Costimulation Blockade in Transplantation

  • Melissa Y. YeungEmail author
  • Tanja Grimmig
  • Mohamed H. Sayegh
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1189)


T cells play a pivotal role in orchestrating immune responses directed against a foreign (allogeneic) graft. For T cells to become fully activated, the T-cell receptor (TCR) must interact with the major histocompatibility complex (MHC) plus peptide complex on antigen-presenting cells (APCs), followed by a second “positive” costimulatory signal. In the absence of this second signal, T cells become anergic or undergo deletion. By blocking positive costimulatory signaling, T-cell allo-responses can be aborted, thus preventing graft rejection and promoting long-term allograft survival and possibly tolerance (Alegre ML, Najafian N, Curr Mol Med 6:843–857, 2006; Li XC, Rothstein DM, Sayegh MH, Immunol Rev 229:271–293, 2009). In addition, costimulatory molecules can provide negative “coinhibitory” signals that inhibit T-cell activation and terminate immune responses; strategies to promote these pathways can also lead to graft tolerance (Boenisch O, Sayegh MH, Najafian N, Curr Opin Organ Transplant 13:373–378, 2008). However, T-cell costimulation involves an incredibly complex array of interactions that may act simultaneously or at different times in the immune response and whose relative importance varies depending on the different T-cell subsets and activation status. In transplantation, the presence of foreign alloantigen incites not only destructive T effector cells but also protective regulatory T cells, the balance of which ultimately determines the fate of the allograft (Lechler RI, Garden OA, Turka LA, Nat Rev Immunol 3:147–158, 2003). Since the processes of alloantigen-specific rejection and regulation both require activation of T cells, costimulatory interactions may have opposing or synergistic roles depending on the cell being targeted. Such complexities present both challenges and opportunities in targeting T-cell costimulatory pathways for therapeutic purposes. In this chapter, we summarize our current knowledge of the various costimulatory pathways in transplantation and review the current state and challenges of harnessing these pathways to promote graft tolerance (summarized in Table 10.1).


Transplant Allograft Alloimmune Costimulation blockade Tolerance Belatacept 


  1. Adams AB, Larsen CP, Pearson TC, Newell KA (2002) The role of TNF receptor and TNF superfamily molecules in organ transplantation. Am J Transplant 2:12–18PubMedCrossRefPubMedCentralGoogle Scholar
  2. Adams AB, Williams MA, Jones TR, Shirasugi N, Durham MM, Kaech SM, Wherry EJ, Onami T, Lanier JG, Kokko KE, Pearson TC, Ahmed R, Larsen CP (2003) Heterologous immunity provides a potent barrier to transplantation tolerance. J Clin Invest 111:1887–1895PubMedPubMedCentralCrossRefGoogle Scholar
  3. Akalin E, Dikman S, Murphy B, Bromberg JS, Hancock WW (2003) Glomerular infiltration by CXCR3+ ICOS+ activated T cells in chronic allograft nephropathy with transplant glomerulopathy. Am J Transplant 3:1116–1120PubMedCrossRefPubMedCentralGoogle Scholar
  4. Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, Berry G, DeKruyff RH, Umetsu DT (2002) Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 8:1024–1032PubMedPubMedCentralCrossRefGoogle Scholar
  5. Akhmetzyanova I, Zelinskyy G, Littwitz-Salomon E, Malyshkina A, Dietze KK, Streeck H, Brandau S, Dittmer U (2016) CD137 agonist therapy can reprogram regulatory T cells into cytotoxic CD4+ T cells with antitumor activity. J Immunol 196:484–492PubMedCrossRefPubMedCentralGoogle Scholar
  6. Akiba H, Takeda K, Kojima Y, Usui Y, Harada N, Yamazaki T, Ma J, Tezuka K, Yagita H, Okumura K (2005) The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo. J Immunol 175:2340–2348CrossRefGoogle Scholar
  7. Alegre ML, Najafian N (2006) Costimulatory molecules as targets for the induction of transplantation tolerance. Curr Mol Med 6:843–857PubMedCrossRefPubMedCentralGoogle Scholar
  8. Alegre ML, Noel PJ, Eisfelder BJ, Chuang E, Clark MR, Reiner SL, Thompson CB (1996) Regulation of surface and intracellular expression of CTLA4 on mouse T cells. J Immunol 157:4762–4770PubMedPubMedCentralGoogle Scholar
  9. Angiari S, Donnarumma T, Rossi B, Dusi S, Pietronigro E, Zenaro E, Della Bianca V, Toffali L, Piacentino G, Budui S, Rennert P, Xiao S, Laudanna C, Casasnovas JM, Kuchroo VK, Constantin G (2014) TIM-1 glycoprotein binds the adhesion receptor P-selectin and mediates T cell trafficking during inflammation and autoimmunity. Immunity 40:542–553PubMedPubMedCentralCrossRefGoogle Scholar
  10. Archdeacon P, Dixon C, Belen O, Albrecht R, Meyer J (2012) Summary of the US FDA approval of belatacept. Am J Transplant 12:554–562PubMedCrossRefPubMedCentralGoogle Scholar
  11. Astellas Pharma Global Development, Inc., Limited Kyowa Hakko Kirin Company, and Astellas Pharma Inc (2013) A study to assess the efficacy and safety of ASKP1240 in de novo kidney transplant recipients.
