200
Views
10
CrossRef citations to date
0
Altmetric
Reviews

Potential and limitations of regulatory T-cell therapy in solid organ transplantation

, &

References

  • Lechler RI, Batchelor JR. Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor strain. dendritic cells. J Exp Med 1982;155:31-41
  • Lechler RI, Batchelor JR. Immunogenicity of retransplanted rat kidney allografts. Effect of inducing chimerism in the first recipient and quantitative studies on immunosuppression of the second recipient. J Exp Med 1982;156:1835-41
  • Golshayan D, Pascual M. Tolerance-inducing immunosuppressive strategies in clinical transplantation: an overview. Drugs 2008;68:2113-30
  • Celli S, Albert ML, Bousso P. Visualizing the innate and adaptive immune responses underlying allograft rejection by two-photon microscopy. Nat Med 2011;17:744-9
  • Benichou G, Valujskikh A, Heeger PS. Contributions of direct and indirect T cell alloreactivity during allograft rejection in mice. J Immunol 1999;162:352-8
  • Hornick PI, Mason PD, Baker RJ, et al. Significant frequencies of T cells with indirect anti-donor specificity in heart graft recipients with chronic rejection. Circulation 2000;101:2405-10
  • Baker RJ, Hernandez-Fuentes MP, Brookes PA, et al. Loss of direct and maintenance of indirect alloresponses in renal allograft recipients: implications for the pathogenesis of chronic allograft nephropathy. J Immunol 2001;167:7199-206
  • Smyth LA, Herrera OB, Golshayan D, et al. A novel pathway of antigen presentation by dendritic and endothelial cells: implications for allorecognition and infectious diseases. Transplantation 2006;82:S15-18
  • Krieger NR, Yin DP, Fathman CG. CD4+ but not CD8+ cells are essential for allorejection. J Exp Med 1996;184:2013-18
  • Yuan X, Paez-Cortez J, Schmitt-Knosalla I, et al. A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med 2008;205:3133-44
  • Deteix C, Attuil-Audenis V, Duthey A, et al. Intragraft Th17 infiltrate promotes lymphoid neogenesis and hastens clinical chronic rejection. J Immunol 2010;184:5344-51
  • Surquin M, Le Moine A, Flamand V, et al. Skin graft rejection elicited by beta 2-microglobulin as a minor transplantation antigen involves multiple effector pathways: role of Fas-Fas ligand interactions and Th2-dependent graft eosinophil infiltrates. J Immunol 2002;169:500-6
  • Lee RS, Grusby MJ, Glimcher LH, et al. Indirect recognition by helper cells can induce donor-specific cytotoxic T lymphocytes in vivo. J Exp Med 1994;179:865-72
  • Steele DJ, Laufer TM, Smiley ST, et al. Two levels of help for B cell alloantibody production. J Exp Med 1996;183:699-703
  • Valujskikh A, Lakkis FG. In remembrance of things past: memory T cells and transplant rejection. Immunol Rev 2003;196:65-74
  • Macedo C, Orkis EA, Popescu I, et al. Contribution of naive and memory T-cell populations to the human alloimmune response. Am J Transplant 2009;9:2057-66
  • Heeger PS, Greenspan NS, Kuhlenschmidt S, et al. Pretransplant frequency of donor-specific, IFN-gamma-producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of posttransplant rejection episodes. J Immunol 1999;163:2267-75
  • Bestard O, Cruzado JM, Lucia M, et al. Prospective assessment of antidonor cellular alloreactivity is a tool for guidance of immunosuppression in kidney transplantation. Kidney Int 2013;84:1226-36
  • Bouma GJ, van Caubergh P, van Bree SP, et al. Pregnancy can induce priming of cytotoxic T lymphocytes specific for paternal HLA antigens that is associated with antibody formation. Transplantation 1996;62:672-8
  • Poggio ED, Augustine JJ, Clemente M, et al. Pretransplant cellular alloimmunity as assessed by a panel of reactive T cells assay correlates with acute renal graft rejection. Transplantation 2007;83:847-52
  • Pantenburg B, Heinzel F, Das L, et al. T cells primed by Leishmania major infection cross-react with alloantigens and alter the course of allograft rejection. J Immunol 2002;169:3686-93
  • Adams AB, Williams MA, Jones TR, et al. Heterologous immunity provides a potent barrier to transplantation tolerance. J Clin Invest 2003;111:1887-95
  • Zhai Y, Meng L, Gao F, et al. Allograft rejection by primed/memory CD8+ T cells is CD154 blockade resistant: therapeutic implications for sensitized transplant recipients. J Immunol 2002;169:4667-73
  • Wu Z, Bensinger SJ, Zhang J, et al. Homeostatic proliferation is a barrier to transplantation tolerance. Nat Med 2004;10:87-92
  • Yang J, Brook MO, Carvalho-Gaspar M, et al. Allograft rejection mediated by memory T cells is resistant to regulation. Proc Natl Acad Sci USA 2007;104:19954-9
