Strategies and Immun Mechanisms for Inducing Tolerance in Transplantation

Öz

Organ and tissue transplantation is a life saving procedure for various end stage diseases. However, the recipient can develop a rejection process that attacks and destroys the donated foreign organ or tissue. To reduce this rejection risk, the recipient may need to use lifelong immunosuppressive drugs. The requirement for lifelong immunosuppressive drug usage comes with a series of side effects, such as infection, neoplasm development and organ toxicity. Therefore, minimizing or discontinuing immunosuppressive drugs is the primary goal in transplantation. This goal has been achieved in patients who have developed tolerance to grafts. Immune tolerance or immunological tolerance, is a condition in which the immune system of an organism loses its capacity to mount an immune response against a specific substance or tissue. In this review, we will examine the latest developments in the search for tolerance mechanisms.

Anahtar Kelimeler

• Transplantation
• Immune Tolerance
• Tolerance Mechanisms

Transplantasyonda Tolerans Oluşturma Stratejileri ve İmmün Mekanizmalar

Öz

Doku ve organ nakli, çeşitli son evre hastalıklar için hayat kurtaran bir prosedürdür. Ancak, alıcıda bağışlanan yabancı organa veya dokuya saldıran ve yok eden bir reddetme süreci yaratabilir. Bu reddetme riskini azaltmak için alıcı ömür boyu immunosupresif ilaçları kullanmak zorunda kalabilir. Ömür boyu immunosupresif ilaç gereksinimi; enfeksiyon, neoplazma gelişimi, organ toksisitesi gibi bir dizi yan etkiyle birlikte gelir. Bu nedenle immunosupresif ilaçların en aza indirilmesi veya kesilmesi transplantasyonda en önemli hedeftir. Greftlere karşı tolerans geliştirilmiş olan hastalarda bu hedefe ulaşılmıştır. Bağışıklık toleransı veya immünolojik tolerans, bir organizmada bağışıklık sisteminin, belirli bir madde veya dokuya karşı bağışıklık tepkisi oluşturma kapasitesinin kaybolduğu bir durumdur. Bu derlemede, tolerans mekanizmaları arayışındaki en son gelişmeleri gözden geçireceğiz.

Anahtar Kelimeler

• Transplantasyon
• Bağışıklık Toleransı
• Tolerans Mekanizmaları

Kaynakça

1. 1. Orlando G, Hematti P, Stratta RJ, Burke GW, Cocco P Di, Pisani F, et al. Clinical Operational Tolerance After Renal Transplantation. Ann Surg. 2010 Dec;252(6):915–28.
2. 2. 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.
3. 3. Brent L. The discovery of immunologic tolerance. Hum Immunol. 1997 Feb;52(2):75–81.
4. 4. Owen RD. Immunogenetic Consequences of Vascular Anastomoses Between Bovine Twins. Science (1979). 1945 Oct 19;102(2651):400–1.
5. 5. Feng G, Wood KJ, Bushell A. Interferon-γ 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.
6. 6. 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 17;41(3):726–38.
7. 7. Afzali B, Lechler RI, Hernandez-Fuentes MP. Allorecognition and the alloresponse: clinical implications. Tissue Antigens. 2007 Jun 23;69(6):545–56.
8. 8. Salisbury EM, Game DS, Lechler RI. Transplantation tolerance. Pediatric Nephrology. 2014 Dec 10;29(12):2263–72.

9. 9. Griesemer AD, Sorenson EC, Hardy MA. The Role of the Thymus in Tolerance. Transplantation. 2010 Sep 15;90(5):465–74.
10. 10. Page E, Kwun J, Oh B, Knechtle S. Lymphodepletional Strategies in Transplantation. Cold Spring Harb Perspect Med. 2013 Jul 1;3(7):a015511– a015511.
11. 12. Hoffman BE, Martino AT, Sack BK, Cao O, Liao G, Terhorst C, et al. Nonredundant Roles of IL- 10 and TGF-β in Suppression of Immune Responses to Hepatic AAV-Factor IX Gene Transfer. Molecular Therapy. 2011 Jul;19(7):1263–72.
12. 13. Martin E, O’Sullivan B, Low P, Thomas R. Antigen-Specific Suppression of a Primed Immune Response by Dendritic Cells Mediated by Regulatory T Cells Secreting Interleukin-10. Immunity. 2003 Jan;18(1):155–67.
13. 14. Abdel-Gadir A, Massoud AH, Chatila TA. Antigen-specific Treg cells in immunological tolerance: implications for allergic diseases. F1000Res. 2018 Jan 10;7:38.
14. 15. Sakaguchi S, Kawakami R, Mikami N. Treg-based immunotherapy for antigen-specific immune suppression and stable tolerance induction: a perspective. Immunotherapy Advances. 2023 Jan 1;3(1).
15. 16. Chruscinski A, Sadozai H, Rojas-Luengas V, Bartczak A, Khattar R, Selzner N, et al. Role of Regulatory T Cells (Treg) and the Treg Effector Molecule Fibrinogen-like Protein 2 in Alloimmunity and Autoimmunity. Rambam Maimonides Med J. 2015 Jul 30;6(3):e0024.
16. 17. Ikegawa S, Matsuoka K ichi. Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives. Front Im- munol. 2021 Aug 30;12.
17. 18. Shevyrev D, Tereshchenko V. Treg Heterogeneity, Function, and Homeostasis. Front Immunol. 2020 Jan 14;10.
18. 19. Steiner R, Pilat N. The potential for Treg-enhancing therapies in transplantation. Clin Exp Immunol. 2023 Mar 16;211(2):122–37.
19. 20. Sasaki K, Kubo M, Wang Y chao, Lu L, Vujevich V, Wood-Trageser MA, et al. Multiple infusions of ex vivo-expanded regulatory T cells promote CD163+ myeloid cells and kidney allograft survival in non-lymphodepleted non-human primates. Kidney Int. 2024 Jan;105(1):84–98.
20. 21. Oo YH, Ackrill S, Cole R, Jenkins L, Anderson P, Jeffery HC, et al. Liver homing of clinical grade Tregs after therapeutic infusion in patients with auto- immune hepatitis. JHEP Reports. 2019 Oct;1(4):286– 96.
21. 22. Redfield RR, Rodriguez E, Parsons R, Vivek K, Mustafa MM, Noorchashm H, et al. Essential role for B cells in transplantation tolerance. Curr Opin Immunol. 2011 Oct;23(5):685–91.
22. 23. Newell KA, Asare A, Kirk AD, Gisler TD, Bour- cier K, Suthanthiran M, et al. Identification of a B cell signature associated with renal transplant tolerance in humans. Journal of Clinical Investigation. 2010 Jun 1;120(6):1836–47.
23. 24. Eng HS, Bennett G, Tsiopelas E, Lake M, Humphreys I, Chang SH, et al. Anti-HLA Donor-Specific Antibodies Detected in Positive B-Cell Crossmatches by Luminex® Predict Late Graft Loss. American Journal of Transplantation. 2008 Nov;8(11):2335–42.
24. 25. Lefaucheur C, Suberbielle-Boissel C, Hill GS, Nochy D, Andrade J, Antoine C, et al. Clinical Rele- vance of Preformed HLA Donor-Specific Antibodies in Kidney Transplantation. In: Humoral Immunity in Kidney Transplantation. Basel: KARGER; 2008. p. 1–12.
25. 26. Terasaki PI, Cai J. Human Leukocyte Antigen Antibodies and Chronic Rejection: From Association Causation. Transplantation. 2008 Aug 15;86(3):377–83.
26. 27. 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.
27. 28. Liu C, Noorchashm H, Sutter JA, Naji M, Prak EL, Boyer J, et al. B lymphocyte–directed immunotherapy promotes long-term islet allograft survival in nonhuman primates. Nat Med. 2007 Nov 28;13(11):1295–8.
28. 29. Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, 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.
29. 30. Mackay F, Schneider P, Rennert P, Browning J. BAFF and APRIL: A Tutorial on B Cell Survival. Annu Rev Immunol. 2003 Apr;21(1):231–64.
30. 31. Xu H, He X, Liu Q, Shi D, Chen Y, Zhu Y, 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.
31. 32. 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.
32. 33. Vo AA, Lukovsky M, Toyoda M, Wang J, Reinsmoen NL, Lai CH, et al. Rituximab and Intravenous Immune Globulin for Desensitization during Renal Transplantation. New England Journal of Medicine. 2008 Jul 17;359(3):242–51.
33. 34. 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.
34. 35. Larsen CP, Pearson TC, Adams AB, Tso P, Shirasugi N, Strobertb E, et al. Rational Development of LEA29Y (belatacept), a High-Affinity Variant of CTLA4-Ig with Potent Immunosuppressive Properties. American Journal of Transplantation. 2005 Mar;5(3):443–53.
35. 36. Larsen CP, Grinyó J, Medina-Pestana J, Vanrenterghem Y, Vincenti F, Breshahan B, 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.
36. 37. Vanrenterghem Y, Bresnahan B, Campistol J, Durrbach A, Grinyó J, Neumayer HH, 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.
37. 38. Medina Pestana JO, Grinyo JM, Vanrenterghem Y, Becker T, Campistol JM, Florman S, et al. Thre- e-Year Outcomes From BENEFIT-EXT: A Phase III Study of Belatacept Versus Cyclosporine in Recipients of Extended Criteria Donor Kidneys. American Journal of Transplantation. 2012 Mar;12(3):630–9.
38. 39. Carbone M, M. Neuberger J. Solid Organ Transplantation. In: Regenerative Medicine Applications in Organ Transplantation. Elsevier; 2014. p. 17–28.
39. 40. Ildstad ST, Sachs DH. Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature. 1984 Jan;307(5947):168–70.
40. 41. 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.
41. 42. Kaufman CL, Ildstad ST. Induction of donor-specific tolerance by transplantation of bone marrow. Ther Immunol. 1994 Apr;1(2):101–11.
42. 43. Erdal Y. Dendritic cells and clinical applications in transplantation. Istanbul Bilim University Floren- ce Nightingale Transplantation Journal. 2017 Nov 20;2(2):45–51.
43. 44. Hasegawa H, Matsumoto T. Mechanisms of To- lerance Induction by Dendritic Cells In Vivo. Front Immunol. 2018 Feb 26;9.
44. 45. Powell JD. The induction and maintenance of T cell anergy. Clinical Immunology. 2006 Sep;120(3):239–46.
45. 46. Chappert P, Schwartz RH. Induction of T cell anergy: integration of environmental cues and infectious tolerance. Curr Opin Immunol. 2010 Oct;22(5):552–9.