  12. Azimzadeh AM, Pfeiffer S, Wu G, Schroder C, Zorn GL 3rd, Kelishadi SS, Ozkaynak E, Kehry M, Atkinson JB, Miller GG, Pierson RN 3rd. (2006) Alloimmunity in primate heart recipients with CD154 blockade: evidence for alternative costimulation mechanisms. Transplantation 81:255–264PubMedCrossRefPubMedCentralGoogle Scholar
  13. Binne LL, Scott ML, Rennert PD (2007) Human TIM-1 associates with the TCR complex and up-regulates T cell activation signals. J Immunol 178:4342–4350PubMedCrossRefPubMedCentralGoogle Scholar
  14. Blattman JN, Antia R, Sourdive DJ, Wang X, Kaech SM, Murali-Krishna K, Altman JD, Ahmed R (2002) Estimating the precursor frequency of naive antigen-specific CD8 T cells. J Exp Med 195:657–664PubMedPubMedCentralCrossRefGoogle Scholar
  15. Bluestone JA, Liu W, Yabu JM, Laszik ZG, Putnam A, Belingheri M, Gross DM, Townsend RM, Vincenti F (2008) The effect of costimulatory and interleukin 2 receptor blockade on regulatory T cells in renal transplantation. Am J Transplant 8:2086–2096PubMedPubMedCentralCrossRefGoogle Scholar
  16. Boenisch O, Sayegh MH, Najafian N (2008) Negative T-cell costimulatory pathways: their role in regulating alloimmune responses. Curr Opin Organ Transplant 13:373–378PubMedCrossRefPubMedCentralGoogle Scholar
  17. Boenisch O, D’Addio F, Watanabe T, Elyaman W, Magee CN, Yeung MY, Padera RF, Rodig SJ, Murayama T, Tanaka K, Yuan X, Ueno T, Jurisch A, Mfarrej B, Akiba H, Yagita H, Najafian N (2010) TIM-3: a novel regulatory molecule of alloimmune activation. J Immunol 185:5806–5819PubMedPubMedCentralCrossRefGoogle Scholar
  18. Brooks CR, Yeung MY, Brooks YS, Chen H, Ichimura T, Henderson JM, Bonventre JV (2015) KIM-1-/TIM-1-mediated phagocytosis links ATG5-/ULK1-dependent clearance of apoptotic cells to antigen presentation. EMBO J 34:2441–2464PubMedPubMedCentralCrossRefGoogle Scholar
  19. Burrell BE, Csencsits K, Lu G, Grabauskiene S, Bishop DK (2008) CD8+ Th17 mediate costimulation blockade-resistant allograft rejection in T-bet-deficient mice. J Immunol 181:3906–3914PubMedPubMedCentralCrossRefGoogle Scholar
  20. Burrell BE, Lu G, Li XC, Bishop DK (2009) OX40 costimulation prevents allograft acceptance induced by CD40-CD40L blockade. J Immunol 182:379–390PubMedPubMedCentralCrossRefGoogle Scholar
  21. Bushell A, Wood K (2007) GITR ligation blocks allograft protection by induced CD25+CD4+ regulatory T cells without enhancing effector T-cell function. Am J Transplant 7:759–768PubMedCrossRefPubMedCentralGoogle Scholar
  22. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ (2007) Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27:111–122PubMedPubMedCentralCrossRefGoogle Scholar
  23. Castriconi R, Dondero A, Augugliaro R, Cantoni C, Carnemolla B, Sementa AR, Negri F, Conte R, Corrias MV, Moretta L, Moretta A, Bottino C (2004) Identification of 4Ig-B7-H3 as a neuroblastoma-associated molecule that exerts a protective role from an NK cell-mediated lysis. Proc Natl Acad Sci U S A 101:12640–12645PubMedPubMedCentralCrossRefGoogle Scholar
  24. Chapoval AI, Ni J, Lau JS, Wilcox RA, Flies DB, Liu D, Dong H, Sica GL, Zhu G, Tamada K, Chen L (2001) B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol 2:269–274Google Scholar
  25. Chen AI, McAdam AJ, Buhlmann JE, Scott S, Lupher ML Jr, Greenfield EA, Baum PR, Fanslow WC, Calderhead DM, Freeman GJ, Sharpe AH (1999) Ox40-ligand has a critical costimulatory role in dendritic cell:T cell interactions. Immunity 11:689–698PubMedPubMedCentralCrossRefGoogle Scholar
  26. Chen L, Hussien Y, Hwang KW, Wang Y, Zhou P, Alegre ML (2008a) Overexpression of program death-1 in T cells has mild impact on allograft survival. Transpl Int 21:21–29PubMedCrossRefPubMedCentralGoogle Scholar
  27. Chen M, Xiao X, Demirci G, Li XC (2008b) OX40 controls islet allograft tolerance in CD154 deficient mice by regulating FoxP3+ Tregs. Transplantation 85:1659–1662PubMedCrossRefPubMedCentralGoogle Scholar
  28. Cho HR, Kwon B, Yagita H, La S, Lee EA, Kim JE, Akiba H, Kim J, Suh JH, Vinay DS, Ju SA, Kim BS, Mittler RS, Okumura K, Kwon BS (2004) Blockade of 4-1BB (CD137)/4-1BB ligand interactions increases allograft survival. Transpl Int 17:351–361PubMedCrossRefPubMedCentralGoogle Scholar
  29. Claus C, Riether C, Schurch C, Matter MS, Hilmenyuk T, Ochsenbein AF (2012) CD27 signaling increases the frequency of regulatory T cells and promotes tumor growth. Cancer Res 72:3664–3676PubMedCrossRefPubMedCentralGoogle Scholar
  30. Cordoba F, Wieczorek G, Audet M, Roth L, Schneider MA, Kunkler A, Stuber N, Erard M, Ceci M, Baumgartner R, Apolloni R, Cattini A, Robert G, Ristig D, Munz J, Haeberli L, Grau R, Sickert D, Heusser C, Espie P, Bruns C, Patel D, Rush JS (2015) A novel, blocking, Fc-silent anti-CD40 monoclonal antibody prolongs nonhuman primate renal allograft survival in the absence of B cell depletion. Am J Transplant 15:2825–2836PubMedCrossRefPubMedCentralGoogle Scholar
  31. D’Addio F, Yuan X, Habicht A, Williams J, Ruzek M, Iacomini J, Turka LA, Sayegh MH, Najafian N, Ansari MJ (2010) A novel clinically relevant approach to tip the balance toward regulation in stringent transplant model. Transplantation 90:260–269PubMedPubMedCentralCrossRefGoogle Scholar
  32. Degauque N, Mariat C, Kenny J, Zhang D, Gao W, Vu MD, Alexopoulos S, Oukka M, Umetsu DT, DeKruyff RH, Kuchroo V, Zheng XX, Strom TB (2008) Immunostimulatory Tim-1-specific antibody deprograms Tregs and prevents transplant tolerance in mice. J Clin Invest 118:735–741PubMedPubMedCentralCrossRefGoogle Scholar
  33. del Rio ML, Buhler L, Gibbons C, Tian J, Rodriguez-Barbosa JI (2008) PD-1/PD-L1, PD-1/PD-L2, and other co-inhibitory signaling pathways in transplantation. Transpl Int 21:1015–1028PubMedPubMedCentralGoogle Scholar
  34. Demirci G, Li XC (2008) Novel roles of OX40 in the allograft response. Curr Opin Organ Transplant 13:26–30PubMedCrossRefPubMedCentralGoogle Scholar
  35. Demirci G, Amanullah F, Kewalaramani R, Yagita H, Strom TB, Sayegh MH, Li XC (2004) Critical role of OX40 in CD28 and CD154-independent rejection. J Immunol 172:1691–1698PubMedCrossRefPubMedCentralGoogle Scholar
  36. Dengler TJ, Szabo G, Sido B, Nottmeyer W, Zimmerman R, Vahl CF, Hunig T, Meuer SC (1999) Prolonged allograft survival but no tolerance induction by modulating CD28 antibody JJ319 after high-responder rat heart transplantation. Transplantation 67:392–398PubMedCrossRefPubMedCentralGoogle Scholar
  37. Ding Q, Yeung M, Camirand G, Zeng Q, Akiba H, Yagita H, Chalasani G, Sayegh MH, Najafian N, Rothstein DM (2011) Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice. J Clin Invest 121:3645–3656PubMedPubMedCentralCrossRefGoogle Scholar
  38. Ding Q, Mohib K, Kuchroo VK, Rothstein DM (2017) TIM-4 identifies IFN-gamma-expressing Proinflammatory B effector 1 cells that promote tumor and allograft rejection. J Immunol 199:2585–2595PubMedPubMedCentralCrossRefGoogle Scholar
  39. Dong VM, Yuan X, Coito AJ, Waaga AM, Sayegh MH, Chandraker A (2002) Mechanisms of targeting CD28 by a signaling monoclonal antibody in acute and chronic allograft rejection. Transplantation 73:1310–1317PubMedCrossRefPubMedCentralGoogle Scholar
  40. Dudler J, Li J, Pagnotta M, Pascual M, von Segesser LK, Vassalli G (2006) Gene transfer of programmed death ligand-1.Ig prolongs cardiac allograft survival. Transplantation 82:1733–1737PubMedCrossRefPubMedCentralGoogle Scholar
  41. Durrbach A, Pestana JM, Pearson T, Vincenti F, Garcia VD, Campistol J, Rial Mdel C, Florman S, Block A, Di Russo G, Xing J, Garg P, Grinyo J (2010) A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant 10:547–557PubMedCrossRefPubMedCentralGoogle Scholar
  42. Durrbach A, Pestana JM, Florman S, Del Carmen Rial M, Rostaing L, Kuypers D, Matas A, Wekerle T, Polinsky M, Meier-Kriesche HU, Munier S, Grinyo JM (2016) Long-term outcomes in Belatacept- versus cyclosporine-treated recipients of extended criteria donor kidneys: final results from BENEFIT-EXT, a phase III randomized study. Am J Transplant 16:3192–3201PubMedPubMedCentralCrossRefGoogle Scholar
  43. Echbarthi M, Zonca M, Mellwig R, Schwab Y, Kaplan G, DeKruyff RH, Roda-Navarro P, Casasnovas JM (2015) Distinct trafficking of cell surface and endosomal TIM-1 to the immune synapse. Traffic 16:1193–1207PubMedPubMedCentralCrossRefGoogle Scholar
  44. Espinosa J, Herr F, Tharp G, Bosinger S, Song M, Farris AB 3rd, George R, Cheeseman J, Stempora L, Townsend R, Durrbach A, Kirk AD (2016) CD57(+) CD4 T cells underlie Belatacept-resistant allograft rejection. Am J Transplant 16:1102–1112PubMedPubMedCentralCrossRefGoogle Scholar
  45. Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, Belladonna ML, Fioretti MC, Alegre ML, Puccetti P (2003) Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 4:1206–1212CrossRefGoogle Scholar
  46. Ferguson R, Grinyo J, Vincenti F, Kaufman DB, Woodle ES, Marder BA, Citterio F, Marks WH, Agarwal M, Wu D, Dong Y, Garg P (2011) Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients. Am J Transplant 11:66–76PubMedCrossRefPubMedCentralGoogle Scholar
  47. Ford ML, Koehn BH, Wagener ME, Jiang W, Gangappa S, Pearson TC, Larsen CP (2007) Antigen-specific precursor frequency impacts T cell proliferation, differentiation, and requirement for costimulation. J Exp Med 204:299–309PubMedPubMedCentralCrossRefGoogle Scholar
  48. Freeman GJ, Casasnovas JM, Umetsu DT, DeKruyff RH (2010) TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev 235:172–189PubMedPubMedCentralCrossRefGoogle Scholar
  49. Fu S, Yang Y, Xiao B, Li Y, Yi CG, Xia W, Guo SZ (2010) Use of genetically modified allograft to deliver local immunomodulatory molecule with minimal systemic toxicity in a rat model of allogeneic skin flap transplantation. Transplant Proc 42:3815–3819PubMedCrossRefPubMedCentralGoogle Scholar
  50. Futagawa T, Akiba H, Kodama T, Takeda K, Hosoda Y, Yagita H, Okumura K (2002) Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells. Int Immunol 14:275–286PubMedCrossRefPubMedCentralGoogle Scholar
  51. Gao W, Demirci G, Strom TB, Li XC (2003) Stimulating PD-1-negative signals concurrent with blocking CD154 co-stimulation induces long-term islet allograft survival. Transplantation 76:994–999PubMedCrossRefPubMedCentralGoogle Scholar
  52. Ge W, Jiang J, Liu W, Lian D, Saito A, Garcia B, Li XC, Wang H (2010) Regulatory T cells are critical to tolerance induction in presensitized mouse transplant recipients through targeting memory T cells. Am J Transplant 10:1760–1773PubMedCrossRefPubMedCentralGoogle Scholar
  53. Goldrath AW, Bogatzki LY, Bevan MJ (2000) Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J Exp Med 192:557–564PubMedPubMedCentralCrossRefGoogle Scholar
  54. Goldwater R, Keirns J, Blahunka P, First R, Sawamoto T, Zhang W, Kowalski D, Kaibara A, Holman J (2013) A phase 1, randomized ascending single-dose study of antagonist anti-human CD40 ASKP1240 in healthy subjects. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 13:1040–1046CrossRefGoogle Scholar
  55. Greenwald RJ, Freeman GJ, Sharpe AH (2005) The B7 family Revisited. Annu Rev Immunol 23:515–548PubMedPubMedCentralCrossRefGoogle Scholar
  56. Grohmann U, Orabona C, Fallarino F, Vacca C, Calcinaro F, Falorni A, Candeloro P, Belladonna ML, Bianchi R, Fioretti MC, Puccetti P (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3:1097–1101PubMedPubMedCentralCrossRefGoogle Scholar
  57. Guiducci C, Valzasina B, Dislich H, Colombo MP (2005) CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell-produced IL-2. Eur J Immunol 35:557–567PubMedCrossRefPubMedCentralGoogle Scholar
  58. Guillonneau C, Seveno C, Dugast AS, Li XL, Renaudin K, Haspot F, Usal C, Veziers J, Anegon I, Vanhove B (2007) Anti-CD28 antibodies modify regulatory mechanisms and reinforce tolerance in CD40Ig-treated heart allograft recipients. J Immunol 179:8164–8171PubMedCrossRefPubMedCentralGoogle Scholar
  59. Gupta S, Thornley TB, Gao W, Larocca R, Turka LA, Kuchroo VK, Strom TB (2012) Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs. J Clin Invest 122:2395–2404PubMedPubMedCentralCrossRefGoogle Scholar
  60. Halstead ES, Mueller YM, Altman JD, Katsikis PD (2002) In vivo stimulation of CD137 broadens primary antiviral CD8+ T cell responses. Nat Immunol 3:536–541PubMedCrossRefPubMedCentralGoogle Scholar
  61. Hamann D, Baars PA, Rep MHG, Hooibrink B, Kerkhof-Garde SR, Klein MR, van Lier RAW (1997) Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med 186:1407–1418PubMedPubMedCentralCrossRefGoogle Scholar
  62. Harada H, Salama AD, Sho M, Izawa A, Sandner SE, Ito T, Akiba H, Yagita H, Sharpe AH, Freeman GJ, Sayegh MH (2003) The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity. J Clin Invest 112:234–243PubMedPubMedCentralCrossRefGoogle Scholar
  63. Hashiguchi M, Kobori H, Ritprajak P, Kamimura Y, Kozono H, Azuma M (2008) Triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses. Proc Natl Acad Sci U S A 105:10495–10500PubMedPubMedCentralCrossRefGoogle Scholar
  64. He W, Fang Z, Wang F, Wu K, Xu Y, Zhou H, Du D, Gao Y, Zhang WN, Niki T, Hirashima M, Yuan J, Chen ZK (2009) Galectin-9 significantly prolongs the survival of fully mismatched cardiac allografts in mice. Transplantation 88:782–790PubMedCrossRefPubMedCentralGoogle Scholar
  65. Hunig T, Dennehy K (2005) CD28 superagonists: mode of action and therapeutic potential. Immunol Lett 100:21–28PubMedCrossRefPubMedCentralGoogle Scholar
  66. Hurtado JC, Kim YJ, Kwon BS (1997) Signals through 4-1BB are costimulatory to previously activated splenic T cells and inhibit activation-induced cell death. J Immunol 158:2600–2609PubMedPubMedCentralGoogle Scholar
  67. Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, Kroczek RA (1999) ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397:263–266CrossRefGoogle Scholar
  68. Imai A, Suzuki T, Sugitani A, Itoh T, Ueki S, Aoyagi T, Yamashita K, Taniguchi M, Takahashi N, Miura T, Shimamura T, Furukawa H, Todo S (2007) A novel fully human anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys. Transplantation 84:1020–1028PubMedCrossRefPubMedCentralGoogle Scholar
  69. Ji H, Liu Y, Zhang Y, Shen XD, Gao F, Busuttil RW, Kuchroo VK, Kupiec-Weglinski JW (2014) T-cell immunoglobulin and mucin domain 4 (TIM-4) signaling in innate immune-mediated liver ischemia-reperfusion injury. Hepatology 60:2052–2064PubMedPubMedCentralCrossRefGoogle Scholar
  70. Judge TA, Wu Z, Zheng XG, Sharpe AH, Sayegh MH, Turka LA (1999) The role of CD80, CD86, and CTLA4 in alloimmune responses and the induction of long-term allograft survival. J Immunol 162:1947–1951Google Scholar
  71. Kanamaru F, Youngnak P, Hashiguchi M, Nishioka T, Takahashi T, Sakaguchi S, Ishikawa I, Azuma M (2004) Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells. J Immunol 172:7306–7314PubMedPubMedCentralCrossRefGoogle Scholar
  72. Kane LP (2010) T cell Ig and mucin domain proteins and immunity. J Immunol 184:2743–2749PubMedPubMedCentralCrossRefGoogle Scholar
  73. Kanmaz T, Fechner JJ Jr, Torrealba J, Kim HT, Dong Y, Oberley TD, Schultz JM, Bloom DD, Katayama M, Dar W, Markovits J, Schuler W, Hu H, Hamawy MM, Knechtle SJ (2004) Monotherapy with the novel human anti-CD154 monoclonal antibody ABI793 in rhesus monkey renal transplantation model. Transplantation 77:914–920PubMedCrossRefPubMedCentralGoogle Scholar
  74. Kashizuka H, Sho M, Nomi T, Ikeda N, Kuzumoto Y, Akashi S, Tsurui Y, Mizuno T, Kanehiro H, Yagita H, Nakajima Y, Sayegh MH (2005) Role of the ICOS-B7h costimulatory pathway in the pathophysiology of chronic allograft rejection. Transplantation 79:1045–1050PubMedCrossRefPubMedCentralGoogle Scholar
  75. Kawai T, Andrews D, Colvin RB, Sachs DH, Cosimi AB (2000) Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 6:114PubMedCrossRefPubMedCentralGoogle Scholar
  76. Kean LS, Turka LA, Blazar BR (2017) Advances in targeting co-inhibitory and co-stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy. Immunol Rev 276:192–212PubMedPubMedCentralCrossRefGoogle Scholar
  77. Khayyamian S, Hutloff A, Buchner K, Grafe M, Henn V, Kroczek RA, Mages HW (2002) ICOS-ligand, expressed on human endothelial cells, costimulates Th1 and Th2 cytokine secretion by memory CD4+ T cells. Proc Natl Acad Sci U S A 99:6198–6203PubMedPubMedCentralCrossRefGoogle Scholar
  78. Khoury SJ, Akalin E, Chandraker A, Turka LA, Linsley PS, Sayegh MH, Hancock WW (1995) CD28-B7 costimulatory blockade by CTLA4Ig prevents actively induced experimental autoimmune encephalomyelitis and inhibits Th1 but spares Th2 cytokines in the central nervous system. J Immunol 155:4521–4524Google Scholar
  79. Kim JI, Sonawane SB, Lee MK, Lee SH, Duff PE, Moore DJ, O’Connor MR, Lian MM, Deng S, Choi Y, Yeh H, Caton AJ, Markmann JF (2010) Blockade of GITR-GITRL interaction maintains Treg function to prolong allograft survival. Eur J Immunol 40:1369–1374PubMedPubMedCentralCrossRefGoogle Scholar
  80. Kinnear G, Wood KJ, Marshall D, Jones ND (2010) Anti-OX40 prevents effector T-cell accumulation and CD8+ T-cell mediated skin allograft rejection. Transplantation 90:1265–1271PubMedCrossRefPubMedCentralGoogle Scholar
  81. Kinnear G, Wood KJ, Fallah-Arani F, Jones ND (2013) A diametric role for OX40 in the response of effector/memory CD4+ T cells and regulatory T cells to alloantigen. J Immunol 191:1465–1475PubMedPubMedCentralCrossRefGoogle Scholar
  82. Kirk AD, Harlan DM, Armstrong NN, Davis TA, Dong Y, Gray GS, Hong X, Thomas D, Fechner JH Jr, Knechtle SJ (1997) CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci U S A 94:8789–8794CrossRefGoogle Scholar
  83. 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 (1999) Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med 5:686–693PubMedCrossRefPubMedCentralGoogle Scholar
  84. Kirk AD, Tadaki DK, Abbie C, Scott Batty D, Berning JD, Colonna JO, Cruzata F, Elster EA, Gray GS, Kampen RL, Patterson NB, Szklut P, Swanson J, Xu H, Harlan DM (2001) Induction therapy with monoclonal antibodies specific for Cd80 and Cd86 delays the onset of acute renal allograft rejection in non-human Primates1. Transplantation 72:377–384PubMedCrossRefPubMedCentralGoogle Scholar
  85. Kobayashi N, Karisola P, Pena-Cruz V, Dorfman DM, Jinushi M, Umetsu SE, Butte MJ, Nagumo H, Chernova I, Zhu B, Sharpe AH, Ito S, Dranoff G, Kaplan GG, Casasnovas JM, Umetsu DT, Dekruyff RH, Freeman GJ (2007) TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27:927–940PubMedPubMedCentralCrossRefGoogle Scholar
  86. Kopf M, Ruedl C, Schmitz N, Gallimore A, Lefrang K, Ecabert B, Odermatt B, Bachmann MF (1999) OX40-deficient mice are defective in Th cell proliferation but are competent in generating B cell and CTL responses after virus infection. Immunity 11:699–708CrossRefGoogle Scholar
  87. Kosuge H, Suzuki J, Gotoh R, Koga N, Ito H, Isobe M, Inobe M, Uede T (2003) Induction of immunologic tolerance to cardiac allograft by simultaneous blockade of inducible co-stimulator and cytotoxic T-lymphocyte antigen 4 pathway. Transplantation 75:1374–1379PubMedCrossRefPubMedCentralGoogle Scholar
  88. Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S, Russell A, Dougados M, Emery P, Nuamah IF, Rhys Williams G, Becker J-C, Hagerty DT, Moreland LW (2003) Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 349:1907–1915PubMedCrossRefPubMedCentralGoogle Scholar
  89. Kryczek I, Wei S, Zou L, Zhu G, Mottram P, Xu H, Chen L, Zou W (2006) Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells. J Immunol 177:40–44PubMedCrossRefPubMedCentralGoogle Scholar
  90. Kuchroo VK, Das MP, Brown JA, Ranger AM, Zamvil SS, Sobel RA, Weiner HL, Nabavi N, Glimcher LH (1995) B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell 80:707–718PubMedCrossRefPubMedCentralGoogle Scholar
  91. Kwon BS, Weissman SM (1989) cDNA sequences of two inducible T-cell genes. Proc Natl Acad Sci U S A 86:1963–1967PubMedPubMedCentralCrossRefGoogle Scholar