  • Nadazdin O, Boskovic S, Murakami T, et al. Host alloreactive memory T cells influence tolerance to kidney allografts in nonhuman primates. Sci Transl Med 2011;3:86ra51
  • Stegall MD, Raghavaiah S, Gloor JM. The (re)emergence of B cells in organ transplantation. Curr Opin Organ Transplant 2010;15:451-5
  • Loupy A, Hill GS, Jordan SC. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol 2012;8:348-57
  • Thaunat O. 2011;Pathophysiologic significance of B-cell clusters in chronically rejected grafts. Transplantation 2012;92:121-6
  • Taylor PA, Ehrhardt MJ, Roforth MM, et al. Preformed antibody, not primed T cells, is the initial and major barrier to bone marrow engraftment in allosensitized recipients. Blood 2007;109:1307-15
  • Ruhil R, Huang D, Bulut O, et al. Humoral immunity induced by viral infection provides a major barrier to hematopoietic cell transplantation (published abstract). Blood 2013;122
  • Penn I. Post-transplant malignancy: the role of immunosuppression. Drug Saf 2000;23:101-13
  • Pascual M, Theruvath T, Kawai T, et al. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med 2002;346:580-90
  • Golshayan D, Pascual M. Minimization of calcineurin inhibitors to improve long-term outcomes in kidney transplantation. Transpl Immunol 2008;20:21-8
  • De Serres SA, Sayegh MH, Najafian N. Immunosuppressive drugs and Tregs: a critical evaluation!. Clin J Am Soc Nephrol 2009;4:1661-9
  • Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature 1953;172:603-6
  • Lechler RI, Garden OA, Turka LA. The complementary roles of deletion and regulation in transplantation tolerance. Nat Rev Immunol 2003;3:147-58
  • Gershon RK, Kondo K. Infectious immunological tolerance. Immunology 1971;21:903-14
  • Sakaguchi S, Sakaguchi N, Asano M, et al. 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;155:1151-64
  • Golshayan D, Jiang S, Tsang J, et al. In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance. Blood 2007;109:827-35
  • 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
  • Tang Q, Henriksen KJ, Bi M, et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 2004;199:1455-65
  • Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003;9:1144-50
  • Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 2011;365:2055-66
  • Mottet C, Uhlig HH, Powrie F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 2003;170:3939-43
  • Tarbell KV, Petit L, Zuo X, et al. Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med 2007;204:191-201
  • 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;208:2043-53
  • Nafady-Hego H, Li Y, Ohe H, et al. The generation of donor-specific CD4+CD25++CD45RA+ naive regulatory T cells in operationally tolerant patients after pediatric living-donor liver transplantation. Transplantation 2010;90:1547-55
  • Louis S, Braudeau C, Giral M, et al. Contrasting CD25hiCD4+T cells/FOXP3 patterns in chronic rejection and operational drug-free tolerance. Transplantation 2006;81:398-407
  • Ashton-Chess J, Giral M, Brouard S, Soulillou JP. Spontaneous operational tolerance after immunosuppressive drug withdrawal in clinical renal allotransplantation. Transplantation 2007;84:1215-19
  • Maloy KJ, Powrie F. Fueling regulation: IL-2 keeps CD4+ Treg cells fit. Nat Immunol 2005;6:1071-2
  • Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057-61
  • Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001;27:20-1
  • Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001;27:68-73
  • Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-6
  • Barthlott T, Moncrieffe H, Veldhoen M, et al. CD25+CD4+ T cells compete with naive CD4+ T cells for IL-2 and exploit it for the induction of IL-10 production. Int Immunol 2005;17:279-88
  • Pandiyan P, Zheng L, Ishihara S, et al. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol 2007;8:1353-62
  • Collison LW, Workman CJ, Kuo TT, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007;450:566-9
  • Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003;198:1875-86
  • Nakamura K, Kitani A, Fuss I, et al. TGF-beta1 Plays an Important Role in the Mechanism of CD4(+)CD25(+) Regulatory T Cell Activity in Both Humans and Mice. J Immunol 2004;172:834-42
  • Fahlen L, Read S, Gorelik L, et al. T cells that cannot respond to TGF-{beta} escape control by CD4+CD25+ regulatory T cells. J Exp Med 2005;201:737-46
  • Uhlig HH, Coombes J, Mottet C, et al. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol 2006;177:5852-60
  • Fitzgerald DC, Zhang GX, El-Behi M, et al. Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat Immunol 2007;8:1372-9
