Clin Transplant Res.  2024 Dec;38(4):309-325. 10.4285/ctr.24.0058.

Targeting T helper 17 cells: emerging strategies for overcoming transplant rejection

• Lee YJ
• Cho ML

• KMID: 2563953
• DOI: http://doi.org/10.4285/ctr.24.0058

Abstract

Solid organ transplantation has significantly improved the survival rate of patients with terminal organ failure. However, its success is often compromised by allograft rejection, a process in which T helper 17 (Th17) cells play a crucial role. These cells facilitate rejection by enhancing neutrophil infiltration into the graft and by activating endothelial cells and fibroblasts. Additionally, Th17 cells can trigger the activation of other T cell types, including Th1, Th2, and CD8⁺ T cells, further contributing to rejection. An imbalance between Th17 and regulatory T cells (Tregs) is known to promote rejection. To counteract this, immunosuppressive drugs have been developed to inhibit T cell activity and foster transplant tolerance. Another approach involves the adoptive transfer of regulatory cells, such as Tregs and myeloid-derived suppressor cells, to dampen T cell functions. This review primarily focuses on the roles of Th17 cells in rejection and their interactions with other T cell subsets. We also explore various strategies aimed at suppressing T cells to induce tolerance.

Keyword

Transplantation; Allograft rejection; Th17 cells; Immune tolerance

Figure

• 

  Fig. 1 Roles of T cell subtypes in allograft rejection. Th17 cells promote the infiltration of neutrophils into a graft in an interleukin (IL)-17A-independent pathway [9]. Neutrophils undergo NETosis to promote allograft rejection [10,11]. Th17 cells also activate endothelial cells and fibroblasts. Endothelial cells release chemokines and increase their expression of adhesion molecules. In turn, immune cells are recruited and move from the bloodstream across the endothelial monolayer into the blood vessel wall. This immune cell infiltrate is a hallmark of transplant vasculopathy [12]. Activated fibroblasts contribute to fibrosis [13]. Activated endothelial cells and fibroblasts secrete IL-6, promoting the differentiation of Th17 cells [14]. IL-17 modulates allograft rejection by promoting the maturation of dendritic cells (DCs) [15]. Compared to immature DCs, which are specialized in endocytosis, mature DCs express higher levels of MHC and costimulatory molecules on their surface for efficient antigen presentation [16]. Mature DCs present peptides with MHC molecules to activate CD4+ and CD8+ T cells. The peptides are produced by the processing of donor MHC molecules. CD8+ and CD4+ T cells recognize the peptides via the direct, indirect, and semidirect pathways. In the direct pathway, recipient CD8+ T cells and CD4+ T cells engage complexes of MHC molecules and peptides derived from donor MHC molecules on the surface of donor antigen-presenting cells (APCs), and CD8+ T cells receive assistance from recipient CD4+ T cells. In the indirect pathway, CD4+ T cells engage complexes composed of recipient MHC molecules and peptides produced by the processing of donor MHC molecules, thereby forming recipient APC/CD4 T cell couplets. Recipient CD8+ T cells recognize MHC class Ⅰ: peptide complexes on donor APCs and obtain help from CD4+ T cells. In the semidirect pathway, CD8+ T cells recognize intact donor MHC class Ⅰ molecules on recipient APCs presenting donor MHC molecule-derived peptides with recipient MHC Ⅱ molecules to CD4+ T cells. CD8+ T cells obtain help from CD4+ T cells [17]. Activated CD4+ T cells differentiate into Th1, Th2, or Th17 cells, depending on the local cytokine environment [18]. Th1 cells damage allografts via Fas/Fas ligand (FasL)-mediated cytotoxicity and produce interferon (IFN)-γ and the growth factor IL-2, thereby triggering alloreactive CD8+ cytotoxicity. Th1 cells induce delayed-type hypersensitivity (DTH) by macrophages, which release nitric oxide (NO), tumor necrosis factor (TNF)-α, and oxygen species, leading to allograft damage. Th2 cells secrete IL-4 and IL-5 to activate eosinophils, which release harmful enzymes causing graft destruction. Th2 cells induce the production of alloreactive antibodies by B cells. Th2 cells express IL-4 and IL-10, which inhibit Th1 responses. Activated CD8+ T cells produce perforin and granzyme. Perforin forms channels in the allogeneic cell membrane, through which granzyme moves into cytoplasm where it induces apoptosis [19,20]. In addition to cytotoxicity, CD8+ T cells regulate effector T cells. CCR7+CD8+ T cells reduced the proportion of IFN-γ+ (Th1) and IL-17+CD4+ (Th17) T cells [21]. An increased Th17-to-regulatory T cell (Treg) ratio contributes to transplant rejection [22].

• 

  Fig. 2 Immunosuppressive drugs and their sites of action that inhibit the activation of T cells. Some of the sites are linked to signals 1, 2, and 3. Rectangles with red lines, biological drugs; rectangles with blue lines, pharmacological drugs. APC, antigen-presenting cell; IL, interleukin; MHC, major histocompatibility complex; TCR, T cell receptor; JAK, Janus kinase; STAT, signal transducer and activator of transcription; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, inositol trisphosphate; Akt, protein kinase B; mTOR, mammalian target of rapamycin; Itk, inducible T cell kinase; Zap70, zeta-chain-associated protein kinase 70; ITAM, immunoreceptor tyrosine-based activation motif; LAT, linker for activated T cell; PLC, phospholipase C; DAG, diacylglycerol; PKC, protein kinase C; MPA, mycophenolic acid; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor kappa B.

• 

  Fig. 3 Cell-based therapies for the induction of graft tolerance. Regulatory T cells (Tregs) inhibit the activation of effector T cells and antigen-presenting cells (APCs). A high level of high-affinity interleukin (IL)-2 receptor on Tregs prevents the use of IL-2 by effector T cells. The interaction of cytotoxic T lymphocyte antigen-4 (CTLA-4) on Tregs with CD80/86 on effector T cells and APCs inactivates the latter. CD39 and CD73 on Tregs produce the anti-inflammatory factor adenosine from ATP and 5'-adenosine monophosphate (5’-AMP). Tregs secrete granzyme B to induce the apoptosis of effector T cells [22,95]. Tregs produce transforming growth factor (TGF)-β and IL-10. TGF-β induces apoptosis of CD4+ T cells and suppresses the function of CD8+ T cells; IL-10 suppresses the activity of T helper 17 cells. Tregs interact with PD-L1 and PD-L2 on the surface of T cells via PD-1 to inhibit T cell responses. The transfer of cyclic adenosine monophosphate (cAMP) to T cells through intercellular gap junctions inhibits their activation. Tregs transfer miRNAs into T cells via exosomes [64]. Lymphocyte activation gene-3 (LAG-3) on Tregs binds to major histocompatibility complex (MHC) Ⅱ and inhibits antigen presentation by APCs. IL-10 downregulates their expression of MHC Ⅱ and costimulatory molecules. Granzyme B from Tregs induces the apoptosis of APCs. Inducible nitric oxide synthase (iNOS) in myeloid-derived suppressor cells (MDSCs) consumes L-arginine to produce nitric oxide (NO), preventing the use of the former by T cells to proliferate. In addition, arginase 1 (ARG1) produced by MDSCs cleaves L-arginine to ornithine and urea, preventing the use of the former by T cells. The production of a large quantity of heme oxygenase-1 (HO-1) by MDSCs contributes to the inactivation of T cells. CCL5 produced by MDSCs recruits Tregs from secondary lymphoid organs to grafts, where they induce tolerance. The interaction of B7-H1 (PD-L1) on MDSCs with PD-1 on Tregs promotes the migration, proliferation, and function of the latter. In the presence of interferon-γ, MDSCs produce IL-10 and TGF-β, which trigger the activation of Tregs [22]. Indoleamine 2,3-dioxygenase (IDO) on MDSCs consumes tryptophan and promotes kynurenine production. Tryptophan deficiency and excessive kynurenines suppress lymphocyte responses [96,97].

Reference

1. Cozzi E, Colpo A, De Silvestro G. 2017; The mechanisms of rejection in solid organ transplantation. Transfus Apher Sci. 56:498–505. DOI: 10.1016/j.transci.2017.07.005. PMID: 28916402.

2. Rana A, Gruessner A, Agopian VG, Khalpey Z, Riaz IB, Kaplan B, et al. 2015; Survival benefit of solid-organ transplant in the United States. JAMA Surg. 150:252–9. DOI: 10.1001/jamasurg.2014.2038. PMID: 25629390.

3. Black CK, Termanini KM, Aguirre O, Hawksworth JS, Sosin M. 2018; Solid organ transplantation in the 21^st century. Ann Transl Med. 6:409. DOI: 10.21037/atm.2018.09.68. PMID: 30498736. PMCID: PMC6230860.

4. Butcher MJ, Zhu J. 2021; Recent advances in understanding the Th1/Th2 effector choice. Fac Rev. 10:30. DOI: 10.12703/r/10-30. PMID: 33817699. PMCID: PMC8009194.

5. Korn T, Bettelli E, Oukka M, Kuchroo VK. 2009; IL-17 and Th17 cells. Annu Rev Immunol. 27:485–517. DOI: 10.1146/annurev.immunol.021908.132710. PMID: 19132915.

6. Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, Ohkura N. 2020; Regulatory T cells and human disease. Annu Rev Immunol. 38:541–66. DOI: 10.1146/annurev-immunol-042718-041717. PMID: 32017635.

7. Raskov H, Orhan A, Christensen JP, Gögenur I. 2021; Cytotoxic CD8⁺ T cells in cancer and cancer immunotherapy. Br J Cancer. 124:359–67. DOI: 10.1038/s41416-020-01048-4. PMID: 32929195. PMCID: PMC7853123.

8. Reina-Campos M, Scharping NE, Goldrath AW. 2021; CD8⁺ T cell metabolism in infection and cancer. Nat Rev Immunol. 21:718–38. DOI: 10.1038/s41577-021-00537-8. PMID: 33981085. PMCID: PMC8806153.

9. Agorogiannis EI, Regateiro FS, Howie D, Waldmann H, Cobbold SP. 2012; Th17 cells induce a distinct graft rejection response that does not require IL-17A. Am J Transplant. 12:835–45. DOI: 10.1111/j.1600-6143.2011.03971.x. PMID: 22390151.

10. Liu Y, Yan P, Bin Y, Qin X, Wu Z. 2022; Neutrophil extracellular traps and complications of liver transplantation. Front Immunol. 13:1054753. DOI: 10.3389/fimmu.2022.1054753. PMID: 36466888. PMCID: PMC9712194.

11. Torres-Ruiz J, Villca-Gonzales R, Gómez-Martín D, Zentella-Dehesa A, Tapia-Rodríguez M, Uribe-Uribe NO, et al. 2020; A potential role of neutrophil extracellular traps (NETs) in kidney acute antibody mediated rejection. Transpl Immunol. 60:101286. DOI: 10.1016/j.trim.2020.101286. PMID: 32156665.

12. Kummer L, Zaradzki M, Vijayan V, Arif R, Weigand MA, Immenschuh S, et al. 2020; Vascular signaling in allogenic solid organ transplantation: the role of endothelial cells. Front Physiol. 11:443. DOI: 10.3389/fphys.2020.00443. PMID: 32457653. PMCID: PMC7227440.

13. Hurskainen M, Ainasoja O, Lemström KB. 2021; Failing heart transplants and rejection: a cellular perspective. J Cardiovasc Dev Dis. 8:180. DOI: 10.3390/jcdd8120180. PMID: 34940535. PMCID: PMC8708043.

14. Nakagiri T, Inoue M, Minami M, Shintani Y, Okumura M. 2012; Immunology mini-review: the basics of T(H)17 and interleukin-6 in transplantation. Transplant Proc. 44:1035–40. DOI: 10.1016/j.transproceed.2011.12.032. PMID: 22564619.

15. Antonysamy MA, Fanslow WC, Fu F, Li W, Qian S, Troutt AB, et al. 1999; Evidence for a role of IL-17 in organ allograft rejection: IL-17 promotes the functional differentiation of dendritic cell progenitors. J Immunol. 162:577–84. DOI: 10.4049/jimmunol.162.1.577. PMID: 9886435.

16. Tan JK, O'Neill HC. 2005; Maturation requirements for dendritic cells in T cell stimulation leading to tolerance versus immunity. J Leukoc Biol. 78:319–24. DOI: 10.1189/jlb.1104664. PMID: 15809288.

17. Harper SJ, Ali JM, Wlodek E, Negus MC, Harper IG, Chhabra M, et al. 2015; CD8 T-cell recognition of acquired alloantigen promotes acute allograft rejection. Proc Natl Acad Sci U S A. 112:12788–93. DOI: 10.1073/pnas.1513533112. PMID: 26420874. PMCID: PMC4611606.

18. Issa FG, Goto R, Wood KJ. Klein AA, Lewis CJ, Madsen JC, editors. Immunological principles of acute rejection. Organ transplantation: a clinical guide. Cambridge University Press;2011. p. 9–18. DOI: 10.1017/CBO9780511994876.005.

19. Liu Z, Fan H, Jiang S. 2013; CD4(+) T-cell subsets in transplantation. Immunol Rev. 252:183–91. DOI: 10.1111/imr.12038. PMID: 23405905.

20. Le Moine A, Goldman M, Abramowicz D. 2002; Multiple pathways to allograft rejection. Transplantation. 73:1373–81. DOI: 10.1097/00007890-200205150-00001. PMID: 12023610.

21. Kim KW, Kim BM, Doh KC, Cho ML, Yang CW, Chung BH. 2018; Clinical significance of CCR7⁺CD8⁺ T cells in kidney transplant recipients with allograft rejection. Sci Rep. 8:8827. DOI: 10.1038/s41598-018-27141-6. PMID: 29891963. PMCID: PMC5995850.

22. Oberholtzer N, Atkinson C, Nadig SN. 2021; Adoptive transfer of regulatory immune cells in organ transplantation. Front Immunol. 12:631365. DOI: 10.3389/fimmu.2021.631365. PMID: 33737934. PMCID: PMC7960772.

23. Wang Y, Hang G, Wen Q, Wang H, Bao L, Chen B. 2022; Changes and significance of IL-17 in acute renal allograft rejection in rats. Transplant Proc. 54:2021–4. DOI: 10.1016/j.transproceed.2022.05.019. PMID: 35933232.

24. Chung BH, Kim KW, Kim BM, Doh KC, Cho ML, Yang CW. 2015; Increase of Th17 cell phenotype in kidney transplant recipients with chronic allograft dysfunction. PLoS One. 10:e0145258. DOI: 10.1371/journal.pone.0145258. PMID: 26717145. PMCID: PMC4696852.

25. Crispim JC, Grespan R, Martelli-Palomino G, Rassi DM, Costa RS, Saber LT, et al. 2009; Interleukin-17 and kidney allograft outcome. Transplant Proc. 41:1562–4. DOI: 10.1016/j.transproceed.2009.01.092. PMID: 19545679.

26. Haouami Y, Dhaouadi T, Sfar I, Bacha M, Gargah T, Bardi R, et al. 2018; The role of IL-23/IL-17 axis in human kidney allograft rejection. J Leukoc Biol. 104:1229–39. DOI: 10.1002/JLB.5AB0318-148R. PMID: 30024651.

27. Bunte K, Beikler T. 2019; Th17 cells and the IL-23/IL-17 axis in the pathogenesis of periodontitis and immune-mediated inflammatory diseases. Int J Mol Sci. 20:3394. DOI: 10.3390/ijms20143394. PMID: 31295952. PMCID: PMC6679067.

28. Xie XJ, Ye YF, Zhou L, Xie HY, Jiang GP, Feng XW, et al. 2010; Th17 promotes acute rejection following liver transplantation in rats. J Zhejiang Univ Sci B. 11:819–27. DOI: 10.1631/jzus.B1000030. PMID: 21043049. PMCID: PMC2970890.

29. Assadiasl S, Toosi MN, Mohebbi B, Ansaripour B, Soleimanifar N, Sadr M, et al. 2022; Th17/Treg cell balance in stable liver transplant recipients. Transpl Immunol. 71:101540. DOI: 10.1016/j.trim.2022.101540. PMID: 35065203.

30. Fan H, Li LX, Han DD, Kou JT, Li P, He Q. 2012; Increase of peripheral Th17 lymphocytes during acute cellular rejection in liver transplant recipients. Hepatobiliary Pancreat Dis Int. 11:606–11. DOI: 10.1016/S1499-3872(12)60231-8. PMID: 23232631.

31. Afshari A, Yaghobi R, Karimi MH, Darbooie M, Azarpira N. 2014; Interleukin-17 gene expression and serum levels in acute rejected and non-rejected liver transplant patients. Iran J Immunol. 11:29–39.

32. Fábrega E, López-Hoyos M, San Segundo D, Casafont F, Pons-Romero F. 2009; Changes in the serum levels of interleukin-17/interleukin-23 during acute rejection in liver transplantation. Liver Transpl. 15:629–33. DOI: 10.1002/lt.21724. PMID: 19479806.

33. Min SI, Ha J, Park CG, Won JK, Park YJ, Min SK, et al. 2009; Sequential evolution of IL-17 responses in the early period of allograft rejection. Exp Mol Med. 41:707–16. DOI: 10.3858/emm.2009.41.10.077. PMID: 19561402. PMCID: PMC2772973.

34. Wang S, Li J, Xie A, Wang G, Xia N, Ye P, et al. 2011; Dynamic changes in Th1, Th17, and FoxP3+ T cells in patients with acute cellular rejection after cardiac transplantation. Clin Transplant. 25:E177–86. DOI: 10.1111/j.1399-0012.2010.01362.x.

35. Chen H, Wang W, Xie H, Xu X, Wu J, Jiang Z, et al. 2009; A pathogenic role of IL-17 at the early stage of corneal allograft rejection. Transpl Immunol. 21:155–61. DOI: 10.1016/j.trim.2009.03.006. PMID: 19358887.

36. Yang JJ, Feng F, Hong L, Sun L, Li MB, Zhuang R, et al. 2013; Interleukin-17 plays a critical role in the acute rejection of intestinal transplantation. World J Gastroenterol. 19:682–91. DOI: 10.3748/wjg.v19.i5.682. PMID: 23429965. PMCID: PMC3574594.

37. Zheng HL, Shi BY, Du GS, Wang Z. 2014; Changes in Th17 and IL-17 levels during acute rejection after mouse skin transplantation. Eur Rev Med Pharmacol Sci. 18:2720–86.

38. Chen QR, Wang LF, Xia SS, Zhang YM, Xu JN, Li H, et al. 2016; Role of interleukin-17A in early graft rejection after orthotopic lung transplantation in mice. J Thorac Dis. 8:1069–79. DOI: 10.21037/jtd.2015.12.08. PMID: 27293822. PMCID: PMC4886000.

39. Vanaudenaerde BM, Dupont LJ, Wuyts WA, Verbeken EK, Meyts I, Bullens DM, et al. 2006; The role of interleukin-17 during acute rejection after lung transplantation. Eur Respir J. 27:779–87. DOI: 10.1183/09031936.06.00019405. PMID: 16585086.

40. Negi S, Rutman AK, Saw CL, Paraskevas S, Tchervenkov J. 2024; Pretransplant, Th17 dominant alloreactivity in highly sensitized kidney transplant candidates. Front Transplant. 3:1336563. DOI: 10.3389/frtra.2024.1336563. PMID: 38993777. PMCID: PMC11235243.

41. Itoh S, Nakae S, Axtell RC, Velotta JB, Kimura N, Kajiwara N, et al. 2010; IL-17 contributes to the development of chronic rejection in a murine heart transplant model. J Clin Immunol. 30:235–40. DOI: 10.1007/s10875-009-9366-9. PMID: 20130970.

42. Watanabe T, Juvet SC, Berra G, Havlin J, Zhong W, Boonstra K, et al. 2023; Donor IL-17 receptor A regulates LPS-potentiated acute and chronic murine lung allograft rejection. JCI Insight. 8:e158002. DOI: 10.1172/jci.insight.158002. PMID: 37937643. PMCID: PMC10721268.

43. Zhang M, Xu M, Wang K, Li L, Zhao J. 2021; Effect of inhibition of the JAK2/STAT3 signaling pathway on the Th17/IL-17 axis in acute cellular rejection after heart transplantation in mice. J Cardiovasc Pharmacol. 77:614–20. DOI: 10.1097/FJC.0000000000001007. PMID: 33951698. PMCID: PMC8096315.

44. Yuan X, Paez-Cortez J, Schmitt-Knosalla I, D'Addio F, Mfarrej B, Donnarumma M, et al. 2008; A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med. 205:3133–44. DOI: 10.1084/jem.20081937. PMID: 19047438. PMCID: PMC2605226.

45. Rangachari M, Mauermann N, Marty RR, Dirnhofer S, Kurrer MO, Komnenovic V, et al. 2006; T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17. J Exp Med. 203:2009–19. DOI: 10.1084/jem.20052222. PMID: 16880257. PMCID: PMC2118365.

46. Steinman RM. 1991; The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 9:271–96. DOI: 10.1146/annurev.iy.09.040191.001415. PMID: 1910679.

47. Duan L, Chen J, Xia Q, Chen L, Fan K, Sigdel KR, et al. 2014; IL-17 promotes Type 1 T cell response through modulating dendritic cell function in acute allograft rejection. Int Immunopharmacol. 20:290–7. DOI: 10.1016/j.intimp.2014.03.010. PMID: 24680942.

48. Frangou E, Vassilopoulos D, Boletis J, Boumpas DT. 2019; An emerging role of neutrophils and NETosis in chronic inflammation and fibrosis in systemic lupus erythematosus (SLE) and ANCA-associated vasculitides (AAV): implications for the pathogenesis and treatment. Autoimmun Rev. 18:751–60. DOI: 10.1016/j.autrev.2019.06.011. PMID: 31181324.

49. Gökmen MR, Lombardi G, Lechler RI. 2008; The importance of the indirect pathway of allorecognition in clinical transplantation. Curr Opin Immunol. 20:568–74. DOI: 10.1016/j.coi.2008.06.009. PMID: 18655831.

50. Chen Y, Chen J, Liu Z, Liang S, Luan X, Long F, et al. 2008; Relationship between TH1/TH2 cytokines and immune tolerance in liver transplantation in rats. Transplant Proc. 40:2691–5. DOI: 10.1016/j.transproceed.2008.08.014. PMID: 18929837.

51. Sadeghi M, Daniel V, Weimer R, Wiesel M, Hergesell O, Opelz G. 2003; Pre-transplant Th1 and post-transplant Th2 cytokine patterns are associated with early acute rejection in renal transplant recipients. Clin Transplant. 17:151–7. DOI: 10.1034/j.1399-0012.2003.00037.x. PMID: 12709083.

52. Karczewski J, Karczewski M, Glyda M, Wiktorowicz K. 2008; Role of TH1/TH2 cytokines in kidney allograft rejection. Transplant Proc. 40:3390–2. DOI: 10.1016/j.transproceed.2008.07.125. PMID: 19100396.

53. D'Elios MM, Josien R, Manghetti M, Amedei A, de Carli M, Cuturi MC, et al. 1997; Predominant Th1 cell infiltration in acute rejection episodes of human kidney grafts. Kidney Int. 51:1876–84. DOI: 10.1038/ki.1997.256. PMID: 9186878.

54. Deteix C, Attuil-Audenis V, Duthey A, Patey N, McGregor B, Dubois V, et al. 2010; Intragraft Th17 infiltrate promotes lymphoid neogenesis and hastens clinical chronic rejection. J Immunol. 184:5344–51. DOI: 10.4049/jimmunol.0902999. PMID: 20357253.

55. Wang K, Song ZL, Wu B, Zhou CL, Liu W, Gao W. 2019; The T-helper cells 17 instead of Tregs play the key role in acute rejection after pediatric liver transplantation. Pediatr Transplant. 23:e13363. DOI: 10.1111/petr.13363. PMID: 30756444.

56. Loverre A, Divella C, Castellano G, Tataranni T, Zaza G, Rossini M, et al. 2011; T helper 1, 2 and 17 cell subsets in renal transplant patients with delayed graft function. Transpl Int. 24:233–42. DOI: 10.1111/j.1432-2277.2010.01157.x. PMID: 21281362.

57. Illigens BM, Yamada A, Anosova N, Dong VM, Sayegh MH, Benichou G. 2009; Dual effects of the alloresponse by Th1 and Th2 cells on acute and chronic rejection of allotransplants. Eur J Immunol. 39:3000–9. DOI: 10.1002/eji.200838980. PMID: 19658090. PMCID: PMC2911804.

58. Kubota N, Sugitani M, Takano S, Sheikh A, Takayama T, Haga H, et al. 2006; Correlation between acute rejection severity and CD8-positive T cells in living related liver transplantation. Transpl Immunol. 16:60–4. DOI: 10.1016/j.trim.2006.03.002. PMID: 16701178.

59. Posselt AM, Vincenti F, Bedolli M, Lantz M, Roberts JP, Hirose R. 2003; CD69 expression on peripheral CD8 T cells correlates with acute rejection in renal transplant recipients. Transplantation. 76:190–5. DOI: 10.1097/01.TP.0000073614.29680.A8. PMID: 12865808.

60. Ekkens MJ, Shedlock DJ, Jung E, Troy A, Pearce EL, Shen H, et al. 2007; Th1 and Th2 cells help CD8 T-cell responses. Infect Immun. 75:2291–6. DOI: 10.1128/IAI.01328-06. PMID: 17325050. PMCID: PMC1865742.

61. Taylor AL, Negus SL, Negus M, Bolton EM, Bradley JA, Pettigrew GJ. 2007; Pathways of helper CD4 T cell allorecognition in generating alloantibody and CD8 T cell alloimmunity. Transplantation. 83:931–7. DOI: 10.1097/01.tp.0000257960.07783.e3. PMID: 17460565.

62. Vella JP, Spadafora-Ferreira M, Murphy B, Alexander SI, Harmon W, Carpenter CB, et al. 1997; Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction. Transplantation. 64:795–800. DOI: 10.1097/00007890-199709270-00001. PMID: 9326400.

63. Jones ND, Van Maurik A, Hara M, Gilot BJ, Morris PJ, Wood KJ. 1999; T-cell activation, proliferation, and memory after cardiac transplantation in vivo. Ann Surg. 229:570–8. DOI: 10.1097/00000658-199904000-00018. PMID: 10203092. PMCID: PMC1191745.

64. Lu J, Li P, Du X, Liu Y, Zhang B, Qi F. 2021; Regulatory T cells induce transplant immune tolerance. Transpl Immunol. 67:101411. DOI: 10.1016/j.trim.2021.101411. PMID: 34020045.

65. Stenard F, Nguyen C, Cox K, Kambham N, Umetsu DT, Krams SM, et al. 2009; Decreases in circulating CD4+CD25hiFOXP3+ cells and increases in intragraft FOXP3+ cells accompany allograft rejection in pediatric liver allograft recipients. Pediatr Transplant. 13:70–80. DOI: 10.1111/j.1399-3046.2008.00917.x. PMID: 18331536.

66. Demirkiran A, Kok A, Kwekkeboom J, Kusters JG, Metselaar HJ, Tilanus HW, et al. 2006; Low circulating regulatory T-cell levels after acute rejection in liver transplantation. Liver Transpl. 12:277–84. DOI: 10.1002/lt.20612. PMID: 16447185.

67. Brouard S, Mansfield E, Braud C, Li L, Giral M, Hsieh SC, et al. 2007; Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance. Proc Natl Acad Sci U S A. 104:15448–53. DOI: 10.1073/pnas.0705834104. PMID: 17873064. PMCID: PMC2000539.

68. Braza F, Dugast E, Panov I, Paul C, Vogt K, Pallier A, et al. 2015; Central role of CD45RA- Foxp3hi memory regulatory T cells in clinical kidney transplantation tolerance. J Am Soc Nephrol. 26:1795–805. DOI: 10.1681/ASN.2014050480. PMID: 25556168. PMCID: PMC4520169.

69. Chung BH, Oh HJ, Piao SG, Sun IO, Kang SH, Choi SR, et al. 2011; Higher infiltration by Th17 cells compared with regulatory T cells is associated with severe acute T-cell-mediated graft rejection. Exp Mol Med. 43:630–7. DOI: 10.3858/emm.2011.43.11.071. PMID: 21865860. PMCID: PMC3249589.

70. Zhou W, Zhou X, Gaowa S, Meng Q, Zhan Z, Liu J, et al. 2015; The critical role of induced CD4+ FoxP3+ regulatory cells in suppression of Interleukin-17 production and attenuation of mouse orthotopic lung allograft rejection. Transplantation. 99:1356–64. DOI: 10.1097/TP.0000000000000526. PMID: 25856405.

71. Li J, Lai X, Liao W, He Y, Liu Y, Gong J. 2011; The dynamic changes of Th17/Treg cytokines in rat liver transplant rejection and tolerance. Int Immunopharmacol. 11:962–7. DOI: 10.1016/j.intimp.2011.02.010. PMID: 21376155.

72. Parlakpinar H, Gunata M. 2021; Transplantation and immunosuppression: a review of novel transplant-related immunosuppressant drugs. Immunopharmacol Immunotoxicol. 43:651–65. DOI: 10.1080/08923973.2021.1966033. PMID: 34415233.

73. Lee GR. 2018; The balance of Th17 versus Treg cells in autoimmunity. Int J Mol Sci. 19:730. DOI: 10.3390/ijms19030730. PMID: 29510522. PMCID: PMC5877591.

74. Chi H. 2012; Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol. 12:325–38. DOI: 10.1038/nri3198. PMID: 22517423. PMCID: PMC3417069.

75. Druszczyńska M, Godkowicz M, Kulesza J, Wawrocki S, Fol M. 2022; Cytokine receptors-regulators of antimycobacterial immune response. Int J Mol Sci. 23:1112. DOI: 10.3390/ijms23031112. PMID: 35163035. PMCID: PMC8835057.

76. Wojciechowski D, Vincenti F. 2013; Tofacitinib in kidney transplantation. Expert Opin Investig Drugs. 22:1193–9. DOI: 10.1517/13543784.2013.811231. PMID: 23841583.

77. Panackel C, Mathew JF, Fawas N M, Jacob M. 2022; Immunosuppressive drugs in liver transplant: an insight. J Clin Exp Hepatol. 12:1557–71. DOI: 10.1016/j.jceh.2022.06.007. PMID: 36340316. PMCID: PMC9630030.

78. ten Berge IJ, Parlevliet KJ, Raasveld MH, Buysmann S, Bemelman FJ, Schellekens PT. 1999; Guidelines for the optimal use of muromonab CD3 in transplantation. BioDrugs. 11:277–84. DOI: 10.2165/00063030-199911040-00006. PMID: 18031137.

79. Schwarz C, Mahr B, Muckenhuber M, Wekerle T. 2018; Belatacept/CTLA4Ig: an update and critical appraisal of preclinical and clinical results. Expert Rev Clin Immunol. 14:583–92. DOI: 10.1080/1744666X.2018.1485489. PMID: 29874474.

80. Vanhove B, Soulillou JP. 2005; Technology evaluation: Belatacept, Bristol-Myers Squibb. Curr Opin Mol Ther. 7:384–93.

81. Lin M, Ming A, Zhao M. 2006; Two-dose basiliximab compared with two-dose daclizumab in renal transplantation: a clinical study. Clin Transplant. 20:325–9. DOI: 10.1111/j.1399-0012.2005.00488.x. PMID: 16824149.

82. Fukahori H, Chida N, Maeda M, Tasaki M, Kawashima T, Noto T, et al. 2015; Effect of novel PKCθ selective inhibitor AS2521780 on acute rejection in rat and non-human primate models of transplantation. Int Immunopharmacol. 27:232–7. DOI: 10.1016/j.intimp.2015.06.016. PMID: 26122135.

83. Klawitter J, Nashan B, Christians U. 2015; Everolimus and sirolimus in transplantation-related but different. Expert Opin Drug Saf. 14:1055–70. DOI: 10.1517/14740338.2015.1040388. PMID: 25912929. PMCID: PMC6053318.

84. Mimouni D, Nousari HC. 2003; Inhibitors of purine and pyrimidine synthesis: mycophenolate, azathioprine, and leflunomide. Dermatol ther. 15:311–6. DOI: 10.1046/j.1529-8019.2002.01539.x.

85. Hoppe-Seyler K, Sauer P, Lohrey C, Hoppe-Seyler F. 2012; The inhibitors of nucleotide biosynthesis leflunomide, FK778, and mycophenolic acid activate hepatitis B virus replication in vitro. Hepatology. 56:9–16. DOI: 10.1002/hep.25602. PMID: 22271223.

86. Brinkmann V. 2004; FTY720: mechanism of action and potential benefit in organ transplantation. Yonsei Med J. 45:991–7. DOI: 10.3349/ymj.2004.45.6.991. PMID: 15627289.

87. Aki FT, Kahan BD. 2003; FTY720: a new kid on the block for transplant immunosuppression. Expert Opin Biol Ther. 3:665–81. DOI: 10.1517/14712598.3.4.665. PMID: 12831371.

88. De Lucena DD, Rangel ÉB. 2018; Glucocorticoids use in kidney transplant setting. Expert Opin Drug Metab Toxicol. 14:1023–41. DOI: 10.1080/17425255.2018.1530214. PMID: 30265586.

89. Truckenmiller ME, Princiotta MF, Norbury CC, Bonneau RH. 2005; Corticosterone impairs MHC class I antigen presentation by dendritic cells via reduction of peptide generation. J Neuroimmunol. 160:48–60. DOI: 10.1016/j.jneuroim.2004.10.024. PMID: 15710457.

90. Vu D, Tellez-Corrales E, Sakharkar P, Kissen MS, Shah T, Hutchinson I, et al. 2013; Impact of NF-κB gene polymorphism on allograft outcome in Hispanic renal transplant recipients. Transpl Immunol. 28:18–23. DOI: 10.1016/j.trim.2012.11.001. PMID: 23153769.

91. Csizmadia V, Gao W, Hancock SA, Rottman JB, Wu Z, Turka LA, et al. 2001; Differential NF-kappaB and IkappaB gene expression during development of cardiac allograft rejection versus CD154 monoclonal antibody-induced tolerance. Transplantation. 71:835–40. DOI: 10.1097/00007890-200104150-00003. PMID: 11349713.

92. Abadja F, Atemkeng S, Alamartine E, Berthoux F, Mariat C. 2011; Impact of mycophenolic acid and tacrolimus on Th17-related immune response. Transplantation. 92:396–403. DOI: 10.1097/TP.0b013e3182247b5f. PMID: 21818055.

93. Li Y, Shi Y, Liao Y, Yan L, Zhang Q, Wang L. 2015; Differential regulation of Tregs and Th17/Th1 cells by a sirolimus-based regimen might be dependent on STAT-signaling in renal transplant recipients. Int Immunopharmacol. 28:435–43. DOI: 10.1016/j.intimp.2015.07.006. PMID: 26186486.

94. Doh KC, Kim BM, Kim KW, Chung BH, Yang CW. 2019; Effects of resveratrol on Th17 cell-related immune responses under tacrolimus-based immunosuppression. BMC Complement Altern Med. 19:54. DOI: 10.1186/s12906-019-2464-1. PMID: 30832648. PMCID: PMC6399827.

95. Rudd CE. 2009; CTLA-4 co-receptor impacts on the function of Treg and CD8+ T-cell subsets. Eur J Immunol. 39:687–90. DOI: 10.1002/eji.200939261. PMID: 19283722. PMCID: PMC3512132.

96. Hegde S, Leader AM, Merad M. 2021; MDSC: markers, development, states, and unaddressed complexity. Immunity. 54:875–84. DOI: 10.1016/j.immuni.2021.04.004. PMID: 33979585. PMCID: PMC8709560.

97. Mulley WR, Nikolic-Paterson DJ. 2008; Indoleamine 2,3-dioxygenase in transplantation. Nephrology (Carlton). 13:204–11. DOI: 10.1111/j.1440-1797.2007.00921.x. PMID: 18221253.

98. Tang Q, Leung J, Peng Y, Sanchez-Fueyo A, Lozano JJ, Lam A, et al. 2022; Selective decrease of donor-reactive Tregs after liver transplantation limits Treg therapy for promoting allograft tolerance in humans. Sci Transl Med. 14:eabo2628. DOI: 10.1126/scitranslmed.abo2628. PMID: 36322627. PMCID: PMC11016119.

99. Chandran S, Tang Q, Sarwal M, Laszik ZG, Putnam AL, Lee K, et al. 2017; Polyclonal regulatory T cell therapy for control of inflammation in kidney transplants. Am J Transplant. 17:2945–54. DOI: 10.1111/ajt.14415. PMID: 28675676. PMCID: PMC5662482.

100. Salminen A, Kaarniranta K, Kauppinen A. 2018; The role of myeloid-derived suppressor cells (MDSC) in the inflammaging process. Ageing Res Rev. 48:1–10. DOI: 10.1016/j.arr.2018.09.001. PMID: 30248408.

101. Hegde S, Leader AM, Merad M. 2021; MDSC: markers, development, states, and unaddressed complexity. Immunity. 54:875–84. DOI: 10.1016/j.immuni.2021.04.004. PMID: 33979585. PMCID: PMC8709560.

102. Londoño MC, Rimola A, O'Grady J, Sanchez-Fueyo A. 2013; Immunosuppression minimization vs. complete drug withdrawal in liver transplantation. J Hepatol. 59:872–9. DOI: 10.1016/j.jhep.2013.04.003. PMID: 23578883.