Sequential monitoring and stability of Ex vivo-expanded autologous and nonautologous regulatory t cells following infusion in nonhuman primates

American Journal of Transplantation

Volumn 15, Issue 5, 2015, Pages 1253-1266

  Zhang, H ^a   Guo, H ^a   Lu, L ^a   Zahorchak, A F ^a   Wiseman, R W ^b   Raimondi, G ^a,c   Cooper, D K C ^a   Ezzelarab, M B ^a   Thomson, A W ^a,c  

^a UNIVERSITY OF PITTSBURGH MEDICAL CENTER   (United States)

^b UNIVERSITY OF WISCONSIN   (United States)

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

Author keywords

animal models: nonhuman primate; basic (laboratory) research science; immunobiology; immunosuppressant; Immunosuppressant; immunosuppression immune modulation; mechanistic target of rapamycin (mTOR); polyclonal preparations: rabbit antithymocyte globulin; T cell biology; translational research science

Indexed keywords

INTERLEUKIN 7 RECEPTOR; KI 67 ANTIGEN; RAPAMYCIN; THYMOCYTE ANTIBODY; TRANSCRIPTION FACTOR FOXP3; FORKHEAD TRANSCRIPTION FACTOR; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 2 RECEPTOR ALPHA; INTERLEUKIN 7 RECEPTOR ALPHA; LYMPHOCYTE ANTIBODY;

ADOPTIVE TRANSFER; ANIMAL CELL; ANIMAL CELL CULTURE; ANIMAL EXPERIMENT; ANTIGEN EXPRESSION; ARTICLE; AUTOLOGOUS REGULATORY T CELL; CD4+ CD25+ T LYMPHOCYTE; CELL PROLIFERATION; DEMETHYLATION; DONOR; EX VIVO STUDY; HAPLOTYPE; HLA TYPING; IMMUNOSUPPRESSIVE TREATMENT; INFUSION; MACACA FASCICULARIS; MAJOR HISTOCOMPATIBILITY COMPLEX; MALE; NONAUTOLOGOUS REGULATORY T CELL; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PRIORITY JOURNAL; RECIPIENT; REGULATORY T LYMPHOCYTE; ANIMAL; CHEMISTRY; IMMUNOLOGY; METABOLISM; METHYLATION; PHENOTYPE;

ANIMALS; ANTILYMPHOCYTE SERUM; FORKHEAD TRANSCRIPTION FACTORS; HAPLOTYPES; IMMUNOSUPPRESSIVE AGENTS; INTERLEUKIN-2 RECEPTOR ALPHA SUBUNIT; INTERLEUKIN-7 RECEPTOR ALPHA SUBUNIT; KI-67 ANTIGEN; MACACA FASCICULARIS; MAJOR HISTOCOMPATIBILITY COMPLEX; MALE; METHYLATION; PHENOTYPE; SIROLIMUS; T-LYMPHOCYTES, REGULATORY;

EID: 84928011687     PISSN: 16006135     EISSN: 16006143     Source Type: Journal    
DOI: 10.1111/ajt.13113     Document Type: Article

References (73)

1. Halloran PF.; Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004; 351: 2715-2729.
2. Bluestone JA, Thomson AW, Shevach EM, Weiner HL.; What does the future hold for cell-based tolerogenic therapy ? Nat Rev Immunol. 2007; 7: 650-654.
3. June CH, Blazar BR.; Clinical application of expanded CD4 + 25+ cells. Semin Immunol. 2006; 18: 78-88.
4. Wood KJ, Bushell A, Hester J.; Regulatory immune cells in transplantation. Nat Rev Immunol. 2012; 12: 417-430.
5. Sakaguchi S, Powrie F, Ransohoff RM.; Re-establishing immunological self-tolerance in autoimmune disease. Nat Med. 2012; 18: 54-58.
6. Torrealba JR, Katayama M, Fechner JH Jr, et al. Metastable tolerance to rhesus monkey renal transplants is correlated with allograft TGF-beta 1 + CD4+ T regulatory cell infiltrates. J Immunol. 2004; 172: 5753-5764.
7. Bashuda H, Kimikawa M, Seino K, et al. Renal allograft rejection is prevented by adoptive transfer of anergic T cells in nonhuman primates. J Clin Invest. 2005; 115: 1896-1902.
8. Ma A, Qi S, Song L, et al. Adoptive transfer of CD4 + CD25+ regulatory cells combined with low-dose sirolimus and anti-thymocyte globulin delays acute rejection of renal allografts in Cynomolgus monkeys. Int Immunopharmacol. 2011; 11: 618-629.
9. Taflin C, Nochy D, Hill G, et al. Regulatory T cells in kidney allograft infiltrates correlate with initial inflammation and graft function. Transplantation. 2010; 89: 194-199.
10. Bestard O, Cruzado JM, Rama I, et al. Presence of FoxP3+ regulatory T Cells predicts outcome of subclinical rejection of renal allografts. J Am Soc Nephrol. 2008; 19: 2020-2026.
11. Martinez-Llordella M, Puig-Pey I, Orlando G, et al. Multiparameter immune profiling of operational tolerance in liver transplantation. Am J Transplant. 2007; 7: 309-319.
12. Tokita D, Mazariegos GV, Zahorchak AF, et al. High PD-L1/CD86 ratio on plasmacytoid dendritic cells correlates with elevated T-regulatory cells in liver transplant tolerance. Transplantation. 2008; 85: 369-377.
13. Nadig SN, Wieckiewicz J, Wu DC, et al. In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells. Nat Med. 2010; 16 (7): 809-813.
14. Wu DC, Hester J, Nadig SN, et al. Ex vivo expanded human regulatory T cells can prolong survival of a human islet allograft in a humanized mouse model. Transplantation. 2013; 96: 707-716.
15. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA.; CD4 + CD25high regulatory cells in human peripheral blood. J Immunol. 2001; 167: 1245-1253.
16. + T regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med. 2001; 193: 1295-1302.
17. Ng WF, Duggan PJ, Ponchel F, et al. Human CD4(+)CD25(+) cells: a naturally occurring population of regulatory T cells. Blood. 2001; 98: 2736-2744.
18. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH.; Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med. 2001; 193: 1285-1294.
19. Seddiki N, Santner-Nanan B, Martinson J, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006; 203: 1693-1700.
20. 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.
21. Godfrey WR, Ge YG, Spoden DJ, et al. In vitro-expanded human CD4(+)CD25(+) T-regulatory cells can markedly inhibit allogeneic dendritic cell-stimulated MLR cultures. Blood. 2004; 104: 453-461.
22. Anderson A, Martens CL, Hendrix R, et al. Expanded nonhuman primate Tregs exhibit a unique gene expression signature and potently downregulate alloimmune responses. Am J Transplant. 2008; 8: 2252-2264.
23. Singh K, Kozyr N, Stempora L, et al. Regulatory T cells exhibit decreased proliferation but enhanced suppression after pulsing with sirolimus. Am J Transplant. 2012; 12: 1441-1457.
24. Dons EM, Raimondi G, Zhang H, et al. Ex vivo-expanded cynomolgus macaque regulatory T cells are resistant to alemtuzumab-mediated cytotoxicity. Am J Transplant. 2013; 13: 2169-2178.
25. Kean LS, Gangappa S, Pearson TC, Larsen CP.; Transplant tolerance in non-human primates: progress, current challenges and unmet needs. Am J Transplant. 2006; 6: 884-893.
26. Dons EM, Raimondi G, Cooper DK, Thomson AW.; Non-human primate regulatory T cells: Current biology and implications for transplantation. Transplantation. 2010; 90: 811-816.
27. Ezzelarab MB, Zahorchak AF, Lu L, et al. Regulatory dendritic cell infusion prolongs kidney allograft survival in nonhuman primates. Am J Transplant. 2013; 13: 1989-2005.
28. Tchorsh-Yutsis D, Zlotnikov Klionsky Y, Bachar-Lustig E, et al. Embryonic pig pancreatic tissue for the treatment of diabetes: potential role of immune suppression with "off-the-shelf" third-party regulatory T cells. Transplantation. 2011; 91: 398-405.
29. Steiner D, Brunicki N, Blazar BR, Bachar-Lustig E, Reisner Y.; Tolerance induction by third-party "off-the-shelf" CD4 + CD25+ Treg cells. Exp Hematol. 2006; 34: 66-71.
30. Brunstein CG, Miller JS, Cao Q, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: Safety profile and detection kinetics. Blood. 2011; 117: 1061-1070.
31. 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.
32. Feng X, Kajigaya S, Solomou EE, et al. Rabbit ATG but not horse ATG promotes expansion of functional CD4 + CD25highFOXP3+ regulatory T cells in vitro. Blood. 2008; 111: 3675-3683.
33. Boenisch O, Lopez M, Elyaman W, Magee CN, Ahmad U, Najafian N.; Ex vivo expansion of human Tregs by rabbit ATG is dependent on intact STAT3-signaling in CD4(+) T cells and requires the presence of monocytes. Am J Transplant. 2012; 12: 856-866.
34. Tang Q, Leung J, Melli K, et al. Altered balance between effector T cells and FOXP3+ HELIOS+ regulatory T cells after thymoglobulin induction in kidney transplant recipients. Transpl Int. 2012; 25: 1257-1267.
35. Gurkan S, Luan Y, Dhillon N, et al. Immune reconstitution following rabbit antithymocyte globulin. Am J Transplant. 2010; 10: 2132-2141.
36. Raimondi G, Sumpter TL, Matta BM, et al. Mammalian target of rapamycin inhibition and alloantigen-specific regulatory T cells synergize to promote long-term graft survival in immunocompetent recipients. J Immunol. 2010; 184: 624-636.
37. 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.
38. Wiseman RW, Karl JA, Bohn PS, Nimityongskul FA, Starrett GJ, O'Connor DH.; Haplessly hoping: Macaque major histocompatibility complex made easy. ILAR J. 2013; 54: 196-210.
39. Himmel ME, MacDonald KG, Garcia RV, Steiner TS, Levings MK.; Helios+ and Helios- cells coexist within the natural FOXP3+ T regulatory cell subset in humans. J Immunol. 2013; 190: 2001-2008.
40. Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG.; Rapamycin promotes expansion of functional CD4 + CD25 + FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol. 2006; 177: 8338-8347.
41. Hippen KL, Merkel SC, Schirm DK, et al. Massive ex vivo expansion of human natural regulatory T cells (T(regs)) with minimal loss of in vivo functional activity. Sci Transl Med. 2011; 3: 83ra41.
42. Huehn J, Polansky JK, Hamann A.; Epigenetic control of FOXP3 expression: The key to a stable regulatory T-cell lineage ? Nat Rev Immunol. 2009; 9: 83-89.
43. Marco MR, Dons EM, van der Windt DJ, et al. Post-transplant repopulation of naive and memory T cells in blood and lymphoid tissue after alemtuzumab-mediated depletion in heart-transplanted cynomolgus monkeys. Transpl Immunol. 2013; 29: 88-98.
44. Campbell DJ, Koch MA.; Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol. 2011; 11: 119-130.
45. Thornton AM, Korty PE, Tran DQ, et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol. 2010; 184: 3433-3441.
46. Borsellino G, Kleinewietfeld M, Di Mitri D, et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: Hydrolysis of extracellular ATP and immune suppression. Blood. 2007; 110: 1225-1232.
47. Dwyer KM, Hanidziar D, Putheti P, et al. Expression of CD39 by human peripheral blood CD4+ CD25+ T cells denotes a regulatory memory phenotype. Am J Transplant. 2010; 10 (11): 2410-2420.
48. Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007; 204: 1257-1265.
49. Feuerer M, Hill JA, Mathis D, Benoist C.; Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol. 2009; 10: 689-695.
50. Oo YH, Weston CJ, Lalor PF, et al. Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. J Immunol. 2010; 184: 2886-2898.
51. Huehn J, Siegmund K, Lehmann JC, et al. Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J Exp Med. 2004; 199: 303-313.
52. Warnock RA, Askari S, Butcher EC, von Andrian UH.; Molecular mechanisms of lymphocyte homing to peripheral lymph nodes. J Exp Med. 1998; 187: 205-216.
53. Forster R, Schubel A, Breitfeld D, et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell. 1999; 99: 23-33.
54. Burrell BE, Nakayama Y, Xu J, Brinkman CC, Bromberg JS.; Regulatory T cell induction, migration, and function in transplantation. J Immunol. 2012; 189: 4705-4711.
55. Trzonkowski P, Bieniaszewska M, Juscinska J, et al. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4 + CD25 + CD127- T regulatory cells. Clin Immunol. 2009; 133: 22-26.
56. Di Ianni M, Falzetti F, Carotti A, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011; 117: 3921-3928.
57. Tang Q, Henriksen KJ, Bi M, et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med. 2004; 199: 1455-1465.
58. Kohm AP, Carpentier PA, Anger HA, Miller SD.; Cutting edge: CD4 + CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol. 2002; 169: 4712-4716.
59. Zhang H, Podojil JR, Chang J, Luo X, Miller SD.; TGF-beta-induced myelin peptide-specific regulatory T cells mediate antigen-specific suppression of induction of experimental autoimmune encephalomyelitis. J Immunol. 2010; 184: 6629-6636.
60. Joffre O, Gorsse N, Romagnoli P, Hudrisier D, van Meerwijk JP.; Induction of antigen-specific tolerance to bone marrow allografts with CD4 + CD25+ T lymphocytes. Blood. 2004; 103: 4216-4221.
61. 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.
62. Juvet SC, Whatcott AG, Bushell AR, Wood KJ.; Harnessing regulatory T cells for clinical use in transplantation: the end of the beginning. Am J Transplant. 2014; 14: 750-763.
63. Singh K, Stempora L, Garrett A, et al. In-vivo persistence, trafficking and phenotypic stability of autologous, ex-vivo expanded rhesus macaque natural regulatory T cells. Am J Transplant. 2013; 13: 77 (Abstract #155).
64. Banerjee DK, Dhodapkar MV, Matayeva E, Steinman RM, Dhodapkar KM.; Expansion of FOXP3high regulatory T cells by human dendritic cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients. Blood. 2006; 108: 2655-2661.
65. Putnam AL, Safinia N, Medvec A, et al. Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation. Am J Transplant. 2013; 13: 3010-3020.
66. 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.
67. MacDonald KG, Han JM, Himmel ME, et al. Response to comment on "helios+ and helios- cells coexist within the natural FOXP3+ T regulatory cell subset in humans ". J Immunol. 2013; 190 (9): 4440-4441.
68. Issa F, Hester J, Milward R, Goto R, Wood K.; Evaluation and optimisation of non-autologous human regulatory T cell therapy for transplantation. Am J Transplant. 2014; 14: 25 (Abstract 744).
69. Hutchinson JA, Ahrens N, Riquelme P, et al. Clinical management of patients receiving cell-based immunoregulatory therapy. Transfusion. 2014.
70. Lee MKt, Moore DJ, Jarrett BP, et al. Promotion of allograft survival by CD4 + CD25+ regulatory T cells: evidence for in vivo inhibition of effector cell proliferation. J Immunol. 2004; 172: 6539-6544.
71. Vodanovic-Jankovic S, Hari P, Jacobs P, Komorowski R, Drobyski WR.; NF-kappaB as a target for the prevention of graft-versus-host disease: Comparative efficacy of bortezomib and PS-1145. Blood. 2006; 107: 827-834.
72. Zhang N, Schroppel B, Lal G, et al. Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response. Immunity. 2009; 30: 458-469.
73. Hutchinson JA, Riquelme P, Sawitzki B, et al. Cutting Edge: Immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J Immunol. 2011; 187: 2072-2078.