title: GABA protects human islet cells against the deleterious effects of immunosuppressive drugs and exerts immunoinhibitory effects alone.
abstract: BACKGROUND
  We recently found that γ-aminobutyric acid (GABA) protects mouse islet β cells. It prevented autoimmune type 1 diabetes in mice, induced islet β-cell regeneration, and exerted immunoinhibitory effects. However, it is not known whether GABA would be equally active on human islet and immune cells.
  
  
  METHODS
  In vitro culture of human islets and immune cells with or without GABA and immunosuppressive drugs. In vitro analysis of apoptosis, proliferation, nuclear factor (NF)-κB activation, calcium signaling, and insulin secretion.
  
  
  RESULTS
  GABA reduced human islet cell apoptosis in culture, such that the yield of live cells was approximately tripled after 1 week, and it stimulated insulin secretion. It protected against the deleterious effects of rapamycin, tacrolimus, and mycophenolate mofetil. In human immune cells, GABA had inhibitory effects similar to mouse cells, such as suppressed anti-CD3-stimulated T-cell proliferation, in a GABA type A receptor-dependent fashion. The immunosuppressive mechanisms have been unclear, but we found that GABA blocked calcium influx, which is a key activation signal. GABA also suppressed NF-κB activation in both human islet cells and immune cells. We found that it could be combined with rapamycin to increase its suppressive effects.
  
  
  CONCLUSIONS
  GABA improved human islet cell survival and had suppressive effects on human immune cells. It inhibited canonical NF-κB activation in both islet and immune cells. This is important because activation of this pathway is detrimental to islet cells and likely promotes damaging autoimmunity and alloreactivity against transplanted islets. These findings suggest that GABA might find applications in clinical islet transplantation.
authors.affiliation: 1 Keenan Research Centre of the Li Ka Shing Knowledge Institute, Toronto, Ontario, Canada. 2 Department of Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario, Canada. 3 Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Toronto. 4 Department of Surgery, McGill University Health Centre, Montreal, Quebec, Canada. 5 Division of Endocrinology and Metabolism, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada. 6 Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada. 7 Address correspondence to: Gérald J. Prud'homme, M.D., St. Michael's Hospital, 30 Bond Street, Room 418-LKSKI, Toronto, Ontario, Canada M5B 1W8.
authors.forename: Gérald J
authors.initials: GJ
authors.lastname: Prud'homme
authors.forename: Yelena
authors.initials: Y
authors.lastname: Glinka
authors.forename: Craig
authors.initials: C
authors.lastname: Hasilo
authors.forename: Steven
authors.initials: S
authors.lastname: Paraskevas
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D016328:NF-kappa B / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D020123:Sirolimus / Q000633:toxicity; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016559:Tacrolimus / Q000633:toxicity; D013997:Time Factors; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D007328:Insulin; D016328:NF-kappa B; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus