title: Alpha1-antitrypsin gene therapy modulates cellular immunity and efficiently prevents type 1 diabetes in nonobese diabetic mice.
abstract: An imbalance of the immune-regulatory pathways plays an important role in the development of type 1 diabetes. Therefore, immunoregulatory and antiinflammatory strategies hold great potential for the prevention of this autoimmune disease. Studies have demonstrated that two serine proteinase inhibitors, alpha1-antitrypsin (AAT) and elafin, act as potent antiinflammatory agents. In the present study, we sought to develop an efficient gene therapy approach to prevent type 1 diabetes. Cohorts of 4-week-old female nonobese diabetic (NOD) mice were injected intramuscularly with rAAV1-CB-hAAT, rAAV1-CB-hElafin, or saline. AAV1 vector mediated sustained high levels of transgene expression, sufficient to overcome a humoral immune response against hAAT. AAT gene therapy, contrary to elafin and saline, was remarkably effective in preventing type 1 diabetes. T cell receptor spectratyping indicated that AAT gene therapy altered T cell repertoire diversity in splenocytes from NOD mice. Adoptive transfer experiments demonstrated that AAT gene therapy attenuated cellular immunity associated with beta cell destruction. This study demonstrates that AAT gene therapy attenuates cell-mediated autoimmunity, alters the T cell receptor repertoire, and efficiently prevents type 1 diabetes in the NOD mouse model. These results strongly suggest that rAAV1-mediated AAT gene therapy may be useful as a novel approach to prevent type 1 diabetes.
authors.affiliation: Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Lu
authors.forename: Mei
authors.initials: M
authors.lastname: Tang
authors.forename: Clive
authors.initials: C
authors.lastname: Wasserfall
authors.forename: Zhongchen
authors.initials: Z
authors.lastname: Kou
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.forename: Thomas
authors.initials: T
authors.lastname: Gardemann
authors.forename: James
authors.initials: J
authors.lastname: Crawford
authors.forename: Mark
authors.initials: M
authors.lastname: Atkinson
authors.forename: Sihong
authors.initials: S
authors.lastname: Song
mesh_terms: D000818:Animals; D000917:Antibody Formation; D000229:Dependovirus / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D007273:Injections, Intramuscular; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011994:Recombinant Proteins; D000515:alpha 1-Antitrypsin