title: Sustained expression of circulating human alpha-1 antitrypsin reduces inflammation, increases CD4+FoxP3+ Treg cell population and prevents signs of experimental autoimmune encephalomyelitis in mice.
abstract: Alpha-1-antitrypsin (AAT) is the primary circulating serine protease inhibitor, and is known to exert potent anti-inflammatory effects and to inhibit the progression of several autoimmune diseases. In this study, transgenic mice that over-express surfactant-driven human (h)AAT on the C57BL/6 background were evaluated for resistance to MOG-35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE), compared to WT C57BL/6 control mice. According to the results, sustained levels of circulating hAAT profoundly inhibited induction of clinical signs, inflammatory lesions and demyelination observed in WT mice with EAE, concomitant with enhanced levels of CD4+FoxP3+ Treg cells, reduced secretion of MOG peptide-induced pro-inflammatory cytokines, IL-17, IL-1β & IL-6, diminished expression of caspase-1 and enhanced expression of CCR6. These results implicate hAAT as a potent immunoregulatory agent worthy of further investigation as a potential therapy in human autoimmune diseases including multiple sclerosis.
authors: Neuroimmunology Research RD-31, Portland VA Medical Center, OR 97239, USA.
authors: Sandhya
authors: S
authors: Subramanian
authors: Galit
authors: G
authors: Shahaf
authors: Eyal
authors: E
authors: Ozeri
authors: Lisa M
authors: LM
authors: Miller
authors: Arthur A
authors: AA
authors: Vandenbark
authors: Eli C
authors: EC
authors: Lewis
authors: Halina
authors: H
authors: Offner
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D051858:Forkhead Transcription Factors; D006023:Glycoproteins / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000032:analysis / Q000378:metabolism; D053583:Interleukin-1beta / Q000032:analysis / Q000378:metabolism; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D054399:Receptors, CCR6 / Q000032:analysis / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000276:immunology* / Q000378:metabolism
chemical_list: C498126:CCR6 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006023:Glycoproteins; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D054399:Receptors, CCR6; D000515:alpha 1-Antitrypsin; C445081:myelin oligodendrocyte glycoprotein (35-55); D020169:Caspases