title: Combination therapy with an anti-IL-1β antibody and GAD65 DNA vaccine can reverse recent-onset diabetes in the RIP-GP mouse model.
abstract: Type 1 diabetes is thought to be an autoimmune condition in which self-reactive T cells attack insulin-secreting pancreatic β-cells. As a proinflammatory cytokine produced by β-cells or macrophages, interleukin-1β (IL-1β) represents a potential therapeutic target in diabetes. We reasoned IL-1β blockade could be combined with islet antigen-specific approaches involving GAD of 65 kDa (GAD65)-expressing plasmids, as previously shown in combination therapies (CTs) with anti-CD3. Thus, we investigated whether anti-IL-1β antibody alone or combined with GAD65 vaccine could reverse diabetes development in a virus-induced mouse model. Given alone, anti-IL-1β had no effect on diabetes, while GAD65 plasmid resulted in 33% disease reversal after a 5-week observation. However, CTs cured 53% of animals and prevented worsening of glycemic control in nonprotected individuals for up to 12 weeks. While the GAD65 vaccine arm of the CT was associated with increased forkhead box p3(+) regulatory T-cell frequency in pancreatic lymph nodes, islet infiltration by CD11b(+/high) cells was less frequent upon CT, and its extent correlated with treatment success or failure. Altogether, our CTs provided prolonged improvement of clinical and immunological features. Despite unsuccessful clinical trials using anti-IL-1β monotherapy, these data hold promise for treatment of type 1 diabetic patients with IL-1β blockade combined with antigen-specific vaccines.
authors: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors: Philippe P
authors: PP
authors: Pagni
authors: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors: Damien
authors: D
authors: Bresson
authors: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors: Teresa
authors: T
authors: Rodriguez-Calvo
authors: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors: Amira
authors: A
authors: Bel Hani
authors: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors: Yulia
authors: Y
authors: Manenkova
authors: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors: Natalie
authors: N
authors: Amirian
authors: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors: Alecia
authors: A
authors: Blaszczak
authors: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors: Sina
authors: S
authors: Faton
authors: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors: Sowbarnika
authors: S
authors: Sachithanantham
authors: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA matthias@liai.org.
authors: Matthias G
authors: MG
authors: von Herrath
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D039481:CD11b Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology*; D004359:Drug Therapy, Combination; D015316:Genetic Therapy; D005968:Glutamate Decarboxylase / Q000235:genetics* / Q000276:immunology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology; D012074:Remission Induction; D019444:Vaccines, DNA / Q000494:pharmacology*
chemical_list: D000906:Antibodies; D039481:CD11b Antigen; D053583:Interleukin-1beta; D019444:Vaccines, DNA; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2