Alpha-1-antitrypsin in cell and organ transplantation

Mel Berger, Mingyao Liu, Marc E Uknis, Maria Koulmanda, Mel Berger, Mingyao Liu, Marc E Uknis, Maria Koulmanda

Abstract

Limited availability of donor organs and risk of ischemia-reperfusion injury (IRI) seriously restrict organ transplantation. Therapeutics that can prevent or reduce IRI could potentially increase the number of transplants by increasing use of borderline organs and decreasing discards. Alpha-1 antitrypsin (AAT) is an acute phase reactant and serine protease inhibitor that limits inflammatory tissue damage. Purified plasma-derived AAT has been well tolerated in more than 30 years of use to prevent emphysema in AAT-deficient individuals. Accumulating evidence suggests that AAT has additional anti-inflammatory and tissue-protective effects including improving mitochondrial membrane stability, inhibiting apoptosis, inhibiting nuclear factor kappa B activation, modulating pro- vs anti-inflammatory cytokine balance, and promoting immunologic tolerance. Cell culture and animal studies have shown that AAT limits tissue injury and promotes cell and tissue survival. AAT can promote tolerance in animal models by downregulating early inflammation and favoring induction and stabilization of regulatory T cells. The diverse intracellular and immune-modulatory effects of AAT and its well-established tolerability in patients suggest that it might be useful in transplantation. Clinical trials, planned and/or in progress, should help determine whether the promise of the animal and cellular studies will be fulfilled by improving outcomes in human organ transplantation.

Keywords: basic (laboratory) research/science; cell death: apoptosis; immunobiology; innate immunity; islet transplantation; lung transplantation/pulmonology; translational research/science.

© 2018 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.

Figures

Figure 1
Figure 1
Major intracellular effects of alpha‐1‐antitrypsin and how they interrelate to achieve physiologic effects.4, 5, 6, 7 IKB, inhibitor of NFKB; IL, interleukin; NFKB, nuclear factor kappa B; ROS, reactive oxygen species
Figure 2
Figure 2
Immunohistochemistry of accepted allogeneic islet grafts. Isolated islets were grafted under the renal capsule of 6‐ to 7‐week‐old female mice, heterozygous for human AAT (background strain C57BL/6, H‐2b), rendered diabetic by a single injection of STZ, and treated with human AAT after transplantation. A representative section from a functioning 72‐day posttransplant islet is shown. Staining colors are the following: Blue, nuclei (diamidino‐2‐phenylindole [DAPI]); Red, insulin (guinea pig anti–swine insulin antibody and CY‐3‐conjugated donkey anti–guinea pig IgG); Green, Fox‐P3 (Alexa Fluor® 488 anti–mouse foxp3 antibody). Arrows show a “cuff” of FoxP3 positive (presumably) Tregs surrounding the insulin‐containing islet cells in the graft. Reproduced from Shahaf et al 7 with permission of the publisher. AAT, alpha‐1 antitrypsin; STZ, streptozotocin; Treg, regulatory T cells

References

    1. Organ Procurement and Transplantation Network . National data. #. 2017. Accessed March 24, 2017.
    1. de Serres F, Blanco I. Role of alpha‐1 antitrypsin in human health and disease. J Intern Med. 2014;276:311‐335.
    1. Silverman EK, Sandhaus RA. Clinical practice. Alpha1‐antitrypsin deficiency. N Engl J Med. 2009;360:2749‐2757.
    1. Ehlers MR. Immune‐modulating effects of alpha‐1 antitrypsin. Biol Chem. 2014;395:1187‐1193.
    1. Zhou X, Shapiro L, Fellingham G, et al. HIV replication in CD4 + T lymphocytes in the presence and absence of follicular dendritic cells: inhibition of replication mediated by alpha‐1‐antitrypsin through altered IκBα ubiquitination. J Immunol. 2011;186:3148‐3155.
    1. Marcondes AM, Karoopongse E, Lesnikova M, et al. α‐1‐Antitrypsin (AAT)‐modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics. Blood. 2014;124:2881‐2891.
    1. Shahaf G, Moser H, Ozeri E, et al. α‐1‐antitrypsin gene delivery reduces inflammation, increases T‐regulatory cell population size and prevents islet allograft rejection. Mol Med. 2011;17:1000‐1011.
    1. Teckman JH, An JK, Blomenkamp K, et al. Mitochondrial autophagy and injury in the liver in α 1‐antitrypsin deficiency. Am J Physiol Gastrointest Liver Physiol. 2004;286:G851‐G862.
    1. Lewis EC, Shapiro L, Bowers OJ, et al. α1‐antitrypsin monotherapy prolongs islet allograft survival in mice. Proc Natl Acad Sci USA. 2005;102:12153‐12158.
    1. Zhang B, Lu Y, Campbell‐Thompson M, et al. α1‐antitrypsin protects β‐cells from apoptosis. Diabetes. 2007;56:1316‐1323.
    1. Petrache I, Fijalkowska I, Medler TR, et al. α‐1 antitrypsin inhibits caspase‐3 activity, preventing lung endothelial cell apoptosis. Am J Pathol. 2006;169:1155‐1166.
    1. Fleixo‐Lima G, Ventura H, Medini M, et al. Mechanistic evidence in support of alpha1‐antitrypsin as a therapeutic approach for type 1 diabetes. J Diabetes Sci Technol. 2014;8:1193‐1203.
    1. Daemen MA, Heemskerk VH, van't Veer C, et al. Functional protection by acute phase proteins alpha(1)‐acid glycoprotein and alpha(1)‐antitrypsin against ischemia/reperfusion injury by preventing apoptosis and inflammation. Circulation 2000;102:1420‐1426.
    1. Feng Y, Hu L, Xu Q, et al. Cytoprotective role of alpha‐1 antitrypsin in vascular endothelial cell under hypoxia/reoxygenation condition. J Cardiovasc Pharmacol. 2015;66:96‐107.
    1. Gao W, Zhao J, Kim H, et al. α1‐Antitrypsin inhibits ischemia reperfusion‐induced lung injury by reducing inflammatory response and cell death. J Heart Lung Transplant. 2014;33:309‐315.
    1. Toldo S, Seropian IM, Mezzaroma E, et al. Alpha‐1 antitrypsin inhibits caspase‐1 and protects from acute myocardial ischemia‐reperfusion injury. J Mol Cell Cardiol. 2011;51:244‐251.
    1. Serban KA, Petrache I. Alpha‐1 antitrypsin and lung cell apoptosis. Ann Am Thorac Soc. 2016;13:S146‐S149.
    1. Jedicke N, Struever N, Aggrawal N, et al. alpha‐1‐antitrypsin inhibits acute liver failure in mice. Hepatology. 2014;59:2299‐2308.
    1. Guan L, Liu H, Fu P, et al. The protective effects of trypsin inhibitor on hepatic ischemia‐reperfusion injury and liver graft survival. Oxid Med Cell Longev. 2016;2016:1429835.
    1. Churg A, Dai J, Zay K, et al. Alpha‐1‐antitrypsin and a broad spectrum metalloprotease inhibitor, RS113456, have similar acute anti‐inflammatory effects. Lab Invest. 2001;81:12.
    1. Jonigk D, Al‐Omari M, Maegel L, et al. Anti‐inflammatory and immunomodulatory properties of α1‐antitrypsin without inhibition of elastase. Proc Natl Acad Sci USA. 2013;110:15007‐15012.
    1. Wang Y, He Y, Abraham B, et al. Cytosolic, autocrine alpha‐1 proteinase inhibitor (A1PI) inhibits caspase‐1 and blocks IL‐1β dependent cytokine release in monocytes. PLoS ONE. 2012;7:e51078.
    1. Geraghty P, Eden E, Pillai M, et al. α1‐Antitrypsin activates protein phosphatase 2A to counter lung inflammatory responses. Am J Respir Crit Care Med. 2014;190:1229‐1242.
    1. Bata J, Revillard JP. Interaction between alpha 1 antitrypsin and lymphocyte surface proteases: immunoregulatory effects. Agents Actions. 1981;11:614‐616.
    1. Marcondes AM, Li X, Tabellini L, et al. Inhibition of IL‐32 activation by alpha‐1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model. Blood. 2011;118:5031‐5039.
    1. Abecassis A, Schuster R, Shahaf G, et al. α1‐antitrypsin increases interleukin‐1 receptor antagonist production during pancreatic islet graft transplantation. Cell Mol Immunol. 2014;11:377‐386.
    1. Lewis EC, Mizrahi M, Toledano M, et al. α1‐Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice. Proc Natl Acad Sci U S A. 2008;105:16236‐16241.
    1. Koulmanda M, Bhasin M, Hoffman L, et al. Curative and β cell regenerative effects of α1‐antitrypsin treatment in autoimmune diabetic NOD mice. Proc Natl Acad Sci USA. 2008;105:16242‐16247.
    1. Loganathan G, Dawra RK, Pugazhenthi S, et al. Insulin degradation by acinar cell proteases creates a dysfunctional environment for human islets before/after transplantation: benefits of alpha‐1 antitrypsin treatment. Transplantation. 2011;92:1222‐1230.
    1. Shimoda M, Noguchi H, Fujita Y, et al. Improvement of porcine islet isolation by inhibition of trypsin activity during pancreas preservation and digestion using α1‐antitrypsin. Cell Transplant. 2012;21:465‐471.
    1. Kalis M, Kumar R, Janciauskiene S, et al. α 1‐antitrypsin enhances insulin secretion and prevents cytokine‐mediated apoptosis in pancreatic β‐cells. Islets. 2010;2:185‐189.
    1. Eleazu C, Eleazu K, Chukwuma S, et al. Review of the mechanism of cell death resulting from streptozotocin challenge in experimental animals, its practical use and potential risk to humans. J Diabetes Metab Disord. 2013;12:7.
    1. Koulmanda M, Bhasin M, Fan Z, et al. Alpha 1‐antitrypsin reduces inflammation and enhances mouse pancreatic islet transplant survival. Proc Natl Acad Sci USA. 2012;109:15443‐15448.
    1. Aralast NP in inslet transplant, NCT02520076. . Accessed December 6, 2017.
    1. Bennet W, Sundberg B, Groth CG, et al. Incompatibility between human blood and isolated islets of Langerhans: a finding with implication for clinical intraportal islet transplantation? Diabetes. 1999;48:14.
    1. Goto M, Johansson U, Eich TM, et al. Key factors for human islet isolation and clinical transplantation. Transplant Proc. 2005;37:1315‐1316.
    1. Wang J, Sun Z, Gou W, et al. α‐1 antitrypsin enhances islet engraftment by suppression of instant blood‐mediated inflammatory reaction. Diabetes. 2017;66:970‐980.
    1. Koulmanda M, Sampathkumar RS, Bhasin M, et al. Prevention of nonimmunologic loss of transplanted islets in monkeys. Am J Transplant. 2014;14:1543‐1551.
    1. Iskender I, Sakamoto J, Nakajima D, et al. Human alpha1‐antitrypsin improves early post‐transplant lung function: pre‐clinical studies in a pig lung transplant model. J Heart Lung Transplant. 2016;35:913‐921.
    1. Lin H, Chen M, Tian F, et al. Alpha‐1 antitrypsin improves function of porcine donor lungs during ex vivo lung perfusion [published online ahead of print on October 2, 2017]. J Heart Lung Transplant. 10.1016/j.healun.2017.09.019.
    1. Maicas N, van der Vlag J, Bublitz J, et al. Human alpha‐1‐antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia‐reperfusion injury. PLoS ONE. 2017;12:e0168981.
    1. Chen G, Li J, Chen L, et al. α1‐antitrypsin‐primed tolerogenic dendritic cells prolong allograft kidney transplants survival in rats. Int Immunopharmacol. 2016;31:216‐221.
    1. Frenzel E, Wrenger S, Brugger B, et al. Alpha‐1‐antitrypsin combines with plasma fatty acids and induces angiopoietin‐like protein 4 expression. J Immunol. 2015;195:3605‐3616.
    1. Gaggar A, Chen J, Chmiel JF, et al. Inhaled alpha‐proteinase inhibitor therapy in patients with cystic fibrosis. J Cyst Fibros. 2016;15:227‐233.

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