  • Whitehead GS, Wilson RH, Nakano K, et al. IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease. J Allergy Clin Immunol 2012;129:207-15. e1-5
  • Garin MI, Chu CC, Golshayan D, et al. Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells. Blood 2007;109:2058-65
  • Kubach J, Lutter P, Bopp T, et al. Human CD4+CD25+ regulatory T cells: proteome analysis identifies galectin-10 as a novel marker essential for their anergy and suppressive function. Blood 2007;110:1550-8
  • Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 2009;30:636-45
  • Gondek DC, Lu LF, Quezada SA, et al. Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol 2005;174:1783-6
  • Cao X, Cai SF, Fehniger TA, et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 2007;27:635-46
  • Puccetti P, Grohmann U. IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-kappaB activation. Nat Rev Immunol 2007;7:817-23
  • Qureshi OS, Zheng Y, Nakamura K, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 2011;332:600-3
  • Bettelli E, Dastrange M, Oukka M. Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. Proc Natl Acad Sci USA 2005;102:5138-43
  • Koch MA, Tucker-Heard G, Perdue NR, et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 2009;10:595-602
  • Wang Y, Su MA, Wan YY. An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 2011;35:337-48
  • Cretney E, Xin A, Shi W, et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol 2011;12:304-11
  • Wing JB, Sakaguchi S. Multiple Treg suppressive modules and their adaptability. Front Immunol 2012;3:178
  • Linterman MA, Pierson W, Lee SK, et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 2011;17:975-82
  • Chung Y, Tanaka S, Chu F, et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med 2011;17:983-8
  • Gotot J, Gottschalk C, Leopold S, et al. Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo. Proc Natl Acad Sci USA 2012;109:10468-73
  • 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;203:1701-11
  • Fritzsching B, Oberle N, Pauly E, et al. Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death. Blood 2006;108:3371-8
  • Miyara M, Yoshioka Y, Kitoh A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009;30:899-911
  • Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 2010;10:490-500
  • Levings MK, Sangregorio R, Roncarolo MG. Human CD25(+)CD4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med 2001;193:1295-302
  • Hoffmann P, Eder R, Kunz-Schughart LA, et al. Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells. Blood 2004;104:895-903
  • Jiang S, Golshayan D, Tsang J, et al. In vitro expanded alloantigen-specific CD4+CD25+ regulatory T cell treatment for the induction of donor-specific transplantation tolerance. Int Immunopharmacol 2006;6:1879-82
  • Putnam AL, Brusko TM, Lee MR, et al. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 2009;58:652-62
  • Battaglia M, Stabilini A, Migliavacca B, et al. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol 2006;177:8338-47
  • 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
  • Sagoo P, Ali N, Garg G, et al. 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
  • 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;13:3010-20
  • Gregori S, Tomasoni D, Pacciani V, et al. Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood 2010;116:935-44
  • Naranjo-Gomez M, Raich-Regue D, Onate C, et al. Comparative study of clinical grade human tolerogenic dendritic cells. J Transl Med 2011;9:89
  • Gagliani N, Magnani CF, Huber S, et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 2013;19:739-46
  • Bacchetta R, Gregori S, Serafini G, et al. Molecular and functional characterization of allogantigen-specific anergic T cells suitable for cell therapy. Haematologica 2010;95:2134-43
  • Bacchetta R, Lucarelli B, Sartirana C, et al. Immunological Outcome in Haploidentical-HSC Transplanted Patients Treated with IL-10-Anergized Donor T Cells. Front Immunol 2014;5:16
  • Chen Q, Kim YC, Laurence A, et al. IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3+ T cells in vivo. J Immunol 2011;186:6329-37
  • Zeiser R, Negrin RS. Interleukin-2 receptor downstream events in regulatory T cells: implications for the choice of immunosuppressive drug therapy. Cell Cycle 2008;7:458-62
  • Zhou X, Kong N, Wang J, et al. Cutting edge: all-trans retinoic acid sustains the stability and function of natural regulatory T cells in an inflammatory milieu. J Immunol 2010;185:2675-9
  • Lu L, Zhou X, Wang J, et al. Characterization of protective human CD4CD25 FOXP3 regulatory T cells generated with IL-2, TGF-beta and retinoic acid. PLoS One 2010;5:e15150
  • Baron U, Floess S, Wieczorek G, et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol 2007;37:2378-89
  • Koenecke C, Czeloth N, Bubke A, et al. Alloantigen-specific de novo-induced Foxp3+ Treg revert in vivo and do not protect from experimental GVHD. Eur J Immunol 2009;39:3091-6
  • Saadoun D, Rosenzwajg M, Joly F, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med 2011;365:2067-77
  • Boyman O, Kovar M, Rubinstein MP, et al. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 2006;311:1924-7
  • 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;206:751-60
  • Wilson MS, Pesce JT, Ramalingam TR, et al. Suppression of murine allergic airway disease by IL-2:anti-IL-2 monoclonal antibody-induced regulatory T cells. J Immunol 2008;181:6942-54
  • 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;30:458-69
  • Tsang JY, Tanriver Y, Jiang S, et al. Conferring indirect allospecificity on CD4+CD25+ Tregs by TCR gene transfer favors transplantation tolerance in mice. J Clin Invest 2008;118:3619-28
  • Williams KM, Hakim FT, Gress RE. T cell immune reconstitution following lymphodepletion. Semin Immunol 2007;19:318-30
  • 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;16:809-13
  • Hoffmann P, Boeld TJ, Eder R, et al. Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation. Eur J Immunol 2009;39:1088-97
  • Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 2005;105:4743-8
  • Golovina TN, Mikheeva T, Brusko TM, et al. Retinoic acid and rapamycin differentially affect and synergistically promote the ex vivo expansion of natural human T regulatory cells. PLoS One 2011;6:e15868
  • Scotta C, Esposito M, Fazekasova H, et al. Differential effects of rapamycin and retinoic acid on expansion, stability and suppressive qualities of human CD4(+)CD25(+)FOXP3(+) T regulatory cell subpopulations. Haematologica 2013;98:1291-9
  • 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;133:22-6
  • 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;117:1061-70
  • Scully R, Qin S, Cobbold S, Waldmann H. Mechanisms in CD4 antibody-mediated transplantation tolerance: kinetics of induction, antigen dependency and role of regulatory T cells. Eur J Immunol 1994;24:2383-92
  • Sayegh MH, Zheng XG, Magee C, et al. Donor antigen is necessary for the prevention of chronic rejection in CTLA4Ig-treated murine cardiac allograft recipients. Transplantation 1997;64:1646-50
  • Sanchez-Fueyo A, Sandner S, Habicht A, et al. xSpecificity of CD4+CD25+ regulatory T cell function in alloimmunity. J Immunol 1997;176:329-34
  • Wise MP, Bemelman F, Cobbold SP, Waldmann H. Linked suppression of skin graft rejection can operate through indirect recognition. J Immunol 1998;161:5813-16
  • Game DS, Hernandez-Fuentes MP, Chaudhry AN, Lechler RI. CD4+CD25+ regulatory T cells do not significantly contribute to direct pathway hyporesponsiveness in stable renal transplant patients. J Am Soc Nephrol 2003;14:1652-61
  • Salama AD, Najafian N, Clarkson MR, et al. Regulatory CD25+ T cells in human kidney transplant recipients. J Am Soc Nephrol 2003;14:1643-51
  • Veerapathran A, Pidala J, Beato F, et al. Ex vivo expansion of human Tregs specific for alloantigens presented directly or indirectly. Blood 2011;118:5671-80
  • Benson A, Murray S, Divakar P, et al. Microbial infection-induced expansion of effector T cells overcomes the suppressive effects of regulatory T cells via an IL-2 deprivation mechanism. J Immunol 2012;188:800-10
  • Chong AS, Alegre ML. The impact of infection and tissue damage in solid-organ transplantation. Nat Rev Immunol 2012;12:459-71
  • Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. Immunity 2009;30:646-55
  • Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235-8
  • Yang XO, Nurieva R, Martinez GJ, et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 2008;29:44-56
  • Kim HP, Leonard WJ. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med 2007;204:1543-51
  • Lal G, Zhang N, van der Touw W, et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol 2009;182:259-73
  • Wells AD, Li XC, Strom TB, Turka LA. The role of peripheral T-cell deletion in transplantation tolerance. Philos Trans R Soc Lond B Biol Sci 2001;356:617-23
  • Zheng XX, Sanchez-Fueyo A, Sho M, et al. Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance. Immunity 2003;19:503-14
  • Furtado GC, Curotto de Lafaille MA, Kutchukhidze N, Lafaille JJ. Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med 2002;196:851-7
  • Gao W, Lu Y, El Essawy B, et al. Contrasting effects of cyclosporine and rapamycin in de novo generation of alloantigen-specific regulatory T cells. Am J Transplant 2007;7:1722-32
  • Li Y, Zheng XX, Li XC, et al. Combined costimulation blockade plus rapamycin but not cyclosporine produces permanent engraftment. Transplantation 1998;66:1387-8
  • Baan CC, van der Mast BJ, Klepper M, et al. Differential effect of calcineurin inhibitors, anti-CD25 antibodies and rapamycin on the induction of FOXP3 in human T cells. Transplantation 2005;80:110-17
  • Coenen JJ, Koenen HJ, van Rijssen E, et al. Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+CD25+ regulatory T cells. Blood 2006;107:1018-23
  • Horibe EK, Sacks J, Unadkat J, et al. Rapamycin-conditioned, alloantigen-pulsed dendritic cells promote indefinite survival of vascularized skin allografts in association with T regulatory cell expansion. Transpl Immunol 2008;18:307-18
  • 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;184:624-36
  • Lange CM, Tran TY, Farnik H, et al. Increased frequency of regulatory T cells and selection of highly potent CD62L+ cells during treatment of human lung transplant recipients with rapamycin. Transpl Int 2010;23:266-76
  • Vincenti F, Blancho G, Durrbach A, et al. Five-year safety and efficacy of belatacept in renal transplantation. J Am Soc Nephrol 2010;21:1587-96
  • 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;8:2086-96
  • Poirier N, Azimzadeh AM, Zhang T, et al. Inducing CTLA-4-dependent immune regulation by selective CD28 blockade promotes regulatory T cells in organ transplantation. Sci Transl Med 2010;2:17ra0
  • Larsen CP, Elwood ET, Alexander DZ, et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1996;381:434-8
  • Kirk AD, Burkly LC, Batty DS, et al. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med 1999;5:686-93
  • Badell IR, Russell MC, Cardona K, et al. CTLA4Ig prevents alloantibody formation following nonhuman primate islet transplantation using the CD40-specific antibody 3A8. Am J Transplant 2012;12:1918-23
  • Ferrer IR, Wagener ME, Song M, et al. Antigen-specific induced Foxp3+ regulatory T cells are generated following CD40/CD154 blockade. Proc Natl Acad Sci USA 2011;108:20701-6
  • Badell IR, Thompson PW, Turner AP, et al. Nondepleting anti-CD40-based therapy prolongs allograft survival in nonhuman primates. Am J Transplant 2012;12:126-35
  • Imai A, Suzuki T, Sugitani A, et al. A novel fully human anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys. Transplantation 2007;84:1020-8
  • Croft M, Bradley LM, Swain SL. Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. J Immunol 1994;152:2675-85
  • 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;5:465-74
  • Floyd TL, Koehn BH, Kitchens WH, et al. Limiting the amount and duration of antigen exposure during priming increases memory T cell requirement for costimulation during recall. J Immunol 2011;186:2033-41
  • Kitchens WH, Haridas D, Wagener ME, et al. Integrin antagonists prevent costimulatory blockade-resistant transplant rejection by CD8(+) memory T cells. Am J Transplant 2012;12:69-80
  • 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;78:503-13
  • Newell KA, Asare A, Kirk AD, et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest 2010;120:1836-47
  • 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;120:1848-61
  • Le Texier L, Thebault P, Lavault A, et al. Long-term allograft tolerance is characterized by the accumulation of B cells exhibiting an inhibited profile. Am J Transplant 2011;11:429-38
  • DiLillo DJ, Griffiths R, Seshan SV, et al. B lymphocytes differentially influence acute and chronic allograft rejection in mice. J Immunol 2011;186:2643-54
  • WHO. Available from: www.who.int/transplantation/gkt/
  • Di Ianni M, Falzetti F, Carotti A, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood 2011;117:3921-8
  • Safety study of using regulatory t cells induce liver transplantation tolerance. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01624077&Search=Search
  • In-vivo regulatory T cell enhancement with cyclophosphamide and sirolimus with or without vidaza (azacitidine) for steroid-refractory acute graft-versus-host disease. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01453140&Search=Search
  • Ex-vivo expanded donor regulatory t cells for prevention of acute graft-versus-host disease. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01795573&Search=Search
  • One study. Available from: www.onestudy.org

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.