Abstract
Allograft rejection is an inflammatory reaction that occurs rapidly after transplantation and is associated with a characteristic cellular and humoral attack on the graft. However, allograft rejection can also occur more chronically, as a result of an insidious immunological process involving delayed type hypersensitivity mechanisms. Both the early acute, and the later chronic rejection processes are mediated by the recipient’s immunological response to donor antigen, which is initiated and coordinated by T cells. All forms of rejection also require the activation of other cell types including B cells and macrophages as well as the induced expression of molecules that enable the trafficking of destructive effector cells into an allograft. New discoveries in the field of immunology have provided many insights into mechanisms that function in the alloimmune response and in the development of rejection. Several of these discoveries have been translated into the clinic, and have resulted in new therapeutics that have the potential to promote long term graft survival. In this chapter, we will review the cellular and molecular basis for the alloimmune response, and we will discuss mechanisms and concepts that have resulted in new targeted therapeutic strategies.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Barth R, Counce S, Smith P, Snell GD. Strong and weak histocompatibility gene differences in mice and their role in the rejection of homografts of tumors and skin. Ann Surg 1956;144(2):198–204.
Benacerraf B, McDevitt HO. Histocompatibility-linked immune response genes. Science 1972;175(19):273–279.
Briscoe DM, Sayegh MH. A rendezvous before rejection: where do T cells meet transplant antigens? Nat Med 2002;8(3):220–222.
Briscoe DM, Alexander SI, Lichtman AH. Interactions between T lymphocytes and endothelial cells in allograft rejection. Curr Opin Immunol 1998;10:525–531.
Briscoe DM, Ganz P, Alexander SI, Melder RJ, Jain RK, Cotran RS, Lichtman AH. The problem of chronic rejection: influence of leukocyte-endothelial interactions. Kidney Int 1997;51:S58:S‐22-S-7.
Briscoe DM, Cotran RS. Role of leukocyte-endothelial cell adhesion molecules in renal inflammation: invitro and in vivo studies. Kidney Int 1993;44(Suppl 42):S27–S34.
Krensky AM, Weiss A, Crabtree G, Davis MM, Parham P. T-lymphocyte-antigen interactions in transplant rejection. N Engl J Med 1990;322(8):510–517.
Strominger JL, Humphreys RE, McCune JM, Parham P, Robb R, Springer T, Terhorst C. The immunoglobulin-like structure of human histocompatibility antigens. Fed Proc 1976;35(5):1177–1182.
Tynan FE, Burrows SR, Buckle AM, Clements CS, Borg NA, Miles JJ, Beddoe T, Whisstock JC, Wilce MC, Silins SL, Burrows JM, Kjer-Nielsen L, Kostenko L, Purcell AW, McCluskey J, Rossjohn J. T cell receptor recognition of a “super-bulged” major histocompatibility complex class I-bound peptide. Nat Immunol 2005;6(11):1114–1122.
Simpson E, Roopenian D, Goulmy E. Much ado about minor histocompatibility antigens. Immunol Today 1998;19(3):108–112.
Simpson E, Scott D, James E, Lombardi G, Cwynarski K, Dazzi F, Millrain JM, Dyson PJ. Minor H antigens: genes and peptides. Eur J Immunogenet 2001;28(5):505–513.
Valujskikh A, Lantz O, Celli S, Matzinger P, Heeger PS. Cross-primed CD8 + T cells mediate graft rejection via a distinct effector pathway. Nat Immunol 2002;3(9):844–851.
Chen Y, Demir Y, Valujskikh A, Heeger PS. The male minor transplantation antigen preferentially activates recipient CD4 + T cells through the indirect presentation pathway in vivo. J Immunol 2003;171(12):6510–6518.
Roopenian D, Choi EY, Brown A. The immunogenomics of minor histocompatibility antigens. Immunol Rev 2002;190:86–94.
Akatsuka Y, Nishida T, Kondo E, Miyazaki M, Taji H, Iida H, Tsujimura K, Yazaki M, Naoe T, Morishima Y, Kodera Y, Kuzushima K, Takahashi T. Identification of a polymorphic gene, BCL2A1, encoding two novel hematopoietic lineage-specific minor histocompatibility antigens. J Exp Med 2003;197(11):1489–1500.
Simpson E, Scott D, Chandler P. The male-specific histocompatibility antigen, H-Y: a history of transplantation, immune response genes, sex determination and expression cloning. Annu Rev Immunol 1997;15:39–61.
Spierings E, Vermeulen CJ, Vogt MH, Doerner LE, Falkenburg JH, Mutis T, Goulmy E. Identification of HLA class II-restricted H-Y-specific T-helper epitope evoking CD4 + T-helper cells in H-Y-mismatched transplantation. Lancet 2003;362(9384):610–615.
Haskova Z, Sproule TJ, Roopenian DC, Ksander AB. An immunodominant minor histocompatibility alloantigen that initiates corneal allograft rejection. Transplantation 2003;75(8):1368–1374.
Chen Y, Heeger PS, Valujskikh A. In vivo helper functions of alloreactive memory CD4 + T cells remain intact despite donor-specific transfusion and anti-CD40 ligand therapy. J Immunol 2004;172(9):5456–5466.
Hornick PI, Mason PD, Baker RJ, Hernandez-Fuentes M, Frasca L, Lombardi G, Taylor K, Weng L, Rose ML, Yacoub MH, Batchelor R, Lechler RI. Significant frequencies of T cells with indirect anti-donor specificity in heart graft recipients with chronic rejection. Circulation 2000;101(20):2405–2410.
Hornick PI, Mason PD, Yacoub MH, Rose ML, Batchelor R, Lechler RI. Assessment of the contribution that direct allorecognition makes to the progression of chronic cardiac transplant rejection in humans. Circulation 1998;97(13):1257–1263.
Herrera OB, Golshayan D, Tibbott R, Salcido Ochoa F, James MJ, Marelli-Berg FM, Lechler RI. A novel pathway of alloantigen presentation by dendritic cells. J Immunol 2004;173(8):4828–4837.
Bach FH, Hirschhorn K. Lymphocyte interaction: A potential histocompatibility test in vitro. Science 1964;143:813–814.
Braun MY, McCormack A, Webb G, Batchelor JR. Mediation of acute but not chronic rejection of MHC-incompatible rat kidney grafts by alloreactive CD4 T cells activated by the direct pathway of sensitization. Transplantation 1993;55(1):177–182.
Suchin EJ, Langmuir PB, Palmer E, Sayegh MH, Wells AD, Turka LA. Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J Immunol. 2001;166(2):973–981.
Jameson SC, Hogquist KA, Bevan MJ. Positive selection of thymocytes. Annu Rev Immunol 1995;13:93–126.
Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T cells. Annu Rev Immunol 2003;21:139–176.
Grandjean I, Duban L, Bonney EA, Corcuff E, Di Santo JP, Matzinger P, Lantz O. Are major histocompatibility complex molecules involved in the survival of naive CD4 + T cells? J Exp Med 2003;198(7):1089–1102.
Fischer UB, Jacovetty EL, Medeiros RB, Goudy BD, Zell T, Swanson JB, Lorenz E, Shimizu Y, Miller MJ, Khoruts A, Ingulli E. MHC class II deprivation impairs CD4 T cell motility and responsiveness to antigen-bearing dendritic cells in vivo. Proc Natl Acad Sci USA 2007;104(17):7181–7186.
Bevan MJ. High determinant density may explain the phenomenon of alloreactivity. Immunol Today 1984;5(5):128–130.
Matzinger P, Bevan MJ. Hypothesis: why do so many lymphocytes respond to major histocompatibility antigens? Cell Immunol 1977;29(1):1–5.
Lombardi G, Barber L, Sidhu S, Batchelor JR, Lechler RI. The specificity of alloreactive T cells is determined by MHC polymorphisms which contact the T cell receptor and which influence peptide binding. Int Immunol 1991;3(8):769–775.
Schneck J, Munitz T, Coligan JE, Maloy WL, Margulies DH, Singer A. Inhibition of allorecognition by an H-2Kb-derived peptide is evidence for a T-cell binding region on a major histocompatibility complex molecule. Proc Natl Acad Sci USA 1989;86(21):8516–8520.
Villadangos JA, Galocha B, Lopez de Castro JA. Unusual topology of an HLA-B27 allospecific T cell epitope lacking peptide specificity. J Immunol 1994;152(5):2317–2323.
Daniel C, Horvath S, Allen PM. A basis for alloreactivity: MHC helical residues broaden peptide recognition by the TCR. Immunity 1998;8(5):543–552.
Kaye J, Hedrick SM. Analysis of specificity for antigen, Mls, and allogenic MHC by transfer of T-cell receptor alpha- and beta-chain genes. Nature 1988;336(6199):580–583.
Berkowitz N, Braunstein NS. T cell responses specific for subregions of allogeneic MHC molecules. J Immunol 1992;148(2):309–317.
Bluestone JA, Jameson S, Miller S, Dick R, 2nd. Peptide-induced conformational changes in class I heavy chains alter major histocompatibility complex recognition. J Exp Med 1992;176(6):1757–1761.
Catipovic B, Dal Porto J, Mage M, Johansen TE, Schneck JP. Major histocompatibility complex conformational epitopes are peptide specific. J Exp Med 1992;176(6):1611–1618.
Obst R, Netuschil N, Klopfer K, Stevanovic S, Rammensee HG. The role of peptides in T cell alloreactivity is determined by self-major histocompatibility complex molecules. J Exp Med 2000;191(5):805–812.
Reiser JB, Darnault C, Gregoire C, Mosser T, Mazza G, Kearney A, van der Merwe PA, Fontecilla-Camps JC, Housset D, Malissen B. CDR3 loop flexibility contributes to the degeneracy of TCR recognition. Nat Immunol 2003;4(3):241–247.
Reiser JB, Gregoire C, Darnault C, Mosser T, Guimezanes A, Schmitt-Verhulst AM, Fontecilla-Camps JC, Mazza G, Malissen B, Housset D. A T cell receptor CDR3beta loop undergoes conformational changes of unprecedented magnitude upon binding to a peptide/MHC class I complex. Immunity 2002;16(3):345–354.
Reiser JB, Darnault C, Guimezanes A, Gregoire C, Mosser T, Schmitt-Verhulst AM, Fontecilla-Camps JC, Malissen B, Housset D, Mazza G. Crystal structure of a T cell receptor bound to an allogeneic MHC molecule. Nat Immunol 2000;1(4):291–297.
Afzali B, Lechler RI, Hernandez-Fuentes MP. Allorecognition and the alloresponse: clinical implications. Tissue Antigens 2007;69(6):545–556.
Lafferty KJ, Prowse SJ, Simeonovic CJ, Warren HS. Immunobiology of tissue transplantation: a return to the passenger leukocyte concept. Annu Rev Immunol 1983;1:143–173.
Lafferty K, Woolnough J. The origin and mechanism of the allograft reaction. Immunol Rev 1977;35:231–262.
Lee RS, Yamada K, Houser SL, Womer KL, Maloney ME, Rose HS, Sayegh MH, Madsen JC. Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy. Proc Natl Acad Sci USA 2001;98(6):3276–3281.
Vella JP, Vos L, Carpenter CB, Sayegh MH. The role of indirect allorecognition in experimental late acute rejection. Transplantation 1997;64:1823–1828.
Sayegh MH, Carpenter CB. Role of indirect allorecognition in allograft rejection. Int Rev Immunol 1996;13(3):221–229.
Larsen CP, Austyn JM, Morris PJ. The role of graft-derived dendritic leukocytes in the rejection of vascularized organ allografts. Recent findings on the migration and function of dendritic leukocytes after transplantation. Ann Surg 1990;212(3):308–315, discussion 16-7.
Talmage DW, Dart G, Radovich J, Lafferty KJ. Activation of transplant immunity: effect of donor leukocytes on thyroid allograft rejection. Science 1976;191(4225):385–388.
Lafferty KJ, Bootes A, Dart G, Talmage DW. Effect of organ culture on the survival of thyroid allografts in mice. Transplantation 1976;22(2):138–149.
Lafferty KJ, Bootes A, Killby VA, Burch W. Mechanism of thyroid allograft rejection. Aust J Exp Biol Med Sci 1976;54(6):573–586.
Lafferty KJ, Talmage DW. Theory of allogeneic reactivity and its relevance to transplantation biology. Transplant Proc 1976;8(3):349–353.
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(1):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(6):1835–1841.
Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med 1973;137(5):1142–1162.
Schuler G, Steinman RM. Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro. J Exp Med 1985;161(3):526–546.
Kimber I, Cumberbatch M. Stimulation of Langerhans cell migration by tumor necrosis factor alpha (TNF-alpha). J Invest Dermatol 1992;99(5):S48–S50.
Enk AH, Angeloni VL, Udey MC, Katz SI. An essential role for Langerhans cell-derived IL-1 beta in the initiation of primary immune responses in skin. J Immunol 1993;150(9):3698–3704.
Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF, Heath WR. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 1998;393(6684):478–480.
Ridge JP, Di Rosa F, Matzinger P. A conditioned dendritic cell can be a temporal bridge between a CD4 + T-helper and a T-killer cell. Nature 1998;393(6684):474–478.
Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 1998;393(6684):480–483.
Barker CF, Billingham RE. The role of afferent lymphatics in the rejection of skin homografts. J Exp Med 1968;128(1):197–221.
Larsen CP, Steinman RM, Whitmer-Pack M, Hankins DF, Morris PJ, Austyn JM. Migration and maturation of Langerhans cells in skin transplants and explants. J Exp Med 1990;172:1483–1493.
Ingulli E, Mondino A, Khoruts A, Jenkins MK. In vivo detection of dendritic cell antigen presentation to CD4+ T cells. J Exp Med 1997;185:2133–2141.
Steinman RM, Pack M, Inaba K. Dendritic cells in the T-cell areas of lymphoid organs. Immunol Rev 1997;156:25–37.
Land W. Postischemic reperfusion injury to allografts – a case for ‘innate immunity’? Eur Surg Res 2002;34(1–2):160–169.
Mueller AR, Platz KP, Heckert C, Hausler M, Guckelberger O, Schuppan D, Lobeck H, Neuhaus P. The extracellular matrix: an early target of preservation/reperfusion injury and acute rejection after small bowel transplantation. Transplantation 1998;65(6):770–776.
Warger T, Hilf N, Rechtsteiner G, Haselmayer P, Carrick DM, Jonuleit H, von Landenberg P, Rammensee HG, Nicchitta CV, Radsak MP, Schild H. Interaction of TLR2 and TLR4 ligands with the N-terminal domain of Gp96 amplifies innate and adaptive immune responses. J Biol Chem 2006;281(32):22545–22553.
Zhai Y, Shen XD, O’Connell R, Gao F, Lassman C, Busuttil RW, Cheng G, Kupiec-Weglinski JW. Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway. J Immunol 2004;173(12):7115–7119.
Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T, Miyake K, Freudenberg M, Galanos C, Simon JC. Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med 2002;195(1):99–111.
Tesar BM, Jiang D, Liang J, Palmer SM, Noble PW, Goldstein DR. The role of hyaluronan degradation products as innate alloimmune agonists. Am J Transplant 2006;6(11):2622–2635.
Yang D, Chen Q, Yang H, Tracey KJ, Bustin M, Oppenheim JJ. High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin. J Leukoc Biol 2007;81(1):59–66.
Oh KH, Kim JY, Kim D, Lee EM, Oh HY, Seo JS, Han JS, Kim S, Lee JS, Ahn C. Targeted gene disruption of the heat shock protein 72 gene (hsp70.1) in the donor tissue is associated with a prolonged rejection-free survival in the murine skin allograft model. Transpl Immunol 2004;13(4):273–281.
McKay D, Shigeoka A, Rubinstein M, Surh C, Sprent J. Simultaneous deletion of MyD88 and Trif delays major histocompatibility and minor antigen mismatch allograft rejection. Eur J Immunol 2006;36(8):1994–2002.
Goldstein DR, Tesar BM, Akira S, Lakkis FG. Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection. J Clin Invest 2003;111(10):1571–1578.
Shigeoka AA, Holscher TD, King AJ, Hall FW, Kiosses WB, Tobias PS, Mackman N, McKay DB. TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways. J Immunol 2007;178(10):6252–6258.
Laxmanan S, Datta D, Geehan C, Briscoe DM, Pal S. CD40: A mediator of pro- and anti-inflammatory signals in renal tubular epithelial cells. J Am Soc Nephrol 2005;16(9):2714–2723.
Randolph GJ, Inaba K, Robbiani DF, Steinman RM, Muller WA. Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 1999;11(6):753–761.
Randolph GJ, Beaulieu S, Lebecque S, Steinman RM, Muller WA. Differentiation of monocytes into dendritic cells in a model of transendothelial trafficking. Science 1998;282:480–483.
Kupiec-Weglinski JW, Busuttil RW. Ischemia and reperfusion injury in liver transplantation. Transplant Proc 2005;37(4):1653–1656.
Tsuchihashi S, Fondevila C, Kupiec-Weglinski JW. Heme oxygenase system in ischemia and reperfusion injury. Ann Transplant 2004;9(1):84–87.
Kreisel D, Krupnick AS, Gelman AE, Engels FH, Popma SH, Krasinskas AM, Balsara KR, Szeto WY, Turka LA, Rosengard BR. Non-hematopoietic allograft cells directly activate CD8 + T cells and trigger acute rejection: an alternative mechanism of allorecognition. Nat Med 2002;8(3):233–239.
Krupnick AS, Kreisel D, Popma SH, Balsara KR, Szeto WY, Krasinskas AM, Riha M, Wells AD, Turka LA, Rosengard BR. Mechanism of T cell-mediated endothelial apoptosis. Transplantation 2002;74(6):871–876.
Frasca L, Amendola A, Hornick P, Brookes P, Aichinger G, Marelli-Berg F, Lechler RI, Lombardi G. Role of donor and recipient antigen-presenting cells in priming and maintaining T cells with indirect allospecificity. Transplantation 1998;66(9):1238–1243.
Rogers NJ, Lechler RI. Allorecognition. Am J Transplant 2001;1(2):97–102.
Auchincloss H Jr., Lee R, Shea S, Markowitz JS, Grusby MJ, Glimcher LH. The role of ‘indirect’ recognition in initiating rejection of skin grafts from major histocompatibility complex class II-deficient mice. Proc Natl Acad Sci USA 1993;90:3373–3377.
Gokmen MR, Lombardi G, Lechler RI. The importance of the indirect pathway of allorecognition in clinical transplantation. Curr Opin Immunol 2008;20(5):568–574.
Libby P, Pober JS. Chronic rejection. Immunity 2001 Apr;14(4):387–397.
