New Targets for the Prevention of Chronic Rejection after Thoracic Organ Transplantation

Abstract

The gold standard for the treatment of terminal heart failure and irreversible lung diseases includes thoracic organ transplantation. The major obstacle for long-term survival after successful transplantation is chronic rejection, an ongoing immunomodulatory disease so far without effective therapy. Therefore, the aim of this review is to elucidate scientific efforts targeting different new mechanisms of cardiac allograft vasculopathy (CAV) and chronic lung allograft dysfunction (CLAD). For this purpose, we performed a systematic review of the literature to assess recent strategies in transplant immunology research. We searched MEDLINE from 2015 up to date for articles addressing the following keywords: CAV, transplant vasculopathy, transplant arteriosclerosis, CLAD, bronchiolitis obliterans transplant, and obliterative bronchiolitis transplant. All articles including experimental models in the field of transplant immunology addressing new aspects for the prevention of chronic rejection after heart and lung transplantation were included in this review. The prevention of chronic rejection would clearly improve the survival of patients after heart and lung transplantation. Interesting targets were addressed in recent research, but further research is necessary to effectively treat this life-threatening disease in transplant recipients.

Keywords

experimental - immunology - rejection - transplantation - heart - lung

• References

• 1 Wilhelm MJ. Long-term outcome following heart transplantation: current perspective. J Thorac Dis 2015; 7 (03) 549-551
• 2 Gray AL, Mulvihill MS, Hartwig MG. Lung transplantation at Duke. J Thorac Dis 2016; 8 (03) E185-E196
• 3 Lund LH, Edwards LB, Dipchand AI. , et al; International Society for Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: Thirty-third Adult Heart Transplantation Report-2016; Focus Theme: Primary Diagnostic Indications for Transplant. J Heart Lung Transplant 2016; 35 (10) 1158-1169
• 4 Yusen RD, Edwards LB, Dipchand AI. , et al; International Society for Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: Thirty-third Adult Lung and Heart-Lung Transplant Report-2016; Focus Theme: Primary Diagnostic Indications for Transplant. J Heart Lung Transplant 2016; 35 (10) 1170-1184
• 5 Labarrere CA, Jaeger BR, Kassab GS. Cardiac allograft vasculopathy: past, present and future!. JSM Atheroscler 2016; 1 (01) 1004
• 6 Jansen MA, Otten HG, de Weger RA, Huibers MM. Immunological and fibrotic mechanisms in cardiac allograft vasculopathy. Transplantation 2015; 99 (12) 2467-2475
• 7 Li J, Xiong J, Yang B. , et al. Endothelial cell apoptosis induces TGF-β signaling-dependent host endothelial-mesenchymal transition to promote transplant arteriosclerosis. Am J Transplant 2015; 15 (12) 3095-3111
• 8 Chih S, Chong AY, Mielniczuk LM, Bhatt DL, Beanlands RS. Allograft vasculopathy: the Achilles' heel of heart transplantation. J Am Coll Cardiol 2016; 68 (01) 80-91
• 9 Campagnolo P, Hong X, di Bernardini E, Smyrnias I, Hu Y, Xu Q. Resveratrol-induced vascular progenitor differentiation towards endothelial lineage via MiR-21/Akt/β-catenin is protective in vessel graft models. PLoS One 2015; 10 (05) e0125122
• 10 Bogossian H, Frommeyer G, Ninios I. , et al. Expression of NO synthase under medication with cyclosporine A, mycophenolate mofetil, and tacrolimus during development of transplant vasculopathy on rat cardiac allograft. Cardiovasc Ther 2016; 34 (04) 183-190
• 11 Ziqiang X, Jingjun W, Jianjian Z, Yong L, Peng X. Tadalafil attenuates graft arteriosclerosis of aortic transplant in a rat model. Iran J Basic Med Sci 2015; 18 (09) 927-931
• 12 Koupparis AJ, Jeremy JY, Muzaffar S, Persad R, Shukla N. Sildenafil inhibits the formation of superoxide and the expression of gp47 NAD[P]H oxidase induced by the thromboxane A2 mimetic, U46619, in corpus cavernosal smooth muscle cells. BJU Int 2005; 96 (03) 423-427
• 13 Das A, Xi L, Kukreja RC. Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. J Biol Chem 2005; 280 (13) 12944-12955
• 14 Heim C, Bernhardt W, Jalilova S. , et al. Prolyl-hydroxylase inhibitor activating hypoxia-inducible transcription factors reduce levels of transplant arteriosclerosis in a murine aortic allograft model. Interact Cardiovasc Thorac Surg 2016; 22 (05) 561-570
• 15 Oberhuber R, Riede G, Cardini B. , et al. Impaired endothelial nitric oxide synthase homodimer formation triggers development of transplant vasculopathy - insights from a murine aortic transplantation model. Sci Rep 2016; 6: 37917
• 16 Cunnington C, Van Assche T, Shirodaria C. , et al. Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease. Circulation 2012; 125 (11) 1356-1366
• 17 Sommer W, Knöfel AK, Izykowski N. , et al. Physical exercise reduces transplant arteriosclerosis in a mouse aorta transplantation model. J Thorac Cardiovasc Surg 2015; 149 (01) 330-337
• 18 Costanzo MR, Dipchand A, Starling R. , et al; International Society of Heart and Lung Transplantation Guidelines. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010; 29 (08) 914-956
• 19 van den Hoogen P, Huibers MM, Sluijter JP, de Weger RA. Cardiac allograft vasculopathy: a donor or recipient induced pathology?. J Cardiovasc Transl Res 2015; 8 (02) 106-116
• 20 Ingulli E. Mechanism of cellular rejection in transplantation. Pediatr Nephrol 2010; 25 (01) 61-74
• 21 Heim C, Eckl S, Preidl R. , et al. Delayed therapy with clopidogrel and everolimus prevents progression of transplant arteriosclerosis and impairs humoral alloimmunity in murine aortic allografts. Eur J Cardiothorac Surg 2015; 47 (01) 180-187
• 22 Abele S, Spriewald BM, Ramsperger-Gleixner M. , et al. Attenuation of transplant arteriosclerosis with clopidogrel is associated with a reduction of infiltrating dendritic cells and macrophages in murine aortic allografts. Transplantation 2009; 87 (02) 207-216
• 23 Abele S, Weyand M, Wollin M. , et al. Clopidogrel reduces the development of transplant arteriosclerosis. J Thorac Cardiovasc Surg 2006; 131 (05) 1161-1166
• 24 Eckl S, Heim C, Abele-Ohl S. , et al. Combination of clopidogrel and everolimus dramatically reduced the development of transplant arteriosclerosis in murine aortic allografts. Transpl Int 2010; 23 (09) 959-966
• 25 Motsch B, Heim C, Koch N, Ramsperger-Gleixner M, Weyand M, Ensminger SM. Microvascular integrity plays an important role for graft survival after experimental skin transplantation. Transpl Immunol 2015; 33 (03) 204-209
• 26 Andreassen AK, Andersson B, Gustafsson F. , et al; SCHEDULE investigators. Everolimus initiation with early calcineurin inhibitor withdrawal in de novo heart transplant recipients: three-year results from the randomized SCHEDULE study. Am J Transplant 2016; 16 (04) 1238-1247
• 27 Arora S, Andreassen AK, Andersson B. , et al; SCHEDULE (SCandinavian HEart transplant everolimus De novo stUdy with earLy calcineurin inhibitors avoidancE) Investigators. The effect of everolimus initiation and calcineurin inhibitor elimination on cardiac allograft vasculopathy in de novo recipients: one-year results of a Scandinavian randomized trial. Am J Transplant 2015; 15 (07) 1967-1975
• 28 Tona F, Fedrigo M, Famoso G. , et al. Everolimus prevents coronary microvasculopathy in heart transplant recipients with normal coronary angiograms: an anatomo-functional study. Transplant Proc 2014; 46 (07) 2339-2344
• 29 Yan T, Luo C, Yang X, Ji L, Luo S. [Short-term use of rapamycin combined with Tregs prolongs mouse cardiac graft survival but attenuates recipient's anti-tumor immunity]. Xibao Yu Fenzi Mianyixue Zazhi 2017; 33 (02) 174-178
• 30 Zhang A, Wang K, Zhou C. , et al. Knockout of microRNA-155 ameliorates the Th1/Th17 immune response and tissue injury in chronic rejection. J Heart Lung Transplant 2017; 36 (02) 175-184
• 31 Kleinert E, Langenmayer MC, Reichart B. , et al. Ribonuclease (RNase) prolongs survival of grafts in experimental heart transplantation. J Am Heart Assoc 2016; 5 (05) e003429
• 32 Nakamura K, Inami M, Morio H. , et al. AS2553627, a novel JAK inhibitor, prevents chronic rejection in rat cardiac allografts. Eur J Pharmacol 2017; 796: 69-75
• 33 Hoskova L, Malek I, Kopkan L. , et al. Pathophysiological mechanisms of calcineurin inhibitor-induced nephrotoxicity and arterial hypertension. Physiol Res 2017; 66 (02) 167-180
• 34 Zhang T, Pierson III RN, Azimzadeh AM. Update on CD40 and CD154 blockade in transplant models. Immunotherapy 2015; 7 (08) 899-911
• 35 Merola J, Jane-Wit DD, Pober JS. Recent advances in allograft vasculopathy. Curr Opin Organ Transplant 2017; 22 (01) 1-7
• 36 Wood KJ, Bushell A, Hester J. Regulatory immune cells in transplantation. Nat Rev Immunol 2012; 12 (06) 417-430
• 37 Sommer W, Buechler G, Jansson K. , et al. Irradiation before and donor splenocyte infusion immediately after transplantation induce tolerance to lung, but not heart allografts in miniature swine. Transpl Int 2017; 30 (04) 420-431
• 38 Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol 2014; 5: 491
• 39 Luckheeram RV, Zhou R, Verma AD, Xia B. CD4⁺T cells: differentiation and functions. Clin Dev Immunol 2012; 2012 (12) 925135
• 40 Sprague AH, Khalil RA. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 2009; 78 (06) 539-552
• 41 Franz M, Doll F, Grün K. , et al. Targeted delivery of interleukin-10 to chronic cardiac allograft rejection using a human antibody specific to the extra domain A of fibronectin. Int J Cardiol 2015; 195: 311-322
• 42 Moll HP, Lee A, Peterson CR. , et al. A20 haploinsufficiency aggravates transplant arteriosclerosis in mouse vascular allografts: implications for clinical transplantation. Transplantation 2016; 100 (11) e106-e116
• 43 Siracuse JJ, Fisher MD, da Silva CG. , et al. A20-mediated modulation of inflammatory and immune responses in aortic allografts and development of transplant arteriosclerosis. Transplantation 2012; 93 (04) 373-382
• 44 Wedel J, Hottenrott MC, Bulthuis M, Huitema S, Yard BA, Hillebrands JL. N-octanoyl dopamine attenuates the development of transplant vasculopathy in rat aortic allografts via smooth muscle cell protective mechanisms. Transplantation 2016; 100 (01) 80-90
• 45 Benck U, Hoeger S, Brinkkoetter PT. , et al. Effects of donor pre-treatment with dopamine on survival after heart transplantation: a cohort study of heart transplant recipients nested in a randomized controlled multicenter trial. J Am Coll Cardiol 2011; 58 (17) 1768-1777
• 46 Deuse T, Hua X, Wang D. , et al. Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. Nature 2014; 509 (7502): 641-644
• 47 James MO, Jahn SC, Zhong G, Smeltz MG, Hu Z, Stacpoole PW. Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1. Pharmacol Ther 2017; 170: 166-180
• 48 Booth AJ, Csencsits-Smith K, Wood SC, Lu G, Lipson KE, Bishop DK. Connective tissue growth factor promotes fibrosis downstream of TGFbeta and IL-6 in chronic cardiac allograft rejection. Am J Transplant 2010; 10 (02) 220-230
• 49 Chatur S, Wong BW, Carthy JM, McManus BM. Inhibition of vascular endothelial growth factor reduces cardiac allograft vasculopathy. J Heart Lung Transplant 2016; 35 (09) 1124-1130
• 50 Raines EW. PDGF and cardiovascular disease. Cytokine Growth Factor Rev 2004; 15 (04) 237-254
• 51 Levitzki A. PDGF receptor kinase inhibitors for the treatment of restenosis. Cardiovasc Res 2005; 65 (03) 581-586
• 52 Tuuminen R, Dashkevich A, Keränen MA. , et al. Platelet-derived growth factor-B protects rat cardiac allografts from ischemia-reperfusion injury. Transplantation 2016; 100 (02) 303-313
• 53 Wedel J, Jansen PA, Botman PN, Rutjes FP, Schalkwijk J, Hillebrands JL. Pharmacological inhibition of vanin activity attenuates transplant vasculopathy in rat aortic allografts. Transplantation 2016; 100 (08) 1656-1666
• 54 Skorić B, Čikeš M, Ljubas Maček J. , et al. Cardiac allograft vasculopathy: diagnosis, therapy, and prognosis. Croat Med J 2014; 55 (06) 562-576
• 55 Labarrere CA, Jaeger BR, Kassab GS. Cardiac allograft vasculopathy: Microvascular arteriolar capillaries ('capioles") and survival. Front Biosci (Elite Ed) 2017; 9: 110-128
• 56 Labarrere CA, Jaeger BR. Biomarkers of heart transplant rejection: the good, the bad, and the ugly!. Transl Res 2012; 159 (04) 238-251
• 57 Freystaetter K, Andreas M, Bilban M. , et al. The recipient's heme oxygenase-1 promoter region polymorphism is associated with cardiac allograft vasculopathy. Transpl Int 2017; 30 (05) 510-518
• 58 Deuse T, Hua X, Stubbendorff M. , et al. The selective JAK1/3-inhibitor R507 mitigates obliterative airway disease both with systemic administration and aerosol inhalation. Transplantation 2016; 100 (05) 1022-1031
• 59 Guihaire J, Itagaki R, Stubbendorff M. , et al. Orthotopic tracheal transplantation using human bronchus: an original xenotransplant model of obliterative airway disorder. Transpl Int 2016; 29 (12) 1337-1348
• 60 Hayes Jr D. A review of bronchiolitis obliterans syndrome and therapeutic strategies. J Cardiothorac Surg 2011; 6: 92
• 61 Fiser SM, Tribble CG, Long SM. , et al. Ischemia-reperfusion injury after lung transplantation increases risk of late bronchiolitis obliterans syndrome. Ann Thorac Surg 2002; 73 (04) 1041-1047 , discussion 1047–1048
• 62 Heim C, Motsch B, Jalilova S. , et al. Reduction of obliterative bronchiolitis (OB) by prolyl-hydroxylase-inhibitors activating hypoxia-inducible transcription factors in an experimental mouse model. Transpl Immunol 2016; 39: 66-73
• 63 von Suesskind-Schwendi M, Heigel E, Pfaehler S. , et al. Protective function of pirfenidone and everolimus on the development of chronic allograft rejection after experimental lung transplantation. Histol Histopathol 2016; 31 (07) 793-805
• 64 Belperio JA, Lake K, Tazelaar H, Keane MP, Strieter RM, Lynch III JP. Bronchiolitis obliterans syndrome complicating lung or heart-lung transplantation. Semin Respir Crit Care Med 2003; 24 (05) 499-530
• 65 Gräfe K. Rheumatoide arthritis - Zweiter Anlauf für Tofacitinib. Pharm Ztg 2016; 39
• 66 Sommer W, Knöfel AK, Madrahimov N. , et al. Allogeneic CD4+CD25 high T cells regulate obliterative bronchiolitis of heterotopic bronchus allografts in both porcinized and humanized mouse models. Transplantation 2015; 99 (03) 482-491
• 67 Salman J, Ius F, Knoefel AK. , et al. Association of higher CD4+ CD25 high CD127 low, FoxP3+, and IL-2+ T cell frequencies early after lung transplantation with less chronic lung allograft dysfunction at two years. Am J Transplant 2017; 17 (06) 1637-1648
• 68 Salama M, Jaksch P, Andrukhova O, Taghavi S, Klepetko W, Aharinejad S. Endothelin-1 is a useful biomarker for early detection of bronchiolitis obliterans in lung transplant recipients. J Thorac Cardiovasc Surg 2010; 140 (06) 1422-1427
• 69 LaPar DJ, Burdick MD, Emaminia A. , et al. Circulating fibrocytes correlate with bronchiolitis obliterans syndrome development after lung transplantation: a novel clinical biomarker. Ann Thorac Surg 2011; 92 (02) 470-477 , discussion 477
• 70 Budding K, van de Graaf EA, Kardol-Hoefnagel T. , et al. Soluble CD59 is a Novel Biomarker for the Prediction of Obstructive Chronic Lung Allograft Dysfunction After Lung Transplantation. Sientific Reports 2016; 06: 26274
• 71 Willis BC, Borok Z. Epithelial-mesenchymal transition: potential role in obliterative bronchiolitis?. Thorax 2009; 64 (09) 742-743
• 72 Boehler A, Estenne M. Post-transplant bronchiolitis obliterans. Eur Respir J 2003; 22 (06) 1007-1018