title: The Hsp60 peptide p277 enhances anti-CD3 mediated diabetes remission in non-obese diabetic mice.
abstract: Type 1 diabetes (T1D) is characterized by the immune-mediated destruction of pancreatic beta cells leading to inadequate glycemic control. Trials with immunomodulatory monotherapies have shown that the disease course can in principle be altered. The observed preservation of endogenous insulin secretion however is typically transient and chronic treatment is often associated with significant side effects. Here we combined anti-CD3 with the Hsp60 peptide p277, two drugs that have been evaluated in Phase 3 trials, to test for enhanced efficacy. Female NOD mice with recent onset diabetes were given 5 μg anti-CD3 i.v., on three consecutive days in combination with 100 μg of p277 peptide in IFA s.c., once weekly for four weeks. Anti-CD3 alone restored normoglycemia in 44% of the mice while combination therapy with anti-CD3 and p277 induced stable remission in 83% of mice. The observed increase in protection occurred only in part through TLR2 signaling and was characterized by increased Treg numbers and decreased insulitis. These results have important implications for the design of combination therapies for the treatment of T1D.
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
authors.forename: Ghanashyam
authors.initials: G
authors.lastname: Sarikonda
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
authors.forename: Sowbarnika
authors.initials: S
authors.lastname: Sachithanantham
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Miller
authors.affiliation: Type 1 Diabetes R&D Center, Novo Nordisk, Inc., Seattle, WA, USA.
authors.forename: Philippe P
authors.initials: PP
authors.lastname: Pagni
authors.affiliation: Type 1 Diabetes R&D Center, Novo Nordisk, Inc., Seattle, WA, USA.
authors.forename: Ken T
authors.initials: KT
authors.lastname: Coppieters
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA; Type 1 Diabetes R&D Center, Novo Nordisk, Inc., Seattle, WA, USA. Electronic address: matthias@liai.org.
authors.forename: Matthias
authors.initials: M
authors.lastname: von Herrath
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D017252:CD3 Complex / Q000276:immunology; D049109:Cell Proliferation; D018834:Chaperonin 60 / Q000008:administration & dosage*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000008:administration & dosage*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D018834:Chaperonin 60; D010446:Peptide Fragments; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C095402:peptide 277, heat shock protein 60
keywords: Anti-CD3; Combination therapy; Hsp60; Immunotherapy; Type 1 diabetes; p277