Treg-Centric View of Immunosuppressive Drugs in Transplantation: A Balancing Act

American Journal of Transplantation

Volumn 17, Issue 3, 2017, Pages 601-610

  Camirand, G ^a   Riella, L V ^b  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

basic (laboratory) research science; cellular biology; flow cytometry; immune regulation; immunobiology; immunosuppression immune modulation; immunosuppressive regimens; lymphocyte biology; tolerance; translational research science

Indexed keywords

CD28 ANTIGEN; COMPLEMENT RECEPTOR; CYTOKINE RECEPTOR; HISTONE DEACETYLASE INHIBITOR; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 2 RECEPTOR; T LYMPHOCYTE RECEPTOR; THYMOCYTE ANTIBODY;

CELL FUNCTION; CELL SURVIVAL; DRUG TARGETING; GRAFT RECIPIENT; HUMAN; LYMPHOCYTE FUNCTION; NONHUMAN; ONTOGENY; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; SIGNAL TRANSDUCTION; TRANSPLANTATION; ANIMAL; DRUG EFFECTS; GRAFT REJECTION; IMMUNOLOGY; KIDNEY TRANSPLANTATION;

ANIMALS; GRAFT REJECTION; HUMANS; IMMUNOSUPPRESSIVE AGENTS; KIDNEY TRANSPLANTATION; T-LYMPHOCYTES, REGULATORY;

EID: 84994761029     PISSN: 16006135     EISSN: 16006143     Source Type: Journal    
DOI: 10.1111/ajt.14029     Document Type: Review

References (101)

1. Matas AJ, Smith JM, Skeans MA, et al. OPTN/SRTR 2013 Annual Data Report: Kidney. Am J Transplant 2015; 15(Suppl 2): 1–34.
2. Colvin-Adams M, Smith JM, Heubner BM, et al. OPTN/SRTR 2013 Annual Data Report: Heart. Am J Transplant 2015; 15(Suppl 2): 1–28.
3. Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: Mechanisms of differentiation and function. Annu Rev Immunol 2012; 30: 531–564.
4. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008; 133: 775–787.
5. Salvalaggio PR, Camirand G, Ariyan CE, et al. Antigen exposure during enhanced CTLA-4 expression promotes allograft tolerance in vivo. J Immunol 2006; 176: 2292–2298.
6. Kendal AR, Chen Y, Regateiro FS, et al. Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance. J Exp Med 2011; 208: 2043–2053.
7. Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev 2003; 3: 199–210.
8. Joffre O, Santolaria T, Calise D, et al. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nat Med 2008; 14: 88–92.
9. Burzyn D, Kuswanto W, Kolodin D, et al. A special population of regulatory T cells potentiates muscle repair. Cell 2013; 155: 1282–1295.
10. Cipolletta D, Feuerer M, Li A, et al. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 2012; 486: 549–553.
11. Arpaia N, Green JA, Moltedo B, et al. A distinct function of regulatory T cells in tissue protection. Cell 2015; 162: 1078–1089.
12. Andreola G, Chittenden M, Shaffer J, et al. Mechanisms of donor-specific tolerance in recipients of haploidentical combined bone marrow/kidney transplantation. Am J Transplant 2011; 11: 1236–1247.
13. Sachs DH, Kawai T, Sykes M. Induction of tolerance through mixed chimerism. Cold Spring Harb Perspect Med 2014; 4: a015529.
14. Shinoda K, Akiyoshi T, Chase CM, et al. Depletion of foxp3+T cells abrogates tolerance of skin and heart allografts in murine mixed chimeras without the loss of mixed chimerism. Am J Transplant 2014; 14: 2263–2274.
15. Gottschalk RA, Corse E, Allison JP. TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J Exp Med 2010; 207: 1701–1711.
16. Samstein RM, Josefowicz SZ, Arvey A, Treuting PM, Rudensky AY. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 2012; 150: 29–38.
17. Josefowicz SZ, Niec RE, Kim HY, et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 2012; 482: 395–399.
18. Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 2010; 463: 808–812.
19. Smigiel KS, Richards E, Srivastava S, et al. CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J Exp Med 2014; 211: 121–136.
20. Rosenblum MD, Way SS, Abbas AK. Regulatory T cell memory. Nat Rev 2016; 16: 90–101.
21. Levine AG, Arvey A, Jin W, Rudensky AY. Continuous requirement for the TCR in regulatory T cell function. Nat Immunol 2014; 15: 1070–1078.
22. Sanchez Rodriguez R, Pauli ML, Neuhaus IM, et al. Memory regulatory T cells reside in human skin. J Clin Invest 2014; 124: 1027–1036.
23. Rosenblum MD, Gratz IK, Paw JS, Lee K, Marshak-Rothstein A, Abbas AK. Response to self antigen imprints regulatory memory in tissues. Nature 2011; 480: 538–542.
24. Sanchez AM, Zhu J, Huang X, Yang Y. The development and function of memory regulatory T cells after acute viral infections. J Immunol 2012; 189: 2805–2814.
25. Brincks EL, Roberts AD, Cookenham T, et al. Antigen-specific memory regulatory CD4+Foxp3+ T cells control memory responses to influenza virus infection. J Immunol 2013; 190: 3438–3446.
26. Koenen HJ, Smeets RL, Vink PM, van Rijssen E, Boots AM, Joosten I. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 2008; 112: 2340–2352.
27. Voo KS, Wang YH, Santori FR, et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci U S A 2009; 106: 4793–4798.
28. Oldenhove G, Bouladoux N, Wohlfert EA, et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 2009; 31: 772–786.
29. Liu W, Putnam AL, Xu-Yu Z, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006; 203: 1701–1711.
30. Vahl JC, Drees C, Heger K, et al. Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity 2014; 41: 722–736.
31. Zhang R, Huynh A, Whitcher G, Chang J, Maltzman JS, Turka LA. An obligate cell-intrinsic function for CD28 in Tregs. J Clin Invest 2013; 123: 580–593.
32. Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 2004; 21: 267–277.
33. Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol 2006; 7: 401–410.
34. Kolodin D, van Panhuys N, Li C, et al. Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab 2015; 21: 543–557.
35. Feuerer M, Herrero L, Cipolletta D, et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009; 15: 930–939.
36. Riella LV, Liu T, Yang J, et al. Deleterious effect of CTLA4-Ig on a Treg-dependent transplant model. Am J Transplant 2012; 12: 846–855.
37. Levitsky J, Miller J, Huang X, Chandrasekaran D, Chen L, Mathew JM. Inhibitory effects of belatacept on allospecific regulatory T-cell generation in humans. Transplantation 2013; 96: 689–696.
38. Bluestone JA, Liu W, Yabu JM, et al. The effect of costimulatory and interleukin 2 receptor blockade on regulatory T cells in renal transplantation. Am J Transplant 2008; 8: 2086–2096.
39. Yan D, Farache J, Mingueneau M, Mathis D, Benoist C. Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3. Proc Natl Acad Sci USA 2015; 112: 14942–14947.
40. Crellin NK, Garcia RV, Levings MK. Altered activation of AKT is required for the suppressive function of human CD4+CD25+ T regulatory cells. Blood 2007; 109: 2014–2022.
41. Ouyang W, Liao W, Luo CT, et al. Novel Foxo1-dependent transcriptional programs control Treg cell function. Nature 2012; 491: 554–559.
42. Schmidt-Supprian M, Tian J, Grant EP, et al. Differential dependence of CD4+CD25+ regulatory and natural killer-like T cells on signals leading to NF-kappaB activation. Proc Natl Acad Sci USA 2004; 101: 4566–4571.
43. Medoff BD, Sandall BP, Landry A, et al. Differential requirement for CARMA1 in agonist-selected T-cell development. Eur J Immunol 2009; 39: 78–84.
44. Gupta S, Manicassamy S, Vasu C, Kumar A, Shang W, Sun Z. Differential requirement of PKC-theta in the development and function of natural regulatory T cells. Mol Immunol 2008; 46: 213–224.
45. Chang J-H, Xiao Y, Hu H, et al. Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells. Nat Immunol 2012; 13: 481–490.
46. Huynh A, DuPage M, Priyadharshini B, et al. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol 2015; 16: 188–196.
47. Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol 2015; 16: 178–187.
48. Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 2013; 499: 485–490.
49. Procaccini C, De Rosa V, Galgani M, et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 2010; 33: 929–941.
50. Hippen KL, Merkel SC, Schirm DK, et al. Generation and large-scale expansion of human inducible regulatory T cells that suppress graft-versus-host disease. Am J Transplant 2011; 11: 1148–1157.
51. Scotta C, Fanelli G, Hoong SJ, et al. Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells. Haematologica 2016; 101: 91–100.
52. Zhang P, Tey SK, Koyama M, et al. Induced regulatory T cells promote tolerance when stabilized by rapamycin and IL-2 in vivo. J Immunol 2013; 191: 5291–5303.
53. Coenen JJ, Koenen HJ, van Rijssen E, et al. Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+ CD25+ FoxP3+ T cells. Bone Marrow Transplant 2007; 39: 537–545.
54. Strauss L, Whiteside TL, Knights A, Bergmann C, Knuth A, Zippelius A. Selective survival of naturally occurring human CD4+CD25+Foxp3+ regulatory T cells cultured with rapamycin. J Immunol 2007; 178: 320–329.
55. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 2005; 105: 4743–4748.
56. Hester J, Schiopu A, Nadig SN, Wood KJ. Low-dose rapamycin treatment increases the ability of human regulatory T cells to inhibit transplant arteriosclerosis in vivo. Am J Transplant 2012; 12: 2008–2016.
57. Singh K, Stempora L, Harvey RD, et al. Superiority of rapamycin over tacrolimus in preserving nonhuman primate Treg half-life and phenotype after adoptive transfer. Am J Transplant 2014; 14: 2691–2703.
58. Segundo DS, Ruiz JC, Izquierdo M, et al. Calcineurin inhibitors, but not rapamycin, reduce percentages of CD4+CD25+FOXP3+ regulatory T cells in renal transplant recipients. Transplantation 2006; 82: 550–557.
59. Wang Y, Camirand G, Lin Y, et al. Regulatory T cells require mammalian target of rapamycin signaling to maintain both homeostasis and alloantigen-driven proliferation in lymphocyte-replete mice. J Immunol 2011; 186: 2809–2818.
60. Luo CT, Liao W, Dadi S, Toure A, Li MO. Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity. Nature 2016; 529: 532–536.
61. Zwang NA, Zhang R, Germana S, et al. Selective sparing of human tregs by pharmacologic inhibitors of the PI3-kinase and MEK pathways. Am J Transplant 2016; 16: 2624–2638.
62. Li X, Liang Y, LeBlanc M, Benner C, Zheng Y. Function of a Foxp3 cis-element in protecting regulatory T cell identity. Cell 2014; 158: 734–748.
63. Pascual J, Bloom D, Torrealba J, et al. Calcineurin inhibitor withdrawal after renal transplantation with alemtuzumab: Clinical outcomes and effect on T-regulatory cells. Am J Transplant 2008; 8: 1529–1536.
64. Gallon L, Traitanon O, Sustento-Reodica N, et al. Cellular and molecular immune profiles in renal transplant recipients after conversion from tacrolimus to sirolimus. Kidney Int 2015; 87: 828–838.
65. Demirkiran A, Sewgobind VD, van der Weijde J, et al. Conversion from calcineurin inhibitor to mycophenolate mofetil-based immunosuppression changes the frequency and phenotype of CD4+FOXP3+ regulatory T cells. Transplantation 2009; 87: 1062–1068.
66. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155: 1151–1164.
67. Tai X, Erman B, Alag A, et al. Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity 2013; 38: 1116–1128.
68. Klatzmann D, Abbas AK. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev 2015; 15: 283–294.
69. Koreth J, Kim HT, Jones KT, et al. Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease. Blood 2016; 128: 130–137.
70. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 2011; 365: 2055–2066.
71. Matsuoka K, Koreth J, Kim HT, et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med 2013; 5: 179ra143.
72. Lee SY, Cho ML, Oh HJ, et al. Interleukin-2/anti-interleukin-2 monoclonal antibody immune complex suppresses collagen-induced arthritis in mice by fortifying interleukin-2/STAT5 signalling pathways. Immunology 2012; 137: 305–316.
73. Webster KE, Walters S, Kohler RE, et al. In vivo expansion of T reg cells with IL-2-mAb complexes: Induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J Exp Med 2009; 206: 751–760.
74. Wilson MS, Pesce JT, Ramalingam TR, Thompson RW, Cheever A, Wynn TA. Suppression of murine allergic airway disease by IL-2:Anti-IL-2 monoclonal antibody-induced regulatory T cells. J Immunol 2008; 181: 6942–6954.
75. Zhao T, Yang C, Xue Y, et al. Impact of basiliximab on the proportion of regulatory T cells and their subsets early after renal transplantation: A preliminary report. Transplant Proc 2012; 44: 175–178.
76. Zeiser R, Nguyen VH, Beilhack A, et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 2006; 108: 390–399.
77. Sheen JH, Heeger PS. Effects of complement activation on allograft injury. Curr Opin Organ Transplant 2015; 20: 468–475.
78. Lalli PN, Strainic MG, Yang M, Lin F, Medof ME, Heeger PS. Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis. Blood 2008; 112: 1759–1766.
79. Strainic MG, Liu J, Huang D, et al. Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity 2008; 28: 425–435.
80. Kwan W-H, van der Touw W, Paz-Artal E, Li MO, Heeger PS. Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells. J Exp Med 2013; 210: 257–268.
81. Strainic MG, Shevach EM, An F, Lin F, Medof ME. Absence of signaling into CD4(+) cells via C3aR and C5aR enables autoinductive TGF-beta1 signaling and induction of Foxp3(+) regulatory T cells. Nat Immunol 2013; 14: 162–171.
82. van der Touw W, Cravedi P, Kwan WH, Paz-Artal E, Merad M, Heeger PS. Cutting edge: Receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells. J Immunol 2013; 190: 5921–5925.
83. Alfinito F, Ruggiero G, Sica M, et al. Eculizumab treatment modifies the immune profile of PNH patients. Immunobiology 2012; 217: 698–703.
84. Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003; 299: 1033–1036.
85. Srivastava S, Koch LK, Campbell DJ. IFNαR signaling in effector but not regulatory T cells is required for immune dysregulation during type I IFN-dependent inflammatory disease. J Immunol 2014; 193: 2733–2742.
86. Srivastava S, Koch MA, Pepper M, Campbell DJ. Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection. J Exp Med 2014; 211: 961–974.
87. Basu R, Whitley SK, Bhaumik S, et al. IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH17 cell–iTreg cell balance. Nat Immunol 2015; 16: 286–295.
88. Chong AS, Alegre ML. The impact of infection and tissue damage in solid-organ transplantation. Nat Rev 2012; 12: 459–471.
89. Walker LS. Regulatory T cells overturned: The effectors fight back. Immunology 2009; 126: 466–474.
90. Ling Y, Cao X, Yu Z, Ruan C. Circulating dendritic cells subsets and CD4+Foxp3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasone. Eur J Haematol 2007; 79: 310–316.
91. high T cell population in patients with systemic lupus erythematosus treated with glucocorticoids. Ann Rheum Dis 2006; 65: 1512–1517.
92. Seissler N, Schmitt E, Hug F, et al. Methylprednisolone treatment increases the proportion of the highly suppressive HLA-DR(+)-Treg-cells in transplanted patients. Transpl Immunol 2012; 27: 157–161.
93. Gurkan S, Luan Y, Dhillon N, et al. Immune reconstitution following rabbit antithymocyte globulin. Am J Transplant 2010; 10: 2132–2141.
94. Bouvy AP, Klepper M, Kho MM, et al. The impact of induction therapy on the homeostasis and function of regulatory T cells in kidney transplant patients. Nephrol Dial Transplant 2014; 29: 1587–1597.
95. Tao R, de Zoeten EF, Ozkaynak E, et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 2007; 13: 1299–1307.
96. Choi SW, Gatza E, Hou G, et al. Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans. Blood 2015; 125: 815–819.
97. Hancock WW. Isoform-selective HDAC inhibitor therapy for transplantation: Are we ready for HDAC6? Transplantation 2016; 100: 1597–1598.
98. Lagaraine C, Lemoine R, Baron C, Nivet H, Velge-Roussel F, Lebranchu Y. Induction of human CD4+ regulatory T cells by mycophenolic acid-treated dendritic cells. J Leukoc Biol 2008; 84: 1057–1064.
99. He X, Smeets RL, Koenen HJ, et al. Mycophenolic acid-mediated suppression of human CD4+ T cells: More than mere guanine nucleotide deprivation. Am J Transplant 2011; 11: 439–449.
100. Lee MJ, Ye AS, Gardino AK, et al. Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell 2012; 149: 780–794.
101. Grafals M, Smith B, Murakami N, et al. Immunophenotyping and efficacy of low dose ATG in non-sensitized kidney recipients undergoing early steroid withdrawal: A randomized pilot study. PLoS One 2014; 9: e104408.