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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

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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.

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References

  • Aerts NE, De Knop KJ, Leysen J, Ebo DG, Bridts CH, Weyler JJ, Stevens WJ, De Clerck LS (2010) Increased IL-17 production by peripheral T helper cells after tumour necrosis factor blockade in rheumatoid arthritis is accompanied by inhibition of migration-associated chemokine receptor expression. Rheumatol (Oxford) 49:2264–2272

    Article  CAS  Google Scholar 

  • Bergin DA, Reeves EP, Meleady P, Henry M, McElvaney OJ, Carroll TP, Condron C, Chotirmall SH, Clynes M, O'Neill SJ, McElvaney NG (2010) alpha-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8. J Clin Invest 120:4236–4250

    Article  PubMed  CAS  Google Scholar 

  • Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    Article  PubMed  CAS  Google Scholar 

  • Blanco I, Canto H, Flores J, Camblor C, Carcaba V, de Serres FJ, Janciauskiene S, Bustillo EF (2008) Long-term augmentation therapy with alpha-1 antitrypsin in an MZ-AAT severe persistent asthma. Monaldi Arch Chest Dis 69:178–182

    PubMed  CAS  Google Scholar 

  • Cantin AM, Woods DE (1999) Aerosolized prolastin suppresses bacterial proliferation in a model of chronic Pseudomonas aeruginosa lung infection. Am J Respir Crit Care Med 160:1130–1135

    PubMed  CAS  Google Scholar 

  • Chidwick K, Whichelow CE, Zhang Z, Fairburn K, Sachs JA, Blake DR, Winyard PG (1994) Relationship between alpha 1-antitrypsin inactivation and tumor necrosis factor alpha concentration in the synovial fluid of patients with rheumatoid arthritis. Arthritis Rheum 37:1723–1726

    Article  PubMed  CAS  Google Scholar 

  • Dhami R, Zay K, Gilks B, Porter S, Wright JL, Churg A (1999) Pulmonary epithelial expression of human alpha1-antitrypsin in transgenic mice results in delivery of alpha1-antitrypsin protein to the interstitium. J Mol Med 77:377–385

    Article  PubMed  CAS  Google Scholar 

  • Dhami R, Gilks B, Xie C, Zay K, Wright JL, Churg A (2000) Acute cigarette smoke-induced connective tissue breakdown is mediated by neutrophils and prevented by alpha1-antitrypsin. Am J Respir Cell Mol Biol 22:244–252

    PubMed  CAS  Google Scholar 

  • Domingues HS, Mues M, Lassmann H, Wekerle H, Krishnamoorthy G (2010) Functional and pathogenic differences of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. PLoS ONE 5:e15531

    Article  PubMed  CAS  Google Scholar 

  • Duranton J, Bieth JG (2003) Inhibition of proteinase 3 by [alpha]1-antitrypsin in vitro predicts very fast inhibition in vivo. Am J Respir Cell Mol Biol 29:57–61

    Article  PubMed  CAS  Google Scholar 

  • Ekeowa UI, Gooptu B, Belorgey D, Hagglof P, Karlsson-Li S, Miranda E, Perez J, MacLeod I, Kroger H, Marciniak SJ, Crowther DC, Lomas DA (2009) alpha1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies. Clin Sci (Lond) 116:837–850

    Article  CAS  Google Scholar 

  • Elzouki AN, Eriksson S, Lofberg R, Nassberger L, Wieslander J, Lindgren S (1999) The prevalence and clinical significance of alpha 1-antitrypsin deficiency (PiZ) and ANCA specificities (proteinase 3, BPI) in patients with ulcerative colitis. Inflamm Bowel Dis 5:246–252

    Article  PubMed  CAS  Google Scholar 

  • Finotti P, Piccoli A, Carraro P (1992) Alteration of plasma proteinase-antiproteinase system in type 1 diabetic patients. Influence of sex and relationship with metabolic control. Diabetes Res Clin Pract 18:35–42

    Article  PubMed  CAS  Google Scholar 

  • Furlan R, Martino G, Galbiati F, Poliani PL, Smiroldo S, Bergami A, Desina G, Comi G, Flavell R, Su MS, Adorini L (1999) Caspase-1 regulates the inflammatory process leading to autoimmune demyelination. J Immunol 163:2403–2409

