| Autor: |
Heath KE; Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Feduska JM; Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Taylor JP; Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Houp JA; Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Botta D; Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Lund FE; Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Mick GJ; Department of Pediatrics, Division of Pediatric Endocrinology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., McGwin G Jr; Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, USA., McCormick KL; Department of Pediatrics, Division of Pediatric Endocrinology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Tse HM; Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Mail Stop 3029, 1012 Wahl Hall West, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. |
| Abstrakt: |
Type 1 diabetes (T1D) is an autoimmune disease culminating in the destruction of insulin-producing pancreatic cells. There is a need for the development of novel antigen-specific strategies to delay cell destruction, including combinatorial strategies that do not elicit systemic immunosuppression. Gamma-aminobutyric acid (GABA) is expressed by immune cells, β-cells, and gut bacteria and is immunomodulatory. Glutamic-acid decarboxylase 65 (GAD65), which catalyzes GABA from glutamate, is a T1D autoantigen. To test the efficacy of combinatorial GABA treatment with or without GAD65-immunization to dampen autoimmune responses, we enrolled recent-onset children with T1D in a one-year clinical trial (ClinicalTrials.gov NCT02002130) and examined T cell responses. We isolated peripheral blood mononuclear cells and evaluated cytokine responses following polyclonal activation and GAD65 rechallenge. Both GABA alone and GABA/GAD65-alum treatment inhibited Th1 cytokine responses over the 12-month study with both polyclonal and GAD65 restimulation. We also investigated whether patients with HLA-DR3-DQ2 and HLA-DR4-DQ8, the two highest-risk human leukocyte antigen (HLA) haplotypes in T1D, exhibited differences in response to GABA alone and GABA/GAD65-alum. HLA-DR4-DQ8 patients possessed a Th1-skewed response compared to HLA-DR3-DQ2 patients. We show that GABA and GABA/GAD65-alum present an attractive immunomodulatory treatment for children with T1D and that HLA haplotypes should be considered. |
