GABA and Combined GABA with GAD65-Alum Treatment Alters Th1 Cytokine Responses of PBMCs from Children with Recent-Onset Type 1 Diabetes
Katie E. Heath,
Joseph M. Feduska,
Jared P. Taylor,
Julie A. Houp,
Davide Botta,
Frances E. Lund,
Gail J. Mick,
Gerald McGwin,
Kenneth L. McCormick,
Hubert M. Tse
Affiliations
Katie E. Heath
Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Joseph M. Feduska
Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Jared P. Taylor
Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Julie A. Houp
Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Davide Botta
Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Frances E. Lund
Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Gail J. Mick
Department of Pediatrics, Division of Pediatric Endocrinology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Gerald McGwin
Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Kenneth L. McCormick
Department of Pediatrics, Division of Pediatric Endocrinology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Hubert M. Tse
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
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.