  92. Kwon B, Yu KY, Ni J, Yu GL, Jang IK, Kim YJ, Xing L, Liu D, Wang SX, Kwon BS (1999) Identification of a novel activation-inducible protein of the tumor necrosis factor receptor superfamily and its ligand. J Biol Chem 274:6056–6061CrossRefGoogle Scholar
  93. Langstein J, Michel J, Fritsche J, Kreutz M, Andreesen R, Schwarz H (1998) CD137 (ILA/4-1BB), a member of the TNF receptor family, induces monocyte activation via bidirectional signaling. J Immunol 160:2488–2494PubMedPubMedCentralGoogle Scholar
  94. Larsen CP, Alexander DZ, Hollenbaugh D, Elwood ET, Ritchie SC, Aruffo A, Hendrix R, Pearson TC (1996) CD40-gp39 interactions play a critical role during allograft rejection. Suppression of allograft rejection by blockade of the CD40-gp39 pathway. Transplantation 61:4–9PubMedCrossRefPubMedCentralGoogle Scholar
  95. Larsen CP, Pearson TC, Adams AB, Tso P, Shirasugi N, Strobert 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 (2005) Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant 5:443–453PubMedCrossRefPubMedCentralGoogle Scholar
  96. Lechler RI, Garden OA, Turka LA (2003) The complementary roles of deletion and regulation in transplantation tolerance. Nat Rev Immunol 3:147–158PubMedCrossRefPubMedCentralGoogle Scholar
  97. Leitner J, Klauser C, Pickl WF, Stockl J, Majdic O, Bardet AF, Kreil DP, Dong C, Yamazaki T, Zlabinger G, Pfistershammer K, Steinberger P (2009) B7-H3 is a potent inhibitor of human T-cell activation: no evidence for B7-H3 and TREML2 interaction. Eur J Immunol 39:1754–1764PubMedPubMedCentralCrossRefGoogle Scholar
  98. Lenschow DJ, Zeng Y, Thistlethwaite JR, Montag A, Brady W, Gibson MG, Linsley PS, Bluestone JA (1992) Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science 257:789–792PubMedCrossRefPubMedCentralGoogle Scholar
  99. Lenschow DJ, Ho SC, Sattar H, Rhee L, Gray G, Nabavi N, Herold KC, Bluestone JA (1995a) Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse. J Exp Med 181:1145–1155PubMedCrossRefPubMedCentralGoogle Scholar
  100. Lenschow DJ, Zeng Y, Hathcock KS, Zuckerman LA, Freeman G, Thistlethwaite JR, Gray GS, Hodes RJ, Bluestone JA (1995b) Inhibition of transplant rejection following treatment with anti-B7-2 and anti-B7-1 antibodies. Transplantation 60:1171–1178PubMedCrossRefPubMedCentralGoogle Scholar
  101. Lenschow DJ, Herold KC, Rhee L, Patel B, Koons A, Qin H-Y, Fuchs E, Singh B, Thompson CB, Bluestone JA (1996) CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes. Immunity 5:285–293CrossRefGoogle Scholar
  102. Levisetti MG, Padrid PA, Szot GL, Mittal N, Meehan SM, Wardrip CL, Gray GS, Bruce DS, Thistlethwaite JR Jr, Bluestone JA (1997) Immunosuppressive effects of human CTLA4Ig in a non-human primate model of allogeneic pancreatic islet transplantation’. J Immunol (Baltimore, Md: 1950) 159:5187–5191Google Scholar
  103. Li W (2001) Costimulation blockade promotes the apoptotic death of graft-infiltrating T cells and prolongs survival of hepatic allografts from FLT3L-treated donors. Transplantation 78:1423–1432CrossRefGoogle Scholar
  104. Li Y, Li XC, Zheng XX, Wells AD, Turka LA, Strom TB (1999) 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 5:1298–1302PubMedCrossRefPubMedCentralGoogle Scholar
  105. Li XC, Rothstein DM, Sayegh MH (2009) Costimulatory pathways in transplantation: challenges and new developments. Immunol Rev 229:271–293PubMedCrossRefPubMedCentralGoogle Scholar
  106. Li T, Ma R, Zhu J, Wang F, Huang L, Leng X (2014) Blockade of the OX40/OX40L pathway and induction of PD-L1 synergistically protects mouse islet allografts from rejection. Chin Med J 127:2686–2692PubMedPubMedCentralGoogle Scholar
  107. Li T, Ma R, Zhu JY, Wang FS, Huang L, Leng XS (2015) PD-1/PD-L1 costimulatory pathway-induced mouse islet transplantation immune tolerance. Transplant Proc 47:165–170PubMedCrossRefPubMedCentralGoogle Scholar
  108. Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R (1994) Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1:793–801PubMedCrossRefPubMedCentralGoogle Scholar
  109. Lo DJ, Anderson DJ, Weaver TA, Leopardi F, Song M, Farris AB, Strobert EA, Jenkins J, Turgeon NA, Mehta AK, Larsen CP, Kirk AD (2013) Belatacept and sirolimus prolong nonhuman primate renal allograft survival without a requirement for memory T cell depletion. Am J Transplant 13:320–328PubMedPubMedCentralCrossRefGoogle Scholar
  110. Lo DJ, Anderson DJ, Song M, Leopardi F, Farris AB, Strobert E, Chapin S, Devens B, Karrer E, Kirk AD (2015) A pilot trial targeting the ICOS-ICOS-L pathway in nonhuman primate kidney transplantation. Am J Transplant 15:984–992PubMedPubMedCentralCrossRefGoogle Scholar
  111. Lohning M, Hutloff A, Kallinich T, Mages HW, Bonhagen K, Radbruch A, Hamelmann E, Kroczek RA (2003) Expression of ICOS in vivo defines CD4+ effector T cells with high inflammatory potential and a strong bias for secretion of interleukin 10. J Exp Med 197:181–193PubMedPubMedCentralCrossRefGoogle Scholar
  112. Luhder F, Huang Y, Dennehy KM, Guntermann C, Muller I, Winkler E, Kerkau T, Ikemizu S, Davis SJ, Hanke T, Hunig T (2003) Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists. J Exp Med 197:955–966PubMedPubMedCentralCrossRefGoogle Scholar
  113. Luo L, Chapoval AI, Flies DB, Zhu G, Hirano F, Wang S, Lau JS, Dong H, Tamada K, Flies AS, Liu Y, Chen L (2004) B7-H3 enhances tumor immunity in vivo by costimulating rapid clonal expansion of antigen-specific CD8+ cytolytic T cells. J Immunol 173:5445–5450CrossRefGoogle Scholar
  114. Ma D, Duan W, Li Y, Wang Z, Li S, Gong N, Chen G, Chen Z, Wan C, Yang J (2016) PD-L1 deficiency within islets reduces allograft survival in mice. PLoS One 11:e0152087PubMedPubMedCentralCrossRefGoogle Scholar
  115. Mai G, del Rio ML, Tian J, Ramirez P, Buhler L, Rodriguez-Barbosa JI (2007) Blockade of the PD-1/PD-1L pathway reverses the protective effect of anti-CD40L therapy in a rat to mouse concordant islet xenotransplantation model. Xenotransplantation 14:243–248PubMedCrossRefPubMedCentralGoogle Scholar
  116. Malvezzi P, Jouve T, Rostaing L (2016) Costimulation blockade in kidney transplantation: an update. Transplantation 100:2315–2323PubMedPubMedCentralCrossRefGoogle Scholar
  117. McAdam AJ, Greenwald RJ, Levin MA, Chernova T, Malenkovich N, Ling V, Freeman GJ, Sharpe AH (2001) ICOS is critical for CD40-mediated antibody class switching. Nature 409:102–105PubMedPubMedCentralCrossRefGoogle Scholar
  118. Mease P, Genovese MC, Gladstein G, Kivitz AJ, Ritchlin C, Tak PP, Wollenhaupt J, Bahary O, Becker J-C, Kelly S, Sigal L, Teng J, Gladman D (2011) Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial. Arthritis Rheum 63:939–948PubMedCrossRefPubMedCentralGoogle Scholar
  119. Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4:762–774PubMedCrossRefPubMedCentralGoogle Scholar
  120. Meyers JH, Chakravarti S, Schlesinger D, Illes Z, Waldner H, Umetsu SE, Kenny J, Zheng XX, Umetsu DT, DeKruyff RH, Strom TB, Kuchroo VK (2005) TIM-4 is the ligand for TIM-1, and the TIM-1-TIM-4 interaction regulates T cell proliferation. Nat Immunol 6:455–464PubMedCrossRefPubMedCentralGoogle Scholar
  121. Mizui M, Shikina T, Arase H, Suzuki K, Yasui T, Rennert PD, Kumanogoh A, Kikutani H (2008) Bimodal regulation of T cell-mediated immune responses by TIM-4. Int Immunol 20:695–708PubMedCrossRefPubMedCentralGoogle Scholar
  122. Morita M, Fujino M, Jiang G, Kitazawa Y, Xie L, Azuma M, Yagita H, Nagao S, Sugioka A, Kurosawa Y, Takahara S, Fung J, Qian S, Lu L, Li XK (2010) PD-1/B7-H1 interaction contribute to the spontaneous acceptance of mouse liver allograft. Am J Transplant 10:40–46PubMedCrossRefPubMedCentralGoogle Scholar
  123. Moxham VF, Karegli J, Phillips RE, Brown KL, Tapmeier TT, Hangartner R, Sacks SH, Wong W (2008) Homeostatic proliferation of lymphocytes results in augmented memory-like function and accelerated allograft rejection. J Immunol 180:3910–3918PubMedCrossRefPubMedCentralGoogle Scholar
  124. Nadazdin O, Boskovic S, Murakami T, Tocco G, Smith RN, Colvin RB, Sachs DH, Allan J, Madsen JC, Kawai T, Cosimi AB, Benichou G (2011) Host alloreactive memