Future of Solid Organ Transplantation: Organ-Specific Tolerance

Main Article Content

Yusuf Ercin Sonmez

Abstract

A transplant between two people who are not genetically identical is called an allotransplant and the process is called allotransplantation. Donor organs and tissues can be from people who are living, or people who have died because of a significant brain injury or lack of circulation. Allotransplantation can create a rejection process where the immune system of the recipient attacks the foreign donor organ or tissue and destroys it. The recipient may need to take immunosuppressive medication for the rest of their life to reduce the risk of rejection of the donated organ. In general, deliberately induced immunosuppression is performed to prevent the body from rejecting an organ transplant. The adverse effects associated with these agents and the risks of long-term immunosuppression present a number of challenges for the clinician. Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in a given organism.

Article Details

How to Cite
Sonmez, Y. E. “Future of Solid Organ Transplantation: Organ-Specific Tolerance”. KIDNEYS, vol. 10, no. 3, Sept. 2021, pp. 130-6, doi:10.22141/2307-1257.10.3.2021.239589.
Section
Guest Articles

References

Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007 Dec 20;357(25):2601-14. doi: 10.1056/NEJMra064928.

Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplantation in the United States. Am J Transplant. 2004 Jun;4(6):905-13. doi: 10.1111/j.1600-6143.2004.00450.x.

Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003 Sep 4;349(10):931-40. doi: 10.1056/NEJMoa021744.

Li L, Wozniak LJ, Rodder S, et al. A common peripheral blood gene set for diagnosis of operational tolerance in pediatric and adult liver transplantation. Am J Transplant. 2012 May;12(5):1218-28. doi: 10.1111/j.1600-6143.2011.03928.x.

Bohne F, Martínez-Llordella M, Lozano JJ, et al. Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation. J Clin Invest. 2012 Jan;122(1):368-82. doi: 10.1172/JCI59411.

Sagoo P, Perucha E, Sawitzki B, et al. Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans. J Clin Invest. 2010 Jun;120(6):1848-61. doi: 10.1172/JCI39922.

Ashton-Chess J, Giral M, Brouard S, Soulillou JP. Spontaneous operational tolerance after immunosuppressive drug withdrawal in clinical renal allotransplantation. Transplantation. 2007 Nov 27;84(10):1215-9. doi: 10.1097/01.tp.0000290683.54937.1b.

Orlando G, Hematti P, Stratta RJ, et al. Clinical operational tolerance after renal transplantation: current status and future challenges. Ann Surg. 2010 Dec;252(6):915-28. doi: 10.1097/SLA.0b013e3181f3efb0.

Goldman M, Wood K. Transplantation research: will we ever reach the holy grail? Transplantation. 2009 May 15;87(9 Suppl):S99-100. doi: 10.1097/TP.0b013e3181a2e377.

Owen RD. Immunogenetıc consequences of vascular anastomoses between bovıne twıns. Science. 1945 Oct 19;102(2651):400-1. doi: 10.1126/science.102.2651.400.

Brent L. The discovery of immunologic tolerance. Hum Immunol. 1997 Feb;52(2):75-81. doi: 10.1016/S0198-8859(96)00289-3.

Ge W, Jiang J, Arp J, Liu W, Garcia B, Wang H. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation. 2010 Dec 27;90(12):1312-20. doi: 10.1097/TP.0b013e3181fed001.

Collins E, Gu F, Qi M, et al. Differential efficacy of human mesenchymal stem cells based on source of origin. J Immunol. 2014 Nov 1;193(9):4381-90. doi: 10.4049/jimmunol.1401636.

Qi H, Chen G, Huang Y, Si Z, Li J. Foxp3-modified bone marrow mesenchymal stem cells promotes liver allograft tolerance through the generation of regulatory T cells in rats. J Transl Med. 2015 Aug 21;13:274. doi: 10.1186/s12967-015-0638-2.

Feng S, Ekong UD, Lobritto SJ, et al. Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants. JAMA. 2012 Jan 18;307(3):283-93. doi: 10.1001/jama.2011.2014.

Levitsky J. Operational tolerance: past lessons and future prospects. Liver Transpl. 2011 Mar;17(3):222-32. doi: 10.1002/lt.22265.

Afzali B, Lechler RI, Hernandez-Fuentes MP. Allorecognition and the alloresponse: clinical implications. Tissue Antigens. 2007 Jun;69(6):545-56. doi: 10.1111/j.1399-0039.2007.00834.x.

Lamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant. 2011 Mar;11(3):450-62. doi: 10.1111/j.1600-6143.2010.03283.x.

Lodhi SA, Lamb KE, Meier-Kriesche HU. Solid organ allograft survival improvement in the United States: the long-term does not mirror the dramatic short-term success. Am J Transplant. 2011 Jun;11(6):1226-35. doi: 10.1111/j.1600-6143.2011.03539.x.

Newell KA, Phippard D, Turka LA. Regulatory cells and cell signatures in clinical transplantation tolerance. Curr Opin Immunol. 2011 Oct;23(5):655-9. doi: 10.1016/j.coi.2011.07.008.

Francis RS, Feng G, Tha-In T, Lyons IS, Wood KJ, Bushell A. Induction of transplantation tolerance converts potential effector T cells into graft-protective regulatory T cells. Eur J Immunol. 2011 Mar;41(3):726-38. doi: 10.1002/eji.201040509.

Feng G, Wood KJ, Bushell A. Interferon-gamma conditioning ex vivo generates CD25+CD62L+Foxp3+ regulatory T cells that prevent allograft rejection: potential avenues for cellular therapy. Transplantation. 2008 Aug 27;86(4):578-89. doi: 10.1097/TP.0b013e3181806a60.

Page E, Kwun J, Oh B, Knechtle S. Lymphodepletional strategies in transplantation. Cold Spring Harb Perspect Med. 2013 Jul 1;3(7):a015511. doi: 10.1101/cshperspect.a015511.

Groux H, O'Garra A, Bigler M, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997 Oct 16;389(6652):737-42. doi: 10.1038/39614.

Faria AM, Weiner HL. Oral tolerance. Immunol Rev. 2005 Aug;206:232-59. doi: 10.1111/j.0105-2896.2005.00280.x.

Vlad G, Cortesini R, Suciu-Foca N. CD8+ T suppressor cells and the ILT3 master switch. Hum Immunol. 2008 Nov;69(11):681-6. doi: 10.1016/j.humimm.2008.08.286.

Zhang ZX, Yang L, Young KJ, DuTemple B, Zhang L. Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nat Med. 2000 Jul;6(7):782-9. doi: 10.1038/77513.

Seino KI, Fukao K, Muramoto K, et al. Requirement for natural killer T (NKT) cells in the induction of allograft tolerance. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2577-81. doi: 10.1073/pnas.041608298.

Starzl Te, Marchıoro Tl, Waddell WR. The reversal of rejectıon in human renal homografts wıth subsequent development of homograft tolerance. Surg Gynecol Obstet. 1963 Oct;117:385-95.

Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant. 2004 Aug;4(8):1289-95. doi: 10.1111/j.1600-6143.2004.00515.x.

Womer KL, Kaplan B. Recent developments in kidney transplantation--a critical assessment. Am J Transplant. 2009 Jun;9(6):1265-71. doi: 10.1111/j.1600-6143.2009.02639.x.

Markmann J. Immunosuppression With Antithymocyte Globulin, Rituximab, Tacrolimus, Mycophenolate Mofetil and Sirolimus, Followed by Withdrawal of Immunosuppression, in Living-donor Renal Transplant Recipients. National Institute of Allergy and Infectious Diseases (NIAID), 2011. ClinicalTrials.gov identifier: NCT01318915.

Magliocca JF, Knechtle SJ. The evolving role of alemtuzumab (Campath-1H) for immunosuppressive therapy in organ transplantation. Transpl Int. 2006 Sep;19(9):705-14. doi: 10.1111/j.1432-2277.2006.00343.x.

Knechtle SJ, Pirsch JD, H Fechner J Jr, et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant. 2003 Jun;3(6):722-30. doi: 10.1034/j.1600-6143.2003.00120.x.

Pearl JP, Parris J, Hale DA, et al. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant. 2005 Mar;5(3):465-74. doi: 10.1111/j.1600-6143.2005.00759.x.

Trzonkowski P, Zilvetti M, Chapman S, et al. Homeostatic repopulation by CD28-CD8+ T cells in alemtuzumab-depleted kidney transplant recipients treated with reduced immunosuppression. Am J Transplant. 2008 Feb;8(2):338-47. doi: 10.1111/j.1600-6143.2007.02078.x.

Bloom D, Chang Z, Pauly K, et al. BAFF is increased in renal transplant patients following treatment with alemtuzumab. Am J Transplant. 2009 Aug;9(8):1835-45. doi: 10.1111/j.1600-6143.2009.02710.x.

Thompson SA, Jones JL, Cox AL, Compston DA, Coles AJ. B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis. J Clin Immunol. 2010 Jan;30(1):99-105. doi: 10.1007/s10875-009-9327-3.

Redfield RR 3rd, Rodriguez E, Parsons R, et al. Essential role for B cells in transplantation tolerance. Curr Opin Immunol. 2011 Oct;23(5):685-91. doi: 10.1016/j.coi.2011.07.011.

Newell KA, Asare A, Kirk AD, et al; Immune Tolerance Network ST507 Study Group. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest. 2010 Jun;120(6):1836-47. doi: 10.1172/JCI39933.

Eng HS, Bennett G, Tsiopelas E, et al. Anti-HLA donor-specific antibodies detected in positive B-cell crossmatches by Luminex predict late graft loss. Am J Transplant. 2008 Nov;8(11):2335-42. doi: 10.1111/j.1600-6143.2008.02387.x.

Lefaucheur C, Suberbielle-Boissel C, Hill GS, et al. Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation. Am J Transplant. 2008 Feb;8(2):324-31. doi: 10.1111/j.1600-6143.2007.02072.x.

Terasaki PI, Cai J. Human leukocyte antigen antibodies and chronic rejection: from association to causation. Transplantation. 2008 Aug 15;86(3):377-83. doi: 10.1097/TP.0b013e31817c4cb8.

Lee PC, Zhu L, Terasaki PI, Everly MJ. HLA-specific antibodies developed in the first year posttransplant are predictive of chronic rejection and renal graft loss. Transplantation. 2009 Aug 27;88(4):568-74. doi: 10.1097/TP.0b013e3181b11b72.

Liu C, Noorchashm H, Sutter JA, et al. B lymphocyte-directed immunotherapy promotes long-term islet allograft survival in nonhuman primates. Nat Med. 2007 Nov;13(11):1295-8. doi: 10.1038/nm1673.

Schneider P, MacKay F, Steiner V, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999 Jun 7;189(11):1747-56. doi: 10.1084/jem.189.11.1747.

Mackay F, Schneider P, Rennert P, Browning J. BAFF AND APRIL: a tutorial on B cell survival. Annu Rev Immunol. 2003;21:231-64. doi: 10.1146/annurev.immunol.21.120601.141152.

Xu H, He X, Liu Q, et al. Abnormal high expression of B-cell activating factor belonging to the TNF superfamily (BAFF) associated with long-term outcome in kidney transplant recipients. Transplant Proc. 2009 Jun;41(5):1552-6. doi: 10.1016/j.transproceed.2008.10.024.

Zarkhin V, Li L, Sarwal MM. BAFF may modulate the rate of B-cell repopulation after rituximab therapy for acute renal transplant rejection. Transplantation. 2009 Nov 27;88(10):1229-30. doi: 10.1097/TP.0b013e3181bbba1a.

Vivek K, Parsons R Rostami SY, et al. BLyS-directed immunotherapy purges alloreactive specificities from the primary B-cell repertoire and promotes humoral transplantation tolerance. Am J Transplant. 2011;11:171.

Jenkins MK, Schwartz RH. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med. 1987 Feb 1;165(2):302-19. doi: 10.1084/jem.165.2.302.

Munn DH, Sharma MD, Mellor AL. Ligation of B7-1/B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells. J Immunol. 2004 Apr 1;172(7):4100-10. doi: 10.4049/jimmunol.172.7.4100.

Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant. 2005 Mar;5(3):443-53. doi: 10.1111/j.1600-6143.2005.00749.x.

Larsen CP, Grinyó J, Medina-Pestana J, Vanrenterghem Y, et al. Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies. Transplantation. 2010 Dec 27;90(12):1528-35. doi: 10.1097/TP.0b013e3181ff87cd.

Vanrenterghem Y, Bresnahan B, Campistol J, et al. Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation. 2011 May 15;91(9):976-83. doi: 10.1097/TP.0b013e31820c10eb.

Pestana JO, Grinyo JM, Vanrenterghem Y, et al. Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am J Transplant. 2012 Mar;12(3):630-9. doi: 10.1111/j.1600-6143.2011.03914.x.

Thomson AW, Turnquist HR, Zahorchak AF, Raimondi G. Tolerogenic dendritic cell-regulatory T-cell interaction and the promotion of transplant tolerance. Transplantation. 2009 May 15;87(9 Suppl):S86-90. doi: 10.1097/TP.0b013e3181a2dcec.

Fujita S, Sato Y, Sato K, et al. Regulatory dendritic cells protect against cutaneous chronic graft-versus-host disease mediated through CD4+CD25+Foxp3+ regulatory T cells. Blood. 2007 Nov 15;110(10):3793-803. doi: 10.1182/blood-2007-04-086470.

Boks MA, Kager-Groenland JR, Haasjes MS, Zwaginga JJ, van Ham SM, ten Brinke A. IL-10-generated tolerogenic dendritic cells are optimal for functional regulatory T cell induction--a comparative study of human clinical-applicable DC. Clin Immunol. 2012 Mar;142(3):332-42. doi: 10.1016/j.clim.2011.11.011.

Brem-Exner BG, Sattler C, Hutchinson JA, et al. Macrophages driven to a novel state of activation have anti-inflammatory properties in mice. J Immunol. 2008 Jan 1;180(1):335-49. doi: 10.4049/jimmunol.180.1.335.

Singer NG, Caplan AI. Mesenchymal stem cells: mechanisms of inflammation. Annu Rev Pathol. 2011;6:457-78. doi: 10.1146/annurev-pathol-011110-130230.

Karlsson H, Erkers T, Nava S, Ruhm S, Westgren M, Ringdén O. Stromal cells from term fetal membrane are highly suppressive in allogeneic settings in vitro. Clin Exp Immunol. 2012 Mar;167(3):543-55. doi: 10.1111/j.1365-2249.2011.04540.x.

Duijvestein M, Molendijk I, Roelofs H, et al. Mesenchymal stromal cell function is not affected by drugs used in the treatment of inflammatory bowel disease. Cytotherapy. 2011 Oct;13(9):1066-73. doi: 10.3109/14653249.2011.597379.

Jankowski RA, Ildstad ST. Chimerism and tolerance: from freemartin cattle and neonatal mice to humans. Hum Immunol. 1997 Feb;52(2):155-61. doi: 10.1016/S0198-8859(96)00290-X.

Sachs DH, Sykes M, Kawai T, Cosimi AB. Immuno-intervention for the induction of transplantation tolerance through mixed chimerism. Semin Immunol. 2011 Jun;23(3):165-73. doi: 10.1016/j.smim.2011.07.001.

Ildstad ST, Sachs DH. Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature. 1984 Jan 12-18;307(5947):168-70. doi: 10.1038/307168a0.

Sharabi Y, Sachs DH. Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen. J Exp Med. 1989 Feb 1;169(2):493-502. doi: 10.1084/jem.169.2.493.

Kaufman CL, Ildstad ST. Induction of donor-specific tolerance by transplantation of bone marrow. Ther Immunol. 1994 Apr;1(2):101-11.

Kawai T, Cosimi AB, Spitzer TR, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med. 2008 Jan 24;358(4):353-61. doi: 10.1056/NEJMoa071074.

Sachs DH, Sykes M, Kawai T, Cosimi AB. Immuno-intervention for the induction of transplantation tolerance through mixed chimerism. Semin Immunol. 2011 Jun;23(3):165-73. doi: 10.1016/j.smim.2011.07.001.

Spitzer TR, Sykes M, Tolkoff-Rubin N, et al. Long-term follow-up of recipients of combined human leukocyte antigen-matched bone marrow and kidney transplantation for multiple myeloma with end-stage renal disease. Transplantation. 2011 Mar 27;91(6):672-6. doi: 10.1097/TP.0b013e31820a3068.

Newell KA, Asare A, Kirk AD, et al; Immune Tolerance Network ST507 Study Group. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest. 2010 Jun;120(6):1836-47. doi: 10.1172/JCI39933.

Sagoo P, Perucha E, Sawitzki B, et al. Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans. J Clin Invest. 2010 Jun;120(6):1848-61. doi: 10.1172/JCI39922.

Newell KA, Asare A, Kirk AD, et al; Immune Tolerance Network ST507 Study Group. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest. 2010 Jun;120(6):1836-47. doi: 10.1172/JCI39933.

Louis S, Braudeau C, Giral M, et al. Contrasting CD25hiCD4+T cells/FOXP3 patterns in chronic rejection and operational drug-free tolerance. Transplantation. 2006 Feb 15;81(3):398-407. doi: 10.1097/01.tp.0000203166.44968.86.

Pallier A, Hillion S, Danger R, et al. Patients with drug-free long-term graft function display increased numbers of peripheral B cells with a memory and inhibitory phenotype. Kidney Int. 2010 Sep;78(5):503-13. doi: 10.1038/ki.2010.162.

Zarkhin V, Lovelace PA, Li L, Hsieh SC, Sarwal MM. Phenotypic evaluation of B-cell subsets after rituximab for treatment of acute renal allograft rejection in pediatric recipients. Transplantation. 2011 May 15;91(9):1010-8. doi: 10.1097/TP.0b013e318213df29.

Baeten D, Louis S, Braud C, et al. Phenotypically and functionally distinct CD8+ lymphocyte populations in long-term drug-free tolerance and chronic rejection in human kidney graft recipients. J Am Soc Nephrol. 2006 Jan;17(1):294-304. doi: 10.1681/ASN.2005020178.

Brouard S, Mansfield E, Braud C, et al. Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance. Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15448-53. doi: 10.1073/pnas.0705834104.

Kawai T, Cosimi AB, Spitzer TR, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med. 2008 Jan 24;358(4):353-61. doi: 10.1056/NEJMoa071074.

Calne R, Friend P, Moffatt S, et al. Prope tolerance, perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients. Lancet. 1998 Jun 6;351(9117):1701-2. doi: 10.1016/S0140-6736(05)77739-4.

Calne R, Watson CJ. Some observations on prope tolerance. Curr Opin Organ Transplant. 2011 Aug;16(4):353-8. doi: 10.1097/MOT.0b013e328348b44c.

Perry DK, Burns JM, Pollinger HS, et al. Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production. Am J Transplant. 2009 Jan;9(1):201-9. doi: 10.1111/j.1600-6143.2008.02461.x.

Heidt S, Roelen DL, Vergunst M, Doxiadis II, Claas FH, Mulder A. Bortezomib affects the function of human B cells: possible implications for desensitization protocols. Clin Transpl. 2009:387-92.

Most read articles by the same author(s)