Shoskes DA, Wood KJ. Indirect presentation of MHC antigens in transplantation. Immunol Today 1994 Jan;15(1):32–38.
Suciu-Foca N, Ciubotariu R, Colovai A, Foca-Rodi A, Ho E, Rose E, Cortesini R. Persistent allopeptide reactivity and epitope spreading in chronic rejection. Transplant Proc 1999;31(1–2):100–101.
Liu Z, Sun YK, Xi YP, Harris P, Suciu-Foca N. T cell recognition of self-human histocompatibility leukocyte antigens (HLA)-DR peptides in context of syngeneic HLA-DR molecules. J Exp Med 1992;175(6):1663–1668.
Ciubotariu R, Liu Z, Colovai AI, Ho E, Itescu S, Ravalli S, Hardy MA, Cortesini R, Rose EA, Suciu-Foca N. Persistent allopeptide reactivity and epitope spreading in chronic rejection of organ allografts. J Clin Invest 1998;101(2):398–405.
Salama AD, Najafian N, Clarkson MR, Harmon WE, Sayegh MH. Regulatory CD25 + T cells in human kidney transplant recipients. J Am Soc Nephrol 2003;14(6):1643–1651.
Vella JP, Spadafora-Ferreira M, Murphy B, Alexander SI, Harmon W, Carpenter CB, Sayegh MH. Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction. Transplantation 1997;64:795–800.
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(6):1652–1661.
Vu MD, Xiao X, Gao W, Degauque N, Chen M, Kroemer A, Killeen N, Ishii N, Chang Li X. OX40 costimulation turns off Foxp3 + Tregs. Blood 2007;110(7):2501–2510.
Ford ML, Koehn BH, Wagener ME, Jiang W, Gangappa S, Pearson TC, Larsen CP. Antigen-specific precursor frequency impacts T cell proliferation, differentiation, and requirement for costimulation. J Exp Med 2007;204(2):299–309.
Yewdell JW, Norbury CC, Bennink JR. Mechanisms of exogenous antigen presentation by MHC class I molecules in vitro and in vivo: implications for generating CD8 + T cell responses to infectious agents, tumors, transplants, and vaccines. Adv Immunol 1999;73:1–77.
Benichou G, Takizawa PA, Olson CA, McMillan M, Sercarz EE. Donor major histocompatibility complex (MHC) peptides are presented by recipient MHC molecules during graft rejection. J Exp Med 1992;175:305–308.
Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 1998;392(6671):86–89.
Brossart P, Bevan MJ. Presentation of exogenous protein antigens on major histocompatibility complex class I molecules by dendritic cells: pathway of presentation and regulation by cytokines. Blood 1997;90(4):1594–1599.
Harshyne LA, Watkins SC, Gambotto A, Barratt-Boyes SM. Dendritic cells acquire antigens from live cells for cross-presentation to CTL. J Immunol 2001;166(6):3717–3723.
Xu H, Dhanireddy KK, Kirk AD. Human monocytes as intermediaries between allogeneic endothelial cells and allospecific T cells: a role for direct scavenger receptor-mediated endothelial membrane uptake in the initiation of alloimmunity. J Immunol 2006;176(2):750–761.
Bedford P, Garner K, Knight SC. MHC class II molecules transferred between allogeneic dendritic cells stimulate primary mixed leukocyte reactions. Int Immunol 1999;11(11):1739–1744.
Thery C, Duban L, Segura E, Veron P, Lantz O, Amigorena S. Indirect activation of naive CD4 + T cells by dendritic cell-derived exosomes. Nat Immunol 2002;3(12):1156–1162.
Morelli AE, Larregina AT, Shufesky WJ, Sullivan ML, Stolz DB, Papworth GD, Zahorchak AF, Logar AJ, Wang Z, Watkins SC, Falo LD Jr., Thomson AW. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood 2004;104(10):3257–3266.
Lee RS, Grusby MJ, Glimcher LH, Winn HJ, Auchincloss H Jr. Indirect recognition by helper cells can induce donor-specific cytotoxic T lymphocytes in vivo. J Exp Med 1994;179:865–872.
Janeway CA Jr., Bottomly K. Signals and signs for lymphocyte responses. Cell 1994;76:275–285.
Bluestone JA. New perspectives of CD28-B7-mediated T cell costimulation. Immunity 1995;2(6):555–559.
Sharpe AH, Abbas AK. T-cell costimulation–biology, therapeutic potential, and challenges. N Engl J Med 2006;355(10):973–975.
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 2002;2(2):116–126.
Linsley PS, Ledbetter JA. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol 1993;11:191–212.
Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med 1998 Jun 18;338(25):1813–1821.
St Clair EW, Turka LA, Saxon A, Matthews JB, Sayegh MH, Eisenbarth GS, Bluestone J. New reagents on the horizon for immune tolerance. Annu Rev Med 2007;58:329–346.
Clarkson MR, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Transplantation 2005;80(5):555–563.
Guleria I, Khosroshahi A, Ansari MJ, Habicht A, Azuma M, Yagita H, Noelle RJ, Coyle A, Mellor AL, Khoury SJ, Sayegh MH. A critical role for the programmed death ligand 1 in fetomaternal tolerance. J Exp Med 2005;202(2):231–237.
Viola A, Lanzavecchia A. T cell activation determined by T cell receptor number and tunable thresholds. Science 1996;273(5271):104–106.
Kearney ER, Walunas TL, Karr RW, Morton PA, Loh DY, Bluestone JA, Jenkins MK. Antigen-dependent clonal expansion of a trace population of antigen- specific CD4 + T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4. J Immunol 1995;155(3):1032–1036.
Jenkins MK, Taylor PS, Norton SD, Urdahl KB. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol 1991;147:2461–2466.
Fraser JD, Irving BA, Crabtree GR, Weiss A. Regulation of interleukin-2 gene enhancer activity by the T cell accessory molecule CD28. Science 1991;251(4991):313–316.
Norton SD, Zuckerman L, Urdahl KB, Shefner R, Miller J, Jenkins MK. The CD28 ligand, B7, enhances IL-2 production by providing a costimulatory signal to T cells. J Immunol 1992;149(5):1556–1561.
Bonnevier JL, Mueller DL. Cutting edge: B7/CD28 interactions regulate cell cycle progression independent of the strength of TCR signaling. J Immunol 2002;169(12):6659–6663.
Appleman LJ, Berezovskaya A, Grass I, Boussiotis VA. CD28 costimulation mediates T cell expansion via IL-2-independent and IL-2-dependent regulation of cell cycle progression. J Immunol 2000;164(1):144–151.
Boise LH, Minn AJ, Noel PJ, June CH, Accavitti MA, Lindsten T, Thompson CB. CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity 1995;3(1):87–98.
Rulifson IC, Sperling AI, Fields PE, Fitch FW, Bluestone JA. CD28 costimulation promotes the production of Th2 cytokines. J Immunol 1997;158:658–665.
Schweitzer AN, Borriello F, Wong RC, Abbas AK, Sharpe AH. Role of costimulators in T cell differentiation: studies using antigen-presenting cells lacking expression of CD80 or CD86. J Immunol 1997;158(6):2713–2722.
Prilliman KR, Lemmens EE, Palioungas G, Wolfe TG, Allison JP, Sharpe AH, Schoenberger SP. Cutting edge: a crucial role for B7-CD28 in transmitting T help from APC to CTL. J Immunol 2002;169(8):4094–4097.
Lane P, Burdet C, Hubele S, Scheidegger D, Muller U, McConnell F, Kosco-Vilbois M. B cell function in mice transgenic for mCTLA4-H gamma 1: lack of germinal centers correlated with poor affinity maturation and class switching despite normal priming of CD4 + T cells. J Exp Med 1994;179(3):819–830.
Ferguson SE, Han S, Kelsoe G, Thompson CB. CD28 is required for germinal center formation. J Immunol 1996;156(12):4576–4581.
McAdam AJ, Chang TT, Lumelsky AE, Greenfield EA, Boussiotis VA, Duke-Cohan JS, Chernova T, Malenkovich N, Jabs C, Kuchroo VK, Ling V, Collins M, Sharpe AH, Freeman GJ. Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4 + T cells. J Immunol 2000;165(9):5035–5040.
Walker LS, Gulbranson-Judge A, Flynn S, Brocker T, Lane PJ. Co-stimulation and selection for T-cell help for germinal centres: the role of CD28 and OX40. Immunol Today 2000;21(7):333–337.
Hathcock KS, Laszlo G, Pucillo C, Linsley P, Hodes RJ. Comparative analysis of B7–1 and B7–2 costimulatory ligands: expression and function. J Exp Med 1994;180(2):631–640.
Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991;174(3):561–569.
Freeman GJ, Borriello F, Hodes RJ, Reiser H, Gribben JG, Ng JW, Kim J, Goldberg JM, Hathcock K, Laszlo G et al. Murine B7–2, an alternative CTLA4 counter-receptor that costimulates T cell proliferation and interleukin 2 production. J Exp Med 1993;178(6):2185–2192.
Walunas TL, Bakker CY, Bluestone JA. CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med 1996;183(6):2541–2550.
Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB, Bluestone JA. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994;1(5):405–413.
Hainz U, Jurgens B, Heitger A. The role of indoleamine 2,3-dioxygenase in transplantation. Transpl Int 2007;20(2):118–127.
Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995;3:541–547.
Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW. Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 1995;270:985–988.
Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA. B7/CD28 costimulation is essential for the homeostasis of the CD4 + CD25 + immunoregulatory T cells that control autoimmune diabetes. Immunity 2000;12(4):431–440.
Fecteau S, Basadonna GP, Freitas A, Ariyan C, Sayegh MH, Rothstein DM. CTLA-4 up-regulation plays a role in tolerance mediated by CD45. Nat Immunol 2001;2(1):58–63.
Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, Wood CR, Greenfield EA, Freeman GJ. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 2003;170(3):1257–1266.
Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7–1 costimulatory molecule to inhibit T cell responses. Immunity 2007;27(1):111–122.
Butte MJ, Pena-Cruz V, Kim MJ, Freeman GJ, Sharpe AH. Interaction of human PD-L1 and B7–1. Mol Immunol 2008;45(13):3567–3572.
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677–704.
Quezada SA, Jarvinen LZ, Lind EF, Noelle RJ. CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol 2004;22:307–328.
Noelle RJ, Roy M, Shepherd DM, Stamenkovic I, Ledbetter JA, Aruffo A. A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc Natl Acad Sci USA 1992;89:6550–6554.
Schonbeck U, Libby P. The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci 2001a;58(1):4–43.
Grewal IS, Flavell RA. The CD40 ligand. At the center of the immune universe? Immunol Res 1997;16:59–70.
Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998;391:591–594.
Danese S, de la Motte C, Sturm A, Vogel JD, West GA, Strong SA, Katz JA, Fiocchi C. Platelets trigger a CD40-dependent inflammatory response in the microvasculature of inflammatory bowel disease patients. Gastroenterology 2003;124(5):1249–1264.
Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998 Mar 19;392(6673):245–252.
Frleta D, Lin JT, Quezada SA, Wade TK, Barth RJ, Noelle RJ, Wade WF. Distinctive maturation of in vitro versus in vivo anti-CD40 mAb-matured dendritic cells in mice. J Immunother 2003;26(1):72–84.
Josien R, Li HL, Ingulli E, Sarma S, Wong BR, Vologodskaia M, Steinman RM, Choi Y. TRANCE, a tumor necrosis factor family member, enhances the longevity and adjuvant properties of dendritic cells in vivo. J Exp Med 2000;191(3):495–502.
Kawabe T, Naka T, Yoshida K, Tanaka T, Fujiwara H, Suematsu S, Yoshida N, Kishimoto T, Kikutani H. The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1994;1:167–178.
Clark EA, Ledbetter JA. Activation of human B cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. Proc Natl Acad Sci USA 1986;83:4494–0.
Valle A, Zuber CE, Defrance T, Djossou O, De Rie M, Banchereau J. Activation of human B lymphocytes through CD40 and interleukin 4. Eur J Immunol 1989;19(8):1463–1467.
Liu YJ, Joshua DE, Williams GT, Smith CA, Gordon J, MacLennan IC. Mechanism of antigen-driven selection in germinal centres. Nature 1989;342(6252):929–931.
Garside P, Ingulli E, Merica RR, Johnson JG, Noelle RJ, Jenkins MK. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 1998;281:96–99.
Filatenkov AA, Jacovetty EL, Fischer UB, Curtsinger JM, Mescher MF, Ingulli E. CD4 T cell-dependent conditioning of dendritic cells to produce IL-12 results in CD8-mediated graft rejection and avoidance of tolerance. J Immunol 2005;174(11):6909–6917.
Allen RC, Armitage RJ, Conley ME, Rosenblatt H, Jenkins NA, Copeland NG, Bedell MA, Edelhoff S, Disteche CM, Simoneaux DK, et al. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science 1993;259(5097):990–993.
Aruffo A, Farrington M, Hollenbaugh D, Li X, Milatovich A, Nonoyama S, Bajorath J, Grosmaire LS, Stenkamp R, Neubauer M. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell 1993;72:291–300.
DiSanto JP, Bonnefoy JY, Gauchat JF, Fischer A, de Saint Basile G. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature 1993;361(6412):541–543.
Fuleihan R, Ramesh N, Loh R, Jabara H, Rosen RS, Chatila T, Fu SM, Stamenkovic I, Geha RS. Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM. Proc Natl Acad Sci USA 1993;90(6):2170–2173.
Korthauer U, Graf D, Mages HW, Briere F, Munoreedevi P, Malcolm S, Ugazio AG, Notarangelo LD, Levinsky RJ, Kroczek RA. Defective expression of T cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature 1993;361:539–541.
Grewal IS, Flavell RA. A central role of CD40 ligand in the regulation of CD4 + T-cell responses. Immunol Today 1996;17:410–414.
Buhlmann JE, Foy TM, Aruffo AA, Crassi KM, Ledbetter JA, Green WR, Xu JC, Schultz LD, Roopesian D, Flavell RA, Fast L, Noelle RJ, Durie FH. In the absence of a CD40 signal, B cells are tolerogenic. Immunity 1995;2:645–653.
Xu J, Foy TM, Laman JD, Elliott EA, Dunn JJ, Waldschmidt TJ, Elsemore J, Noelle RJ, Flavell RA. Mice deficient for the CD40 ligand. Immunity 1994;1:423–431.
Grewal IS, Xu J, Flavell RA. Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand. Nature 1995;378:617–620.
Borrow P, Tishon A, Lee S, Xu J, Grewal IS, Oldstone MB, Flavell RA. CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8 + CTL response. J Exp Med 1996;183(5):2129–2142.
Sparwasser T, Koch ES, Vabulas RM, Heeg K, Lipford GB, Ellwart JW, Wagner H. Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol 1998;28(6):2045–2054.
Brunner C, Seiderer J, Schlamp A, Bidlingmaier M, Eigler A, Haimerl W, Lehr HA, Krieg AM, Hartmann G, Endres S. Enhanced dendritic cell maturation by TNF-alpha or cytidine-phosphate-guanosine DNA drives T cell activation in vitro and therapeutic anti-tumor immune responses in vivo. J Immunol 2000;165(11):6278–6286.
Jakob T, Walker PS, Krieg AM, Udey MC, Vogel JC. Activation of cutaneous dendritic cells by CpG-containing oligodeoxynucleotides: a role for dendritic cells in the augmentation of Th1 responses by immunostimulatory DNA. J Immunol 1998;161(6):3042–3049.
Melief CJ, Van Der Burg SH, Toes RE, Ossendorp F, Offringa R. Effective therapeutic anticancer vaccines based on precision guiding of cytolytic T lymphocytes. Immunol Rev 2002;188:177–182.
Maxwell JR, Ruby C, Kerkvliet NI, Vella AT. Contrasting the roles of costimulation and the natural adjuvant lipopolysaccharide during the induction of T cell immunity. J Immunol 2002;168(9):4372–4381.
Cho HJ, Hayashi T, Datta SK, Takabayashi K, Van Uden JH, Horner A, Corr M, Raz E. IFN-alpha beta promote priming of antigen-specific CD8 + and CD4 + T lymphocytes by immunostimulatory DNA-based vaccines. J Immunol 2002;168(10):4907–4913.
Burkly LC. CD40 pathway blockade as an approach to immunotherapy. Adv Exp Med Biol 2001;489:135–152.
Becher B, Durell BG, Miga AV, Hickey WF, Noelle RJ. The clinical course of experimental autoimmune encephalomyelitis and inflammation is controlled by the expression of CD40 within the central nervous system. J Exp Med 2001;193(8):967–974.
Howard LM, Dal Canto MC, Miller SD. Transient anti-CD154-mediated immunotherapy of ongoing relapsing experimental autoimmune encephalomyelitis induces long-term inhibition of disease relapses. J Neuroimmunol 2002;129(1–2):58–65.
Davidson A, Wang X, Mihara M, Ramanujam M, Huang W, Schiffer L, Sinha J. Co-stimulatory blockade in the treatment of murine systemic lupus erythematosus (SLE). Ann N Y Acad Sci 2003;987:188–198.
Boumpas DT, Furie R, Manzi S, Illei GG, Wallace DJ, Balow JE, Vaishnaw A. A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 2003;48(3):719–727.
Kalunian KC, Davis JC Jr., Merrill JT, Totoritis MC, Wofsy D. Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46(12):3251–3258.
Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, Rivera M, Ravetch JV, Steinman RM, Nussenzweig MC. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 2001;194(6):769–779.
Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig MC, Steinman RM. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8 + T cell tolerance. J Exp Med 2002;196(12):1627–1638.
Steinman RM, Turley S, Mellman I, Inaba K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 2000;191(3):411–416.
Scheinecker C, McHugh R, Shevach EM, Germain RN. Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J Exp Med 2002;196(8):1079–1090.
Taylor PA, Friedman TM, Korngold R, Noelle RJ, Blazar BR. Tolerance induction of alloreactive T cells via ex vivo blockade of the CD40:CD40L costimulatory pathway results in the generation of a potent immune regulatory cell. Blood 2002;99(12):4601–4609.
Larsen CP, Elwood ET, Alexander DZ, Ritchie SC, Hendrix R, Tucker-Burden C, Cho HR, Aruffo A, Hollenbaugh D, Linsley PS, Winn KJ, Pearson TC. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1996;381:434–438.
Parker DC, Greiner DL, Phillips NE, Appel MC, Steele AW, Durie FH, Noelle RJ, Mordes JP, Rossini AA. Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand. Proc Natl Acad Sci USA 1995;92(21):9560–9564.
Hancock WW, Sayegh MH, Zheng XG, Peach R, Linsley PS, Turka LA. Costimulatory function and expresson of CD40 ligand, CD80, CD86 in vascularized murine cardiac allograft rejection. Proc Natl Acad Sci USA 1996;93:13967–13972.
Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Buhlman J, Xu J, Flavell RA, Korngold R, Noelle R, Vallera DA. Blockade of CD40 ligand-CD40 interaction impairs CD4 + T cell mediated alloreactivity by inhibiting mature donor T cell expansion and function after bone marrow transplantation. J Immunol 1997;158:29–39.
Markees TG, Phillips NE, Noelle RJ, Shultz LD, Mordes JP, Greiner DL, Rossini AA. Prolonged survival of mouse skin allografts in recipients treated with donor splenocytes and antibody to CD40 ligand. Transplantation 1997;64(2):329–335.
Kirk AD, Burkly LC, Batty DS, Baumgartner RE, Berning JD, Buchanan K, Fechner JH Jr., Germond RL, Kampen RL, Patterson NB, Swanson SJ, Tadaki DK, TenHoor CN, White L, Knechtle SJ, Harlan DM. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med 1999;5(6):686–693.
Huddleston SJ, Hays WS, Filatenkov A, Ingulli E, Jenkins MK. CD154 + graft antigen-specific CD4 + T cells are sufficient for chronic rejection of minor antigen incompatible heart grafts. Am J Transplant 2006;6(6):1312–1319.
Sidiropoulos PI, Boumpas DT. Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus 2004;13(5):391–397.
Kawai T, Andrews D, Colvin RB, Sachs DH, Cosimi AB. Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 2000;6(2):114.
Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, Kroczek RA. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 1999;397(6716):263–266.
Beier KC, Hutloff A, Dittrich AM, Heuck C, Rauch A, Buchner K, Ludewig B, Ochs HD, Mages HW, Kroczek RA. Induction, binding specificity and function of human ICOS. Eur J Immunol 2000;30(12):3707–3717.
Mages HW, Hutloff A, Heuck C, Buchner K, Himmelbauer H, Oliveri F, Kroczek RA. Molecular cloning and characterization of murine ICOS and identification of B7h as ICOS ligand. Eur J Immunol 2000;30(4):1040–1047.
Yoshinaga SK, Whoriskey JS, Khare SD, Sarmiento U, Guo J, Horan T, Shih G, Zhang M, Coccia MA, Kohno T, Tafuri-Bladt A, Brankow D, Campbell P, Chang D, Chiu L, Dai T, Duncan G, Elliott GS, Hui A, McCabe SM, Scully S, Shahinian A, Shaklee CL, Van G, Mak TW et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature 1999;402(6763):827–832.
Buonfiglio D, Bragardo M, Redoglia V, Vaschetto R, Bottarel F, Bonissoni S, Bensi T, Mezzatesta C, Janeway CA Jr., Dianzani U. The T cell activation molecule H4 and the CD28-like molecule ICOS are identical. Eur J Immunol 2000;30(12):3463–3467.
Tezuka K, Tsuji T, Hirano D, Tamatani T, Sakamaki K, Kobayashi Y, Kamada M. Identification and characterization of rat AILIM/ICOS, a novel T-cell costimulatory molecule, related to the CD28/CTLA4 family. Biochem Biophys Res Commun 2000;276(1):335–345.
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 2005;23:515–548.
Swallow MM, Wallin JJ, Sha WC. B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNFalpha. Immunity 1999;11(4):423–432.
Ling V, Wu PW, Finnerty HF, Bean KM, Spaulding V, Fouser LA, Leonard JP, Hunter SE, Zollner R, Thomas JL, Miyashiro JS, Jacobs KA, Collins M. Cutting edge: identification of GL50, a novel B7-like protein that functionally binds to ICOS receptor. J Immunol 2000;164(4):1653–1657.
Wang S, Zhu G, Chapoval AI, Dong H, Tamada K, Ni J, Chen L. Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS. Blood 2000;96(8):2808–2813.
Coyle AJ, Lehar S, Lloyd C, Tian J, Delaney T, Manning S, Nguyen T, Burwell T, Schneider H, Gonzalo JA, Gosselin M, Owen LR, Rudd CE, Gutierrez-Ramos JC. The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity 2000;13(1):95–105.
Kopf M, Coyle AJ, Schmitz N, Barner M, Oxenius A, Gallimore A, Gutierrez-Ramos JC, Bachmann MF. Inducible costimulator protein (ICOS) controls T helper cell subset polarization after virus and parasite infection. J Exp Med 2000;192(1):53–61.
McAdam AJ, Greenwald RJ, Levin MA, Chernova T, Malenkovich N, Ling V, Freeman GJ, Sharpe AH. ICOS is critical for CD40-mediated antibody class switching. Nature 2001;409(6816):102–105.
Tafuri A, Shahinian A, Bladt F, Yoshinaga SK, Jordana M, Wakeham A, Boucher LM, Bouchard D, Chan VS, Duncan G, Odermatt B, Ho A, Itie A, Horan T, Whoriskey JS, Pawson T, Penninger JM, Ohashi PS, Mak TW. ICOS is essential for effective T-helper-cell responses. Nature 2001;409(6816):105–109.
Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, Berry G, DeKruyff RH, Umetsu DT. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 2002;8(9):1024–1032.
Ozkaynak E, Gao W, Shemmeri N, Wang C, Gutierrez-Ramos JC, Amaral J, Qin S, Rottman JB, Coyle AJ, Hancock WW. Importance of ICOS-B7RP-1 costimulation in acute and chronic allograft rejection. Nat Immunol 2001;2(7):591–596.
Harada H, Salama AD, Sho M, Izawa A, Sandner SE, Ito T, Akiba H, Yagita H, Sharpe AH, Freeman GJ, Sayegh MH. The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity. J Clin Invest 2003;112(2):234–243.
Zhang QW, Rabant M, Schenk A, Valujskikh A. ICOS-Dependent and -independent functions of memory CD4 T cells in allograft rejection. Am J Transplant 2008;8(3):497–506.
Schenk AD, Gorbacheva V, Rabant M, Fairchild RL, Valujskikh A. Effector functions of donor-reactive CD8 memory T cells are dependent on ICOS Induced during division in cardiac grafts. Am J Transplant 2009;(1):64–73.
Durkop H, Latza U, Himmelreich P, Stein H. Expression of the human OX40 (hOX40) antigen in normal and neoplastic tissues. Br J Haematol 1995;91(4):927–931.
Demirci G, Amanullah F, Kewalaramani R, Yagita H, Strom TB, Sayegh MH, Li XC. Critical role of OX40 in CD28 and CD154-independent rejection. J Immunol 2004;172(3):1691–1698.
Baum PR, Gayle RB, 3rd, Ramsdell F, Srinivasan S, Sorensen RA, Watson ML, Seldin MF, Clifford KN, Grabstein K, Alderson MR et al. Identification of OX40 ligand and preliminary characterization of its activities on OX40 receptor. Circ Shock 1994;44(1):30–34.
Ohshima Y, Tanaka Y, Tozawa H, Takahashi Y, Maliszewski C, Delespesse G. Expression and function of OX40 ligand on human dendritic cells. J Immunol 1997;159(8):3838–3848.
Imura A, Hori T, Imada K, Ishikawa T, Tanaka Y, Maeda M, Imamura S, Uchiyama T. The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothelial cells. J Exp Med 1996;183:2185–2195.
Stuber E, Strober W. The T cell-B cell interaction via OX40-OX40L is necessary for the T cell-dependent humoral immune response. J Exp Med 1996;183(3):979–989.
Gramaglia I, Weinberg AD, Lemon M, Croft M. OX-40 ligand: a potent costimulatory molecule for sustaining primary CD4 T cell responses. J Immunol 1998;161(12):6510–6517.
Lane P. Role of OX40 signals in coordinating CD4 T cell selection, migration, and cytokine differentiation in T helper Th1 and Th2 cells. J Exp Med 2000;191(2):201–206.
Xiao X, Kroemer A, Gao W, Ishii N, Demirci G, Li XC. OX40/OX40L costimulation affects induction of Foxp3 + regulatory T cells in part by expanding memory T cells in vivo. J Immunol 2008;181(5):3193–3201.
Lathrop SK, Huddleston CA, Dullforce PA, Montfort MJ, Weinberg AD, Parker DC. A signal through OX40 (CD134) allows anergic, autoreactive T cells to acquire effector cell functions. J Immunol 2004;172(11):6735–6743.
Yuan X, Salama AD, Dong V, Schmitt I, Najafian N, Chandraker A, Akiba H, Yagita H, Sayegh MH. The role of the CD134-CD134 ligand costimulatory pathway in alloimmune responses in vivo. J Immunol 2003;170(6):2949–2955.
Vu MD, Clarkson MR, Yagita H, Turka LA, Sayegh MH, Li XC. Critical, but conditional, role of OX40 in memory T cell-mediated rejection. J Immunol 2006;176(3):1394–1401.
Valzasina B, Guiducci C, Dislich H, Killeen N, Weinberg AD, Colombo MP. Triggering of OX40 (CD134) on CD4 + CD25 + T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Blood 2005;105(7):2845–2851.
So T, Croft M. Cutting edge: OX40 inhibits TGF-beta- and antigen-driven conversion of naive CD4 T cells into CD25 + Foxp3 + T cells. J Immunol 2007;179(3):1427–1430.
Brian T, Fife JAB. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 2008;224(1):166–182.
Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999;5(12):1365–1369.
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192(7):1027–1034.
Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001;2(3):261–268.
Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol 2001;22(5):265–268.
Nishimura H, Minato N, Nakano T, Honjo T. Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int Immunol 1998;10(10):1563–1572.
Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999;11(2):141–151.
Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001;291(5502):319–322.
Ito T, Ueno T, Clarkson MR, Yuan X, Jurewicz MM, Yagita H, Azuma M, Sharpe AH, Auchincloss H Jr., Sayegh MH, Najafian N. Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo. J Immunol 2005;174(11):6648–6656.
Sandner SE, Clarkson MR, Salama AD, Sanchez-Fueyo A, Domenig C, Habicht A, Najafian N, Yagita H, Azuma M, Turka LA, Sayegh MH. Role of the programmed death-1 pathway in regulation of alloimmune responses in vivo. J Immunol 2005;174(6):3408–3415.
Tao R, Wang L, Han R, Wang T, Ye Q, Honjo T, Murphy TL, Murphy KM, Hancock WW. Differential effects of B and T lymphocyte attenuator and programmed death-1 on acceptance of partially versus fully MHC-mismatched cardiac allografts. J Immunol 2005;175(9):5774–5782.
Blazar BR, Carreno BM, Panoskaltsis-Mortari A, Carter L, Iwai Y, Yagita H, Nishimura H, Taylor PA. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism. J Immunol 2003;171(3):1272–1277.
Gao W, Demirci G, Strom TB, Li XC. Stimulating PD-1-negative signals concurrent with blocking CD154 co-stimulation induces long-term islet allograft survival. Transplantation 2003;76(6):994–999.
Ozkaynak E, Wang L, Goodearl A, McDonald K, Qin S, O’Keefe T, Duong T, Smith T, Gutierrez-Ramos JC, Rottman JB, Coyle AJ, Hancock WW. Programmed death-1 targeting can promote allograft survival. J Immunol 2002;169(11):6546–6553.
Tanaka K, Albin MJ, Yuan X, Yamaura K, Habicht A, Murayama T, Grimm M, Waaga AM, Ueno T, Padera RF, Yagita H, Azuma M, Shin T, Blazar BR, Rothstein DM, Sayegh MH, Najafian N. PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection. J Immunol 2007;179(8):5204–5210.
Yang J, Popoola J, Khandwala S, Vadivel N, Vanguri V, Yuan X, Dada S, Guleria I, Tian C, Ansari MJ, Shin T, Yagita H, Azuma M, Sayegh MH, Chandraker A. Critical role of donor tissue expression of programmed death ligand-1 in regulating cardiac allograft rejection and vasculopathy. Circulation 2008;117(5):660–669.
London CA, Abbas AK, Kelso A. Helper T cell subsets: heterogeneity, functions and development. Vet Immunol Immunopathol 1998;63(1–2):37–44.
Sayegh MH, Turka LA. The role of T cell costimulatory activation in transplant rejection. N Engl J Med 1998;338:1813–1821.
Kist-van Holthe JE, Gasser M, Womer K, Najafian N, Dong V, Samsonov DV, Geehan CS, Chandraker A, Sayegh MH, Waaga AM. Regulatory functions of alloreactive Th2 clones in human renal transplant recipients. Kidney Int 2002;62(2):627–631.
Rothstein DM, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Immunol Rev 2003;196:85–108.
Salama AD, Remuzzi G, Harmon WE, Sayegh MH. Challenges to achieving clinical transplantation tolerance. J Clin Invest 2001 Oct;108(7):943–948.
Lenschow DJ, Zeng Y, Hathcock KS, Zuckerman LA, Freeman G, Thistlethwaite JR, Gray GS, Hodes RJ, Bluestone JA. Inhibition of transplant rejection following treatment with anti-B7-2 and anti-B7-1 antibodies. Transplantation 1995;60:1171–1178.
Solari MG, Thomson AW. Human dendritic cells and transplant outcome. Transplantation 2008;85(11):1513–1522.
Morelli AE, Thomson AW. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol 2007;7(8):610–621.
Moser M, Murphy KM. Dendritic cell regulation of TH1-TH2 development. Nat Immunol 2000;1(3):199–205.
Steinman RM, Inaba K, Turley S, Pierre P, Mellman I. Antigen capture, processing, and presentation by dendritic cells: recent cell biological studies. Hum Immunol 1999;60(7):562–567.
Hackstein H, Taner T, Zahorchak AF, Morelli AE, Logar AJ, Gessner A, Thomson AW. Rapamycin inhibits IL-4 – induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. Blood 2003;101(11):4457–4463.
Woltman AM, de Fijter JW, Kamerling SW, Paul LC, Daha MR, van Kooten C. The effect of calcineurin inhibitors and corticosteroids on the differentiation of human dendritic cells. Eur J Immunol 2000;30(7):1807–1812.
Keir ME, Sharpe AH. The B7/CD28 costimulatory family in autoimmunity. Immunol Rev 2005;204:128–143.
Schweitzer AN, Sharpe AH. Studies using antigen-presenting cells lacking expression of both B7-1 (CD80) and B7-2 (CD86) show distinct requirements for B7 molecules during priming versus restimulation of Th2 but not Th1 cytokine production. J Immunol 1998;161:2762–2771.
Demirci G, Li XC. Novel roles of OX40 in the allograft response. Curr Opin Organ Transplant 2008;13(1):26–30.
Kishimoto K, Sandner S, Imitola J, Sho M, Li Y, Langmuir PB, Rothstein DM, Strom TB, Turka LA, Sayegh MH. Th1 cytokines, programmed cell death, and alloreactive T cell clone size in transplant tolerance. J Clin Invest 2002;109(11):1471–1479.
Steiger J, Nickerson PW, Steurer W, Moscovitch-Lopatin M, Strom TB. IL-2 knockout recipient mice reject islet cell allografts. J Immunol 1995;155:489–498.
Dai Z, Konieczny BT, Baddoura FK, Lakkis FG. Impaired alloantigen-mediated T cell apoptosis and failure to induce long-term allograft survival in IL-2 deficient mice. J Immunol 1998;161(4):1659–1663.
Konieczny BT, Dai Z, Elwood ET, Saleem S, Linsley PS, Baddoura FK, Larsen CP, Pearson TC, Lakkis FG. IFN-gamma is critical for long-term allograft survival induced by blocking the CD28 and CD40 ligand T cell costimulation pathways. J Immunol 1998;160:2059–2064.
Li XC, Strom TB, Turka LA, Wells AD. T cell death and transplantation tolerance. Immunity 2001;14(4):407–416.
Li Y, Li XC, Zheng XX, Wells AD, Turka LA, Strom TB. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat Med 1999;5(11):1298–1302.
Sayegh MH, Akalin E, Hancock WW, Russell ME, Carpenter CB, Linsley PS, Turka LA. CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2. J Exp Med 1995;181(5):1869–1874.
Azuma H, Chandraker A, Nadeau K, Hancock WW, Carpenter CB, Tilney NL, Sayegh MH. Blockade of T-cell costimulation prevents development of experimental chronic renal allograft rejection. Proc Natl Acad Sci USA 1996;93(22):12439–12444.
Sayegh MH. Why do we reject a graft? Role of indirect allorecognition in graft rejection. Kidney Int 1999;56(5):1967–1979.
Piccotti JR, Chan SY, VanBuskirk AM, Eichwald EJ, Bishop DK. Are Th2 helper T lymphocytes beneficial, deleterious, or irrelevant in promoting allograft survival. Transplantation 1997;63:619–624.
Roy-Chaudhury P, Manfro RC, Steiger J, Nickerson PW, Tian Y, Zheng XX, Li YS, Strom TB. IL-2 and IL-4 double knock-out mice reject islet allografts: a role for novel T-cell growth factors? Transplant Proc 1997;29:1083–1084.
Gershon RK, Kondo K. Infectious immunological tolerance. Immunology 1971;21(6):903–914.
Hall BM, Pearce NW, Gurley KE, Dorsch SE. Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. III. Further characterization of the CD4 + suppressor cell and its mechanisms of action. J Exp Med 1990;171(1):141–157.
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.
Sakaguchi S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell 2000;101:455–458.
Nishimura E, Sakihama T, Setoguchi R, Tanaka K, Sakaguchi S. Induction of antigen-specific immunologic tolerance by in vivo and in vitro antigen-specific expansion of naturally arising Foxp3 + CD25 + CD4 + regulatory T cells. Int Immunol 2004;16(8):1189–1201.
Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000;192(2):303–310.
Bennett CL. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutation of FoxP3. Nature Genet 2001;27:20–21.
Van der Vliet HJ, Nieuwenhuis EE. IPEX as a result of mutations in FoxP3. Clin Dev Immunol 2007;2007:89017.
Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299(5609):1057–1061.
Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25 + CD4 + regulatory cells that control intestinal inflammation. J Exp Med 2000;192:295–302.
McHugh RS. CD4 + CD25 + immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002;16:311–323.
Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4 + CD25 + T regulatory cells. Nat Immunol 2003;4(4):337–342.
Yagi H, Nomura T, Nakamura K, Yamazaki S, Kitawaki T, Hori S, Maeda M, Onodera M, Uchiyama T, Fujii S, Sakaguchi S. Crucial role of FoxP3 in the development and function of human CD25 + CD4 + regulatory T cells. Int Immunol 2004;16(11):1643–1656.
Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM. 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(12):1875–1886.
Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol 2003;3(3):199–210.