    PubMed  CAS  Google Scholar 

  • Gambichler T, Reich S, Banasch M, Altmeyer P (2006) Complex extra-intestinal complications of ulcerative colitis in a patient with alpha1-antitrypsin deficiency. Eur J Med Res 11:135–138

    PubMed  CAS  Google Scholar 

  • Grimstein C, Choi YK, Satoh M, Lu Y, Wang X, Campbell-Thompson M, Song S (2010) Combination of alpha-1 antitrypsin and doxycycline suppresses collagen-induced arthritis. J Gene Med 12:35–44

    Article  PubMed  CAS  Google Scholar 

  • Gris D, Ye Z, Iocca HA, Wen H, Craven RR, Gris P, Huang M, Schneider M, Miller SD, Ting JP (2010) NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J Immunol 185:974–981

    Article  PubMed  CAS  Google Scholar 

  • Gross B, Grebe M, Wencker M, Stoller JK, Bjursten LM, Janciauskiene S (2009) New Findings in PiZZ alpha1-antitrypsin deficiency-related panniculitis. Demonstration of skin polymers and high dosing requirements of intravenous augmentation therapy. Dermatology 218:370–375

    Article  PubMed  CAS  Google Scholar 

  • Hashemi M, Naderi M, Rashidi H, Ghavami S (2007) Impaired activity of serum alpha-1-antitrypsin in diabetes mellitus. Diabetes Res Clin Pract 75:246–248

    Article  PubMed  CAS  Google Scholar 

  • Higashimoto Y, Yamagata Y, Taya S, Iwata T, Okada M, Ishiguchi T, Sato H, Itoh H (2008) Systemic inflammation in chronic obstructive pulmonary disease and asthma: similarities and differences. Respirology 13:128–133

    PubMed  Google Scholar 

  • Hu Y, Shen F, Crellin NK, Ouyang W (2011) The IL-17 pathway as a major therapeutic target in autoimmune diseases. Ann NY Acad Sci 1217:60–76

    Article  PubMed  CAS  Google Scholar 

  • Kalis M, Kumar R, Janciauskiene S, Salehi A, Cilio CM (2010) alpha 1-antitrypsin enhances insulin secretion and prevents cytokine-mediated apoptosis in pancreatic beta-cells. Islets 2:185–189

    Article  PubMed  Google Scholar 

  • Kanakasabai S, Chearwae W, Walline CC, Iams W, Adams SM, Bright JJ (2010) Peroxisome proliferator-activated receptor delta agonists inhibit T helper type 1 (Th1) and Th17 responses in experimental allergic encephalomyelitis. Immunology 130:572–588

    Article  PubMed  CAS  Google Scholar 

  • Kitamura K, Farber JM, Kelsall BL (2010) CCR6 marks regulatory T cells as a colon-tropic, IL-10-producing phenotype. J Immunol 185:3295–3304

    Article  PubMed  CAS  Google Scholar 

  • Kong W, Yen JH, Ganea D (2010) Docosahexaenoic acid prevents dendritic cell maturation, inhibits antigen-specific Th1/Th17 differentiation and suppresses experimental autoimmune encephalomyelitis. Brain Behav Immun Sept 18, epub ahead of print.

  • Koulmanda M, Bhasin M, Hoffman L, Fan Z, Qipo A, Shi H, Bonner-Weir S, Putheti P, Degauque N, Libermann TA, Auchincloss H Jr, Flier JS, Strom TB (2008) Curative and beta cell regenerative effects of alpha1-antitrypsin treatment in autoimmune diabetic NOD mice. Proc Natl Acad Sci USA 105:16242–16247

    Article  PubMed  CAS  Google Scholar 

  • Lacki JK, Schochat T, Leszczynski P, Mackiewicz SH, Muller W (1995) IgA-alpha-1-antitrypsin complex in systemic lupus erythematosus: preliminary report. Lupus 4:221–224

    Article  PubMed  CAS  Google Scholar 

  • Lewis EC, Shapiro L, Bowers OJ, Dinarello CA (2005) Alpha1-antitrypsin monotherapy prolongs islet allograft survival in mice. Proc Natl Acad Sci USA 102:12153–12158

    Article  PubMed  CAS  Google Scholar 

  • Lewis EC, Mizrahi M, Toledano M, Defelice N, Wright JL, Churg A, Shapiro L, Dinarello CA (2008) alpha1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice. Proc Natl Acad Sci USA 105:16236–16241

    Article  PubMed  CAS  Google Scholar 

  • Libert C, Van Molle W, Brouckaert P, Fiers W (1996) alpha1-Antitrypsin inhibits the lethal response to TNF in mice. J Immunol 157:5126–5129

    PubMed  CAS  Google Scholar 

  • Lisowska-Myjak B, Pachecka J, Kaczynska B, Miszkurka G, Kadziela K (2006) Serum protease inhibitor concentrations and total antitrypsin activity in diabetic and non-diabetic children during adolescence. Acta Diabetol 43:88–92

    Article  PubMed  CAS  Google Scholar 

  • Ma H, Lu Y, Li H, Campbell-Thompson M, Parker M, Wasserfall C, Haller M, Brantly M, Schatz D, Atkinson M, Song S (2010a) Intradermal alpha1-antitrypsin therapy avoids fatal anaphylaxis, prevents type 1 diabetes and reverses hyperglycaemia in the NOD mouse model of the disease. Diabetologia 53:2198–2204

    Article  PubMed  CAS  Google Scholar 

  • Ma J, McCarl CA, Khalil S, Luthy K, Feske S (2010b) T-cell-specific deletion of STIM1 and STIM2 protects mice from EAE by impairing the effector functions of Th1 and Th17 cells. Eur J Immunol 40:3028–3042

    Article  PubMed  CAS  Google Scholar 

  • Mehling M, Lindberg R, Raulf F, Kuhle J, Hess C, Kappos L, Brinkmann V (2010) Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology 75:403–410

    Article  PubMed  CAS  Google Scholar 

  • Nita IM, Serapinas D, Janciauskiene SM (2007) alpha1-Antitrypsin regulates CD14 expression and soluble CD14 levels in human monocytes in vitro. Int J Biochem Cell Biol 39:1165–1176

    Article  PubMed  CAS  Google Scholar 

  • Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, Ziegler SF, Offner H (2004) Cutting edge: estrogen drives expansion of the CD4 + CD25+ regulatory T cell compartment. J Immunol 173:2227–2230

    PubMed  CAS  Google Scholar 

  • Postigo J, Genre F, Iglesias M, Fernandez-Rey M, Buelta L, Rodriguez-Rey JC, Merino J, Merino R (2011) Exacerbation of collagen type II-induced arthritis in ApoE deficient mice in association with the expansion of Th1 and Th17 cells. Arthritis Rheum Jan 10, epub ahead of print.

  • Pott GB, Chan ED, Dinarello CA, Shapiro L (2009) Alpha-1-antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood. J Leukoc Biol 85:886–895

    Article  PubMed  CAS  Google Scholar 

  • Sandler M, Gemperli BM, Hanekom C, Kuhn SH (1988) Serum alpha 1-protease inhibitor in diabetes mellitus: reduced concentration and impaired activity. Diabetes Res Clin Pract 5:249–255

    Article  PubMed  CAS  Google Scholar 

  • Steinman L, Zamvil SS (2005) Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis. Trends Immunol 26:565–571

    Article  PubMed  CAS  Google Scholar 

  • Stockley RA, Parr DG, Piitulainen E, Stolk J, Stoel BC, Dirksen A (2010) Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry. Respir Res 11:136

    Article  PubMed  Google Scholar 

  • Tilg H, Vannier E, Vachino G, Dinarello CA, Mier JW (1993) Antiinflammatory properties of hepatic acute phase proteins: preferential induction of interleukin 1 (IL-1) receptor antagonist over IL-1 beta synthesis by human peripheral blood mononuclear cells. J Exp Med 178:1629–1636

    Article  PubMed  CAS  Google Scholar 

  • Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189

    Article  PubMed  CAS  Google Scholar 

  • Villares R, Cadenas V, Lozano M, Almonacid L, Zaballos A, Martinez AC, Varona R (2009) CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T-cell recruitment to target tissues. Eur J Immunol 39:1671–1681

    Article  PubMed  CAS  Google Scholar 

  • Wang W, Shao S, Jiao Z, Guo M, Xu H, Wang S (2011) The Th17/Treg imbalance and cytokine environment in peripheral blood of patients with rheumatoid arthritis. Rheumatol Int Jan 11, epub ahead of print.

  • Yaghmaei M, Hashemi M, Shikhzadeh A, Mokhtari M, Niazi A, Ghavami S (2009) Serum trypsin inhibitory capacity in normal pregnancy and gestational diabetes mellitus. Diabetes Res Clin Pract 84:201–204

    Article  PubMed  CAS  Google Scholar 

  • Yamazaki T, Yang XO, Chung Y, Fukunaga A, Nurieva R, Pappu B, Martin-Orozco N, Kang HS, Ma L, Panopoulos AD, Craig S, Watowich SS, Jetten AM, Tian Q, Dong C (2008) CCR6 regulates the migration of inflammatory and regulatory T cells. J Immunol 181:8391–8401

    PubMed  CAS  Google Scholar 

  • Yan Y, Zhang GX, Gran B, Fallarino F, Yu S, Li H, Cullimore ML, Rostami A, Xu H (2010) IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J Immunol 185:5953–5961

    Article  PubMed  CAS  Google Scholar 

  • Yang P, Tremaine WJ, Meyer RL, Prakash UB (2000) Alpha1-antitrypsin deficiency and inflammatory bowel diseases. Mayo Clin Proc 75:450–455

    Article  PubMed  CAS  Google Scholar 

  • Zhang XH, Yan YH, Liang ZQ, Cui XL, Jiang M (1989) Changes of neutrophil elastase and alpha 1-antitrypsin in systemic lupus erythematosus. Proc Chin Acad Med Sci Peking Union Med Coll 4:26–29

    PubMed  CAS  Google Scholar 

  • Zhang B, Lu Y, Campbell-Thompson M, Spencer T, Wasserfall C, Atkinson M, Song S (2007) Alpha1-antitrypsin protects beta-cells from apoptosis. Diabetes 56:1316–1323

    Article  PubMed  CAS  Google Scholar 

  • Zhang R, Tian A, Zhang H, Zhou Z, Yu H, Chen L (2011) Amelioration of Experimental Autoimmune Encephalomyelitis by beta-elemene Treatment is Associated with Th17 and Treg Cell Balance. J Mol Neurosci Epub ahead of print.

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Acknowledgments

The authors wish to thank Ms. Eva Niehaus for assistance with manuscript preparation.

This work was supported by the Biomedical Laboratory R&D Service, Department of Veterans’ Affairs and the Israel Science Foundation 1027/07.

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Authors and Affiliations

  1. Neuroimmunology Research RD-31, Portland VA Medical Center, 3710 SW US Veterans’ Hospital Rd., Portland, 97239, OR, USA

    Sandhya Subramanian, Lisa M. Miller, Arthur A. Vandenbark & Halina Offner

  2. Ben-Gurion University of the Negev, Faculty of Health Sciences, Beer-Sheva, Israel

    Galit Shahaf, Eyal Ozeri & Eli C. Lewis

  3. Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, 97239, OR, USA

    Lisa M. Miller, Arthur A. Vandenbark & Halina Offner

  4. Department of Molecular Microbiology & Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, 97239, OR, USA

    Arthur A. Vandenbark

  5. Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, 97239, OR, USA

    Halina Offner

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  1. Sandhya Subramanian
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  2. Galit Shahaf
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  3. Eyal Ozeri
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Correspondence to Halina Offner.

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Subramanian, S., Shahaf, G., Ozeri, E. et al. 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. Metab Brain Dis 26, 107–113 (2011). https://doi.org/10.1007/s11011-011-9239-9

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  • DOI: https://doi.org/10.1007/s11011-011-9239-9

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