells but does not expand the glutamic acid decarboxylase-specific Th2 population. Given that Th2 effector cells can cause pathology, the glutamic acid decarboxylase–bifunctional peptide inhibitor may represent a novel mechanism to induce interleukin-4 without Th2-associated pathology.
- Subjects
DIABETES; CARBOHYDRATE intolerance; ANTIGEN presenting cells; IMMUNOCOMPETENT cells; LABORATORY mice; ANIMAL diseases
- Publication
Chemical Biology & Drug Design, 2007, Vol 70, Issue 3, p227
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/j.1747-0285.2007.00552.x