Kretschmer K, Apostolou I, Jaeckel E, Khazaie K, von Boehmer H. Making regulatory T cells with defined antigen specificity: role in autoimmunity and cancer. Immunol Rev 2006;212:163–169.
Collison LW. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007;450:566–569.
Borsellino G. Expression of ectonucleotidase CD39 by Foxp3 + Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 2007;110:1225–1232.
Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007;204(6):1257–1265.
Wang L, Pino-Lagos K, de Vries VC, Guleria I, Sayegh MH, Noelle RJ. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3 + CD4 + regulatory T cells. Proc Natl Acad Sci USA 2008;105(27):9331–9336.
Lakkis FG, Arakelov A, Konieczny BT, Inoue Y. Immunologic ‘ignorance’ of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat Med 2000 Jun;6(6):686–688.
Lakkis FG. Where is the alloimmune response initiated? Am J Transplant 2003;3(3):241–242.
Wells AD, Li XC, Li Y, Walsh MC, Zheng XX, Wu Z, Nunez G, Tang A, Sayegh M, Hancock WW, Strom TB, Turka LA. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nat Med 1999;5(11):1303–1307.
Jiang S, Herrera O, Lechler RI. New spectrum of allorecognition pathways: implications for graft rejection and transplantation tolerance. Curr Opin Immunol 2004;16(5):550–557.
Lechler RI, Lombardi G, Batchelor JR, Reinsmoen N, Bach FH. The molecular basis of alloreactivity. Immunol Today 1990;11(3):83–88.
Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol 2003;3(3):199–210.
Lechler RI, Ng WF, Camara NO. Infectious tolerance? Mechanisms and implications. Transplantation 2001;72(8 Suppl):S29–S31.
Bach FH, Ferran C, Hechenleitner P, Mark W, Koyamada N, Miyatake T, Winkler H, Badrichani A, Candinas D, Hancock WW. Accommodation of vascularized xenografts: expression of “protective genes” by donor endothelial cells in a host Th2 cytokine environment. Nat Med 1997;3(2):196–204.
Bach FH, Hancock WW, Ferran C. Protective genes expressed in endothelial cells: a regulatory response to injury. Immunol Today 1997;18(10):483–486.
Otterbein LE, Zuckerbraun BS, Haga M, Liu F, Song R, Usheva A, Stachulak C, Bodyak N, Smith RN, Csizmadia E, Tyagi S, Akamatsu Y, Flavell RJ, Billiar TR, Tzeng E, Bach FH, Choi AM, Soares MP. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med 2003;9(2):183–190.
Chalasani G, Li Q, Konieczny BT, Smith-Diggs L, Wrobel B, Dai Z, Perkins DL, Baddoura FK, Lakkis FG. The allograft defines the type of rejection (acute versus chronic) in the face of an established effector immune response. J Immunol 2004;172(12):7813–7820.
Bickerstaff AA, Wang JJ, Pelletier RP, Orosz CG. The graft helps to define the character of the alloimmune response. Transpl Immunol 2002;9(2–4):137–141.
Denton MD, Davis SF, Baum MA, Melter M, Reinders ME, Exeni A, Samsonov DV, Fang J, Ganz P, Briscoe DM. The role of the graft endothelium in transplant rejection: evidence that endothelial activation may serve as a clinical marker for the development of chronic rejection. Pediatr Transplant 2000;4(4):252–260.
Denton MD, Geehan C, Alexander SI, Sayegh MH, Briscoe DM. Endothelial cells modify the costimulatory capacity of transmigrating leukocytes and promote CD28-mediated CD4 + T cell alloactivation. J Exp Med 1999;190:555–566.
Pober JS, Orosz CG, Rose ML, Savage COS. Can graft endothelial cells initiate a host anti-graft immune response? Transplantation 1996;61:343–349.
Colvin RB. Pathology of Chronic Humoral Rejection. Contrib Nephrol 2009;162:75–86.
Melter M, Exeni A, Briscoe DM. Chemokines and their receptors in human clinical solid organ transplantation. Curr Opin Organ Transplant 2002;7:77–84.
Zhao DX, Hu Y, Miller GG, Luster AD, Mitchell RN, Libby P. Differential expression of the IFN-gamma-inducible CXCR3-binding chemokines, IFN-inducible protein 10, monokine induced by IFN, and IFN-inducible T cell alpha chemoattractant in human cardiac allografts: association with cardiac allograft vasculopathy and acute rejection. J Immunol 2002;169(3):1556–1560.
Miura M, Morita K, Kobayashi H, Hamilton TA, Burdick MD, Strieter RM, Fairchild RL. Monokine induced by IFN-gamma is a dominant factor directing T cells into murine cardiac allografts during acute rejection. J Immunol 2001;167(6):3494–3504.
Labarrere CA, Nelson DR, Faulk WP. Endothelial activation and development of coronary artery disease in transplanted human hearts. JAMA 1997;278(14):1169–1175.
Baggiolini M. Chemokines and leukocyte traffic. Nature 1998;392:565–568.
Lazzeri E, Romagnani P. CXCR3-binding chemokines: novel multifunctional therapeutic targets. Curr Drug Targets Immune Endocr Metabol Disord 2005;5(1):109–118.
Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2001;2(2):108–115.
Moser B, Loetscher P. Lymphocyte traffic control by chemokines. Nat Immunol 2001;2(2):123–128.
Lukacs NW, Hogaboam C, Campbell E, Kunkel SL. Chemokines: function, regulation and alteration of inflammatory responses. Chem Immunol 1999;72:102–120.
Hancock WW, Gao W, Csizmadia V, Faia KL, Shemmeri N, Luster AD. Donor-derived IP-10 initiates development of acute allograft rejection. J Exp Med 2001;193(8):975–980.
Bodnar RJ, Yates CC, Wells A. IP-10 blocks vascular endothelial growth factor-induced endothelial cell motility and tube formation via inhibition of calpain. Circ Res 2006;98(5):617–625.
Colvin RB. Renal allografts. In Diagnostic Immunopathology. Colvin RB, Bahn AK, McCluskey RT (eds.). New York, Raven Press, 1988, pp. 151–197.
Rao KV. Mechanism, pathophysiology, diagnosis, and management of renal transplant rejection. Med Clin North Am 1990;74(4):1039–1057.
Reinders ME, Rabelink TJ, Briscoe DM. Angiogenesis and endothelial cell repair in renal disease and allograft rejection. J Am Soc Nephrol 2006;17(4):932–942.
Contreras AG, Briscoe DM. Every allograft needs a silver lining. J Clin Invest 2007;117(12):3645–3648.
Koskinen P, Lemstrom K, Hayry P. Chronic rejection. Curr Opin Nephrol Hypertens 1996;5(3):269–272.
Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, Kalluri R. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 2007;13(8):952–961.
Coito AJ, Kupiec-Weglinski JW. Extracellular matrix proteins in organ transplantation. Transplantation 2000;69(12):2465–2473.
Kissmeyer-Nielsen F, Olsen S, Petersen VP, Fjeldborg O. Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells. Lancet 1966;2(7465):662–665.
Clayberger C, Krensky AM. Mechanisms of allograft rejection. In Immunologic Renal Diseases, 2nd edn. Nielson EG, Couser WG (eds.). Philadelphia, Lippincott Williams & Wilkins, 2001, pp. 321–346.
Guettier C, Nochy D, Hinglais N, Pelletier L, Mandet C, Bedrossian J, Duboust A, Moulonguet Doleris L, Camilleri JP, Bariety J. Distinct phenotypic composition of diffuse interstitial and perivascular focal infiltrates in renal allografts: a morphometric analysis of cellular infiltration under conventional immunosuppressive therapy and under cyclosporine A. Clin Nephrol 1988;30(2):97–105.
Pober JS. Immunobiology of human vascular endothelium. Immunol Res 1999;19(2–3):225–232.
Collins AB, Schneeberger EE, Pascual MA, Saidman SL, Williams WW, Tolkoff-Rubin N, Cosimi AB, Colvin RB. Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peritubular capillaries. J Am Soc Nephrol 1999;10(10):2208–2214.
Tullius SG, Tilney NL. Both alloantigen-dependent and -independent factors influence chronic allograft rejection. Transplantation 1995;59(3):313–318.
Estenne M, Hertz MI. Bronchiolitis obliterans after human lung transplantation. Am J Respir Crit Care Med 2002;166(4):440–444.
Demetris AJ. Distinguishing between recurrent primary sclerosing cholangitis and chronic rejection. Liver Transpl 2006;12(11 Suppl 2):S68–72.
Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000;342(9):605–612.
Tantravahi J, Womer KL, Kaplan B. Why hasn’t eliminating acute rejection improved graft survival? Annu Rev Med 2007;58:369–385.
Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med 2003;349(24):2326–2333.
Womer KL, Vella JP, Sayegh MH. Chronic allograft dysfunction: mechanisms and new approaches to therapy. Semin Nephrol 2000;20(2):126–147.
Miller GG, Davis SF, Atkinson JB, Chomsky DB, Pedroso P, Reddy VS, Drinkwater DC, Zhao XM, Pierson RN. Longitudinal analysis of fibroblast growth factor expression after transplantation and association with severity of cardiac allograft vasculopathy. Circulation 1999;100(24):2396–2399.
Sharma VK, Bologa RM, Xu GP, Li B, Mouradian J, Wang J, Serur D, Rao V, Suthanthiran M. Intragraft TGF-beta 1 mRNA: a correlate of interstitial fibrosis and chronic allograft nephropathy. Kidney Int 1996;49:1297–1303–303.
Owen RD. Immunogenetic consequences of vascular anastomoses between bovine twins. Science 1945;102(2651):400–401.
Burnet FM. Clonal selection theory of acquired immunity. Cambridge Cambridge University Press, 1959.
Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature 1953;172(4379):603–606.
Kappler JW, Roehm N, Marrack P. T cell tolerance by clonal elimination in the thymus. Cell 1987;49(2):273–280.
Perico N, Rossini M, Imberti O, Remuzzi G. Thymus-mediated immune tolerance to renal allograft is donor but not tissue specific. J Am Soc Nephrol 1991;2(6):1063–1071.
Oluwole OO, DePaz HA, Adeyeri A, Jin MX, Hardy MA, Oluwole SF. Role of CD41CD251 regulatory T cells from naive host thymus in the induction of acquired transplant tolerance by immunization with allo-major histocompatibility complex peptide. Transplantation 2003;75(8):1136–1142.
Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 1995;270(5239):1189–1192.
Chen W, Sayegh MH, Khoury SJ. Mechanisms of acquired thymic tolerance in vivo: intrathymic injection of antigen induces apoptosis of thymocytes and peripheral T cell anergy. J Immunol 1998;160(3):1504–1508.
Sauter B, Albert ML, Francisco L, Larsson M, Somersan S, Bhardwaj N. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J Exp Med 2000;191(3):423–434.
Sakaguchi S, Sakaguchi N. Thymus and autoimmunity: capacity of the normal thymus to produce pathogenic self-reactive T cells and conditions required for their induction of autoimmune disease. J Exp Med 1990;172(2):537–545.
Suri-Payer E, Amar AZ, Thornton AM, Shevach EM. CD4 + CD25 + cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J Immunol 1998;160(3):1212–1218.
Taylor PA, Noelle RJ, Blazar BR. CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. J Exp Med 2001;193(11):1311–1318.
Thornton AM, Shevach EM. Suppressor effector function of CD4 + CD25 + immunoregulatory T cells is antigen nonspecific. J Immunol 2000;164(1):183–190.
Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL. A critical role for transforming growth factor-beta but not interleukin-4 in the suppression of T helper type 1-mediated colitis by CD45RB (low) CD4 + T cells. J Exp Med 1996;183(6):2669–2674.
Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG. A CD4 + T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389(6652):737–742.
Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 2001;182:207–214.
Schwartz RH. Acquisition of immunologic self-tolerance. Cell 1989;57(7):1073–1081.
Schwartz RH. A cell culture model for T lymphocyte clonal anergy. Science 1990;248:1349–1356.
Opelz G, Vanrenterghem Y, Kirste G, Gray DW, Horsburgh T, Lachance JG, Largiader F, Lange H, Vujaklija-Stipanovic K, Alvarez-Grande J, Schott W, Hoyer J, Schnuelle P, Descoeudres C, Ruder H, Wujciak T, Schwarz V. Prospective evaluation of pretransplant blood transfusions in cadaver kidney recipients. Transplantation 1997;63(7):964–967.
Davies HF, Pollard SG, Calne RY. Tolerogenic and immunosuppressive properties of liver grafts in animals and man. Transplant Proc 1991;23(4):2248–2249.
Koshiba T, Li Y, Takemura M, Wu Y, Sakaguchi S, Minato N, Wood KJ, Haga H, Ueda M, Uemoto S. Clinical, immunological, and pathological aspects of operational tolerance after pediatric living-donor liver transplantation. Transpl Immunol 2007;17(2):94–97.
Brouard S, Dupont A, Giral M, Louis S, Lair D, Braudeau C, Degauque N, Moizant F, Pallier A, Ruiz C, Guillet M, Laplaud D, Soulillou JP. Operationally tolerant and minimally immunosuppressed kidney recipients display strongly altered blood T-cell clonal regulation. Am J Transplant 2005;5(2):330–340.
Rao AS, Shapiro R, Corry R, Dodson F, Abu-Elmagd K, Jordan M, Gupta K, Zeevi A, Rastellini C, Keenan R, Reyes J, Griffith B, Fung JJ, Starzl TE. Adjuvant bone marrow infusion in clinical organ transplant recipients. Transplant Proc 1998;30(4):1367–1368.
Starzl TE, Demetris AJ, Murase N, Trucco M, Thomson AW, Rao AS. The lost chord: microchimerism and allograft survival. Immunol Today 1996;17(12):577–584; discussion 88.
Karim M, Bushell AR, Wood KJ. Regulatory T cells in transplantation. Curr Opin Immunol 2002;14(5):584–591.
Cosimi AB, Sachs DH. Mixed chimerism and transplantation tolerance. Transplantation 2004;77(6):943–946.
Sykes M. Mixed chimerism and transplant tolerance. Immunity 2001;14(4):417–424.
Starzl TE, Demetris AJ, Trucco M, Murase N, Ricordi C, Ildstad S, Ramos H, Todo S, Tzakis A, Fung JJ et al. Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology 1993;17(6):1127–1152.
Khan A, Tomita Y, Sykes M. Thymic dependence of loss of tolerance in mixed allogeneic bone marrow chimeras after depletion of donor antigen. Peripheral mechanisms do not contribute to maintenance of tolerance. Transplantation 1996;62(3):380–387.
Caillat-Zucman S, Legendre C, Suberbielle C, Bodemer C, Noel LH, Kreis H, Bach JF. Microchimerism frequency two to thirty years after cadaveric kidney transplantation. Hum Immunol 1994;41(1):91–95.
Schlitt HJ, Raddatz G, Steinhoff G, Wonigeit K, Pichlmayr R. Passenger lymphocytes in human liver allografts and their potential role after transplantation. Transplantation 1993;56(4):951–955.
Spitzer TR, Delmonico F, Tolkoff-Rubin N, McAfee S, Sackstein R, Saidman S, Colby C, Sykes M, Sachs DH, Cosimi AB. Combined histocompatibility leukocyte antigen-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: the induction of allograft tolerance through mixed lymphohematopoietic chimerism. Transplantation 1999;68(4):480–484.
Kawai T, Cosimi AB et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 2008;358(4): 353–361.
Alexander SI, Smith N, Hu M, Verran D, Shun A, Dorney S, Smith A, Webster B, Shaw PJ, Lammi A, Stormon MO. Chimerism and tolerance in a recipient of a deceased-donor liver transplant. N Engl J Med 2008;358(4):369–374.
Pascual J, Bloom D, Torrealba J, Brahmbhatt R, Chang Z, Sollinger HW, Knechtle SJ. Calcineurin inhibitor withdrawal after renal transplantation with alemtuzumab: clinical outcomes and effect on T-regulatory cells. Am J Transplant 2008;8(7):1529–1536.
Bluestone JA, Liu W, Yabu JM, Laszik ZG, Putnam A, Belingheri M, Gross DM, Townsend RM, Vincenti F. The effect of costimulatory and interleukin-2 receptor blockade on regulatory T cells in renal transplantation. Am J Transplant 2008;8(10):2086–2096.
Zeiser R, Leveson-Gower DB, Zambricki EA, Kambham N, Beilhack A, Loh J, Hou JZ, Negrin RS. Differential impact of mammalian target of rapamycin inhibition on CD4 + CD25 + Foxp3 +regulatory T cells compared with conventional CD4 + T cells. Blood 2008;111(1):453–462.
Basu S, Golovina T, Mikheeva T, June CH, Riley JL. Cutting edge: Foxp3-mediated induction of pim 2 allows human T regulatory cells to preferentially expand in rapamycin. J Immunol 2008;180(9):5794–5798.
Linsley PS, Wallace PM, Johnson J, Gibson MG, Greene JL, Ledbetter JA, Singh C, Tepper MA. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 1992;257:792–795.
Lenschow DJ, Zeng Y, Thistlethwaite JR, Montag A, Brady W, Gibson MG, Linsley PS, Bluestone JA. Long term survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig. Science 1992;257:789–792.
Kirk AD, Harlan DM, Armstrong NN, Davis TA, Dong Y, Gray GS, Hong X, Thomas D, Fechner JH Jr., Knechtle SJ. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci USA 1997;94(16):8789–8794.
Vincenti F. Costimulation blockade in autoimmunity and transplantation. J Allergy Clin Immunol 2008;121(2):299–306; quiz 7–8.
Vincenti F, Larsen C, Durrbach A, Wekerle T, Nashan B, Blancho G, Lang P, Grinyo J, Halloran PF, Solez K, Hagerty D, Levy E, Zhou W, Natarajan K, Charpentier B. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005;353(8):770–781.
Larsen CP, Pearson TC, Adams AB, Tso P, Shirasugi N, Strobertm E, Anderson D, Cowan S, Price K, Naemura J, Emswiler J, Greene J, Turk LA, Bajorath J, Townsend R, Hagerty D, Linsley PS, Peach RJ. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant 2005;5(3):443–453.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Springer-Verlag Berlin Heidelberg
About this entry
Cite this entry
Ingulli, E., Alexander, S.I., Briscoe, D.M. (2009). Transplantation Immunobiology. In: Avner, E., Harmon, W., Niaudet, P., Yoshikawa, N. (eds) Pediatric Nephrology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-76341-3_74
Download citation
DOI: https://doi.org/10.1007/978-3-540-76341-3_74
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-76327-7
Online ISBN: 978-3-540-76341-3
eBook Packages: MedicineReference Module Medicine