Advertisement

Current Transplantation Reports

, Volume 4, Issue 3, pp 226–237 | Cite as

Newer Immunosuppression and Strategies on the Horizon in Heart Transplantation

  • Kaspar BrochEmail author
  • Einar Gude
  • Arne K. Andreassen
  • Lars Gullestad
Thoracic Transplantation (J Kobashigawa, Section Editor)
  • 58 Downloads
Part of the following topical collections:
  1. Topical Collection on Thoracic Transplantation

Abstract

Purpose of Review

Balanced immunosuppressive therapy is the key to long-term survival after allograft transplantation. With a worldwide median recipient/graft survival of more than 11 years, heart transplantation is a highly successful treatment for selected patients with end-stage heart failure. However, current immunosuppressive regimens are associated with adverse effects. In the balance between acute rejection, cardiac allograft vasculopathy, infections and an increased risk of malignancy, there is room for improvement. The aim of this review article is to present an overview of immunosuppressive mechanisms and new immune therapy strategies in heart transplantation and to highlight emerging approaches in this field that may influence our immunosuppressive strategies in the future.

Recent Findings

Calcineurin inhibitors have been the central drug class in post-transplant immunosuppressive regimens. New trials have explored alternative drugs, such as inhibitors of mechanistic target of rapamycin and belatacept. There is ongoing research on the development of strategies to induce long-term allograft tolerance.

Summary

This review briefly introduces allograft rejection immunology, and sums up contemporary immunosuppressive strategies with emphasis on the development of calcineurin inhibitor-sparing regimens and the prospect of achieving long-term tolerance.

Keywords

Heart transplantation Immunosuppression Calcineurin inhibitor Tolerance 

Notes

Compliance with Ethical Standards

Conflict of Interest

Arene Andreassen, Einar Gude, Lars Gullestad, and Kaspar Broch declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Calne RY, White DJ, Rolles K, Smith DP, Herbertson BM. Prolonged survival of pig orthotopic heart grafts treated with cyclosporin A. Lancet. 1978;1:1183–5.CrossRefPubMedGoogle Scholar
  2. 2.
    DiBardino DJ. The history and development of cardiac transplantation. Tex Heart Inst J. 1999;26:198–205.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Gude E, Simonsen S, Geiran OR, Fiane AE, Gullestad L, Arora S, et al. Pulmonary hypertension in heart transplantation: discrepant prognostic impact of pre-operative compared with 1-year post-operative right heart hemodynamics. J Heart Lung Transplant. 2010;29:216–23.CrossRefPubMedGoogle Scholar
  4. 4.
    Lund LH, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Goldfarb S, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-second official adult heart transplantation report—2015; focus theme: early graft failure. J Heart Lung Transplant. 2015;34:1244–54.CrossRefPubMedGoogle Scholar
  5. 5.
    Lund LH, Edwards LB, Dipchand AI, Goldfarb S, Kucheryavaya AY, Levvey BJ, et al. 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;35:1158–69.CrossRefPubMedGoogle Scholar
  6. 6.
    Tallaj JA, Pamboukian SV, George JF, Kirklin JK, Brown RN, McGiffin DC, et al. Have risk factors for mortality after heart transplantation changed over time? Insights from 19 years of Cardiac Transplant Research Database study. J Heart Lung Transplant. 2014;33:1304–11.CrossRefPubMedGoogle Scholar
  7. 7.
    Lund LH, Edwards LB, Kucheryavaya AY, Dipchand AI, Benden C, Christie JD, et al. The registry of the International Society for Heart and Lung Transplantation: thirtieth official adult heart transplant report—2013; focus theme: age. J Heart Lung Transplant. 2013;32:951–64.CrossRefPubMedGoogle Scholar
  8. 8.
    Hozumi N, Tonegawa S. Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions. Proc Natl Acad Sci U S A. 1976;73:3628–32.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Vettermann C, Schlissel MS. Allelic exclusion of immunoglobulin genes: models and mechanisms. Immunol Rev. 2010;237:22–42.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T cells. Annu Rev Immunol. 2003;21:139–76.CrossRefPubMedGoogle Scholar
  11. 11.
    Hinterberger M, Aichinger M, Prazeres da Costa O, Voehringer D, Hoffmann R, Klein L. Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat Immunol. 2010;11:512–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Harty JT, Tvinnereim AR, White DW. CD8+ T cell effector mechanisms in resistance to infection. Annu Rev Immunol. 2000;18:275–308.CrossRefPubMedGoogle Scholar
  13. 13.
    Goldberg AL, Rock KL. Proteolysis, proteasomes and antigen presentation. Nature. 1992;357:375–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol. 1996;14:233–58.CrossRefPubMedGoogle Scholar
  15. 15.
    Jiang H, Chess L. Regulation of immune responses by T cells. N Engl J Med. 2006;354:1166–76.CrossRefPubMedGoogle Scholar
  16. 16.
    Pelanda R, Torres RM. Central B-cell tolerance: where selection begins. Cold Spring Harb Perspect Biol. 2012;4:a007146.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Crotty S. A brief history of T cell help to B cells. Nat Rev Immunol. 2015;15:185–9.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Li Z, Woo CJ, Iglesias-Ussel MD, Ronai D, Scharff MD. The generation of antibody diversity through somatic hypermutation and class switch recombination. Genes Dev. 2004;18:1–11.CrossRefPubMedGoogle Scholar
  19. 19.
    Stavnezer J, Amemiya CT. Evolution of isotype switching. Semin Immunol. 2004;16:257–75.CrossRefPubMedGoogle Scholar
  20. 20.
    Kurosaki T, Kometani K, Ise W. Memory B cells. Nat Rev Immunol. 2015;15:149–59.CrossRefPubMedGoogle Scholar
  21. 21.
    • Colvin MM, Cook JL, Chang P, Francis G, Hsu DT, Kiernan MS, et al. Antibody-mediated rejection in cardiac transplantation: emerging knowledge in diagnosis and management: a scientific statement from the American Heart Association. Circulation. 2015;131:1608–39. This scientific statement is a thorough review of the mechanisms behind antibody-mediated rejection in heart transplant recipients and current treatment options.CrossRefPubMedGoogle Scholar
  22. 22.
    Miyara M, Sakaguchi S. Natural regulatory T cells: mechanisms of suppression. Trends Mol Med. 2007;13:108–16.CrossRefPubMedGoogle Scholar
  23. 23.
    Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006;212:8–27.CrossRefPubMedGoogle Scholar
  24. 24.
    Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–87.CrossRefPubMedGoogle Scholar
  25. 25.
    Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, et al. Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol. 1998;10:1969–80.CrossRefPubMedGoogle Scholar
  26. 26.
    Thomson AW. Tolerogenic dendritic cells: all present and correct? Am J Transplant. 2010;10:214–9.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Popow I, Leitner J, Grabmeier-Pfistershammer K, Majdic O, Zlabinger GJ, Kundi M, et al. A comprehensive and quantitative analysis of the major specificities in rabbit antithymocyte globulin preparations. Am J Transplant. 2013;13:3103–13.CrossRefPubMedGoogle Scholar
  28. 28.
    Whitson BA, Kilic A, Lehman A, Wehr A, Hasan A, Haas G, et al. Impact of induction immunosuppression on survival in heart transplant recipients: a contemporary analysis of agents. Clin Transpl. 2015;29:9–17.CrossRefGoogle Scholar
  29. 29.
    Ansari D, Lund LH, Stehlik J, Andersson B, Hoglund P, Edwards L, et al. Induction with anti-thymocyte globulin in heart transplantation is associated with better long-term survival compared with basiliximab. J Heart Lung Transplant. 2015;34:1283–91.CrossRefPubMedGoogle Scholar
  30. 30.
    Azarbal B, Cheng R, Vanichsarn C, Patel JK, Czer LS, Chang DH, et al. Induction therapy with antithymocyte globulin in patients undergoing cardiac transplantation is associated with decreased coronary plaque progression as assessed by intravascular ultrasound. Circ Heart Fail. 2016;9:e002252.PubMedGoogle Scholar
  31. 31.
    Mangiola M, Marrari M, Feingold B, Zeevi A. Significance of anti-HLA antibodies on adult and pediatric heart allograft outcomes. Front Immunol. 2017;8:4.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Cole RM, Kobashigawa JA. Desensitization strategies pre- and post-cardiac transplantation. Curr Treat Options Cardiovasc Med. 2016;18:8.CrossRefPubMedGoogle Scholar
  33. 33.
    Kobashigawa JA, Patel JK, Kittleson MM, Kawano MA, Kiyosaki KK, Davis SN, et al. The long-term outcome of treated sensitized patients who undergo heart transplantation. Clin Transpl. 2011;25:E61–7.CrossRefGoogle Scholar
  34. 34.
    Patel J, Everly M, Chang D, Kittleson M, Reed E, Kobashigawa J. Reduction of alloantibodies via proteasome inhibition in cardiac transplantation. J Heart Lung Transplant. 2011;30:1320–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Reinsmoen NL, Patel J, Mirocha J, Lai CH, Naim M, Ong G, et al. Optimizing transplantation of sensitized heart candidates using 4 antibody detection assays to prioritize the assignment of unacceptable antigens. J Heart Lung Transplant. 2016;35:165–72.CrossRefPubMedGoogle Scholar
  36. 36.
    Sarwal MM. Fingerprints of transplant tolerance suggest opportunities for immunosuppression minimization. Clin Biochem. 2016;49:404–10.CrossRefPubMedGoogle Scholar
  37. 37.
    Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S, et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010;29:914–56.CrossRefPubMedGoogle Scholar
  38. 38.
    Pham MX, Teuteberg JJ, Kfoury AG, Starling RC, Deng MC, Cappola TP, et al. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med. 2010;362:1890–900.CrossRefPubMedGoogle Scholar
  39. 39.
    Starling RC, Stehlik J, Baran DA, Armstrong B, Stone JR, Ikle D, et al. Multicenter analysis of immune biomarkers and heart transplant outcomes: results of the clinical trials in organ transplantation-05 study. Am J Transplant. 2016;16:121–36.CrossRefPubMedGoogle Scholar
  40. 40.
    Michaels PJ, Espejo ML, Kobashigawa J, Alejos JC, Burch C, Takemoto S, et al. Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease. J Heart Lung Transplant. 2003;22:58–69.CrossRefPubMedGoogle Scholar
  41. 41.
    Kfoury AG, Renlund DG, Snow GL, Stehlik J, Folsom JW, Fisher PW, et al. A clinical correlation study of severity of antibody-mediated rejection and cardiovascular mortality in heart transplantation. J Heart Lung Transplant. 2009;28:51–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Singh N, Vanlandingham S, Halverson C, Marques MB, Tallaj J, Kirklin J, et al. Therapeutic plasma exchange rapidly improves cardiac allograft function in patients with presumed antibody-mediated rejection. J Clin Apher. 2014;29:316–21.CrossRefPubMedGoogle Scholar
  43. 43.
    Garrett HE Jr, Duvall-Seaman D, Helsley B, Groshart K. Treatment of vascular rejection with rituximab in cardiac transplantation. J Heart Lung Transplant. 2005;24:1337–42.CrossRefPubMedGoogle Scholar
  44. 44.
    Wang H, Jiang J, Liu W, Kubelik D, Chen G, Gies D, et al. Prevention of acute vascular rejection by a functionally blocking anti-C5 monoclonal antibody combined with cyclosporine. Transplantation. 2005;79:1121–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Thomas KA, Valenzuela NM, Gjertson D, Mulder A, Fishbein MC, Parry GC, et al. An anti-C1s monoclonal, TNT003, inhibits complement activation induced by antibodies against HLA. Am J Transplant. 2015;15:2037–49.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Hogan PG, Chen L, Nardone J, Rao A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003;17:2205–32.CrossRefPubMedGoogle Scholar
  47. 47.
    Taylor DO, Barr ML, Radovancevic B, Renlund DG, Mentzer RM Jr, Smart FW, et al. A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus. J Heart Lung Transplant. 1999;18:336–45.CrossRefPubMedGoogle Scholar
  48. 48.
    Reichart B, Meiser B, Vigano M, Rinaldi M, Martinelli L, Yacoub M, et al. European multicenter tacrolimus (FK506) heart pilot study: one-year results—European Tacrolimus Multicenter Heart Study Group. J Heart Lung Transplant. 1998;17:775–81.PubMedGoogle Scholar
  49. 49.
    Grimm M, Rinaldi M, Yonan NA, Arpesella G, Arizon Del Prado JM, Pulpon LA, et al. Superior prevention of acute rejection by tacrolimus vs. cyclosporine in heart transplant recipients—a large European trial. Am J Transplant. 2006;6:1387–97.CrossRefPubMedGoogle Scholar
  50. 50.
    Kobashigawa JA, Miller LW, Russell SD, Ewald GA, Zucker MJ, Goldberg LR, et al. Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report. Am J Transplant. 2006;6:1377–86.CrossRefPubMedGoogle Scholar
  51. 51.
    Guethoff S, Meiser BM, Groetzner J, Eifert S, Grinninger C, Ueberfuhr P, et al. Ten-year results of a randomized trial comparing tacrolimus versus cyclosporine a in combination with mycophenolate mofetil after heart transplantation. Transplantation. 2013;95:629–34.CrossRefPubMedGoogle Scholar
  52. 52.
    Keogh A. Calcineurin inhibitors in heart transplantation. J Heart Lung Transplant. 2004;23:S202–6.CrossRefPubMedGoogle Scholar
  53. 53.
    Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012;30:39–68.CrossRefPubMedGoogle Scholar
  54. 54.
    Farb A, John M, Acampado E, Kolodgie FD, Prescott MF, Virmani R. Oral everolimus inhibits in-stent neointimal growth. Circulation. 2002;106:2379–84.CrossRefPubMedGoogle Scholar
  55. 55.
    Kushwaha SS, Raichlin E, Sheinin Y, Kremers WK, Chandrasekaran K, Brunn GJ, et al. Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients. Eur Heart J. 2008;29:2742–50.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Shioi T, McMullen JR, Tarnavski O, Converso K, Sherwood MC, Manning WJ, et al. Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation. 2003;107:1664–70.CrossRefPubMedGoogle Scholar
  57. 57.
    Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med. 2003;349:847–58.CrossRefPubMedGoogle Scholar
  58. 58.
    Eisen HJ, Kobashigawa J, Starling RC, Pauly DF, Kfoury A, Ross H, et al. Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial. Am J Transplant. 2013;13:1203–16.CrossRefPubMedGoogle Scholar
  59. 59.
    Lehmkuhl HB, Arizon J, Vigano M, Almenar L, Gerosa G, Maccherini M, et al. Everolimus with reduced cyclosporine versus MMF with standard cyclosporine in de novo heart transplant recipients. Transplantation. 2009;88:115–22.CrossRefPubMedGoogle Scholar
  60. 60.
    Gullestad L, Iversen M, Mortensen SA, Eiskjaer H, Riise GC, Mared L, et al. Everolimus with reduced calcineurin inhibitor in thoracic transplant recipients with renal dysfunction: a multicenter, randomized trial. Transplantation. 2010;89:864–72.CrossRefPubMedGoogle Scholar
  61. 61.
    Zuckermann A, Wang SS, Ross H, Frigerio M, Eisen HJ, Bara C, et al. Efficacy and safety of low-dose cyclosporine with everolimus and steroids in de novo heart transplant patients: a multicentre, randomized trial. J Transplant. 2011;2011:535983.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Cornu C, Dufays C, Gaillard S, Gueyffier F, Redonnet M, Sebbag L, et al. Impact of the reduction of calcineurin inhibitors on renal function in heart transplant patients: a systematic review and meta-analysis. Br J Clin Pharmacol. 2014;78:24–32.CrossRefPubMedGoogle Scholar
  63. 63.
    Gude E, Gullestad L, Andreassen AK. Everolimus immunosuppression for renal protection, reduction of allograft vasculopathy and prevention of allograft rejection in de-novo heart transplant recipients: could we have it all? Curr Opin Organ Transplant. 2017;22:198–206.Google Scholar
  64. 64.
    • Andreassen AK, Andersson B, Gustafsson F, Eiskjaer H, Radegran G, Gude E, et al. Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial. Am J Transplant. 2014;14:1828–38. This randomized controlled trial showed that an early switch from cyclosporine to everolimus provides renoprotection in de novo heart transplant recipients.CrossRefPubMedGoogle Scholar
  65. 65.
    Andreassen AK, Andersson B, Gustafsson F, Eiskjaer H, Radegran G, Gude E, et al. 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;16:1238–47.CrossRefPubMedGoogle Scholar
  66. 66.
    Arora S, Andreassen AK, Andersson B, Gustafsson F, Eiskjaer H, Botker HE, et al. 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;15:1967–75.CrossRefPubMedGoogle Scholar
  67. 67.
    Hunt JB, Starling RC, Rabágo G, Banner NR, Kobashigawa J, Keogh A, et al. Premature termination of a prospective, open label, randomized, multicenter study of sirolimus to replace calcineurin inhibitors (CNI) in a standard care regimen of CNI, MMF and corticosteroids early after heart transplantation. J Heart Lung Transplant. 2007;26:S203.Google Scholar
  68. 68.
    Qiu Y, Wang X, Fan J, Rao Z, Lu Y, Lin T. Conversion from calcineurin inhibitors to mammalian target-of-rapamycin inhibitors in heart transplant recipients: a meta-analysis of randomized controlled trials. Transplant Proc. 2015;47:2952–6.CrossRefPubMedGoogle Scholar
  69. 69.
    Deuse T, Bara C, Barten MJ, Hirt SW, Doesch AO, Knosalla C, et al. The MANDELA study: a multicenter, randomized, open-label, parallel group trial to refine the use of everolimus after heart transplantation. Contemp Clin Trials. 2015;45:356–63.CrossRefPubMedGoogle Scholar
  70. 70.
    Larsen CP, Pearson TC, Adams AB, Tso P, Shirasugi N, Strobert E, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant. 2005;5:443–53.CrossRefPubMedGoogle Scholar
  71. 71.
    Vincenti F, Charpentier B, Vanrenterghem Y, Rostaing L, Bresnahan B, Darji P, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010;10:535–46.CrossRefPubMedGoogle Scholar
  72. 72.
    Durrbach A, Pestana JM, Pearson T, Vincenti F, Garcia VD, Campistol J, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant. 2010;10:547–57.CrossRefPubMedGoogle Scholar
  73. 73.
    Archdeacon P, Dixon C, Belen O, Albrecht R, Meyer J. Summary of the US FDA approval of belatacept. Am J Transplant. 2012;12:554–62.CrossRefPubMedGoogle Scholar
  74. 74.
    • Vincenti F, Rostaing L, Grinyo J, Rice K, Steinberg S, Gaite L, et al. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med. 2016;374:333–43. This trial confirmed the feasibility of non-calcineurin inhibitor-based therapy in solid organ transplantation.CrossRefPubMedGoogle Scholar
  75. 75.
    Durrbach A, Pestana JM, Florman S, Del Carmen RM, Rostaing L, Kuypers D, et al. Long-term outcomes in belatacept- versus cyclosporine-treated recipients of extended criteria donor kidneys: final results from BENEFIT-EXT, a phase III randomized study. Am J Transplant. 2016;16:3192–201.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    • Klintmalm GB, Feng S, Lake JR, Vargas HE, Wekerle T, Agnes S, et al. Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II randomized study. Am J Transplant. 2014;14:1817–27. This trial illustrates that results regarding immunosuppressive therapy are organ specific and cannot necessarily be extrapolated to other organs.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Madariaga ML, Kreisel D, Madsen JC. Organ-specific differences in achieving tolerance. Curr Opin Organ Transplant. 2015;20:392–9.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Zhang Z, Zhu L, Quan D, Garcia B, Ozcay N, Duff J, et al. Pattern of liver, kidney, heart, and intestine allograft rejection in different mouse strain combinations. Transplantation. 1996;62:1267–72.CrossRefPubMedGoogle Scholar
  79. 79.
    •• Kawai T, Sachs DH, Sykes M, Cosimi AB. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med. 2013;368:1850–2. This proof-of-concept trial showed that induction of tolerance is achievable in solid organ transplant recipients.Google Scholar
  80. 80.
    Leventhal JR, Elliott MJ, Yolcu ES, Bozulic LD, Tollerud DJ, Mathew JM, et al. Immune reconstitution/immunocompetence in recipients of kidney plus hematopoietic stem/facilitating cell transplants. Transplantation. 2015;99:288–98.CrossRefPubMedGoogle Scholar
  81. 81.
    Kawai T, Cosimi AB, Wee SL, Houser S, Andrews D, Sogawa H, et al. Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys. Transplantation. 2002;73:1757–64.CrossRefPubMedGoogle Scholar
  82. 82.
    Gorantla VS, Schneeberger S, Brandacher G, Sucher R, Zhang D, Lee WP, et al. T regulatory cells and transplantation tolerance. Transplant Rev. 2010;24:147–59.CrossRefGoogle Scholar
  83. 83.
    Boardman D, Maher J, Lechler R, Smyth L, Lombardi G. Antigen-specificity using chimeric antigen receptors: the future of regulatory T-cell therapy? Biochem Soc Trans. 2016;44:342–8.CrossRefPubMedGoogle Scholar
  84. 84.
    Tsang JY, Tanriver Y, Jiang S, Xue SA, Ratnasothy K, Chen D, et al. Conferring indirect allospecificity on CD4+CD25+ Tregs by TCR gene transfer favors transplantation tolerance in mice. J Clin Invest. 2008;118:3619–28.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Hall BM, Tran G, Hodgkinson SJ. Alloantigen specific T regulatory cells in transplant tolerance. Int Immunopharmacol. 2009;9:570–4.CrossRefPubMedGoogle Scholar
  86. 86.
    Sagoo P, Ali N, Garg G, Nestle FO, Lechler RI, Lombardi G. Human regulatory T cells with alloantigen specificity are more potent inhibitors of alloimmune skin graft damage than polyclonal regulatory T cells. Sci Transl Med. 2011;3:83ra42.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Noyan F, Zimmermann K, Hardtke-Wolenski M, Knoefel A, Schulde E, Geffers R, et al. Prevention of allograft rejection by use of regulatory T cells with an MHC-specific chimeric antigen receptor. Am J Transplant. 2016;17:917–30.CrossRefGoogle Scholar
  88. 88.
    Landwehr-Kenzel S, Issa F, Luu SH, Schmuck M, Lei H, Zobel A, et al. Novel GMP-compatible protocol employing an allogeneic B cell bank for clonal expansion of allospecific natural regulatory T cells. Am J Transplant. 2014;14:594–606.CrossRefPubMedGoogle Scholar
  89. 89.
    Yates SF, Paterson AM, Nolan KF, Cobbold SP, Saunders NJ, Waldmann H, et al. Induction of regulatory T cells and dominant tolerance by dendritic cells incapable of full activation. J Immunol. 2007;179:967–76.CrossRefPubMedGoogle Scholar
  90. 90.
    Luo X, Tarbell KV, Yang H, Pothoven K, Bailey SL, Ding R, et al. Dendritic cells with TGF-beta1 differentiate naive CD4+CD25- T cells into islet-protective Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A. 2007;104:2821–6.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Kleist C, Sandra-Petrescu F, Jiga L, Dittmar L, Mohr E, Greil J, et al. Generation of suppressive blood cells for control of allograft rejection. Clin Sci. 2015;128:593–607.CrossRefPubMedGoogle Scholar
  92. 92.
    Komarowska I, Coe D, Wang G, Haas R, Mauro C, Kishore M, et al. Hepatocyte growth factor receptor c-met instructs T cell cardiotropism and promotes T cell migration to the heart via autocrine chemokine release. Immunity. 2015;42:1087–99.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Kaspar Broch
    • 1
    Email author
  • Einar Gude
    • 1
  • Arne K. Andreassen
    • 1
    • 2
  • Lars Gullestad
    • 1
    • 2
  1. 1.Department of CardiologyOslo University Hospital, RikshospitaletOsloNorway
  2. 2.Faculty of MedicineUniversity of OsloOsloNorway

Personalised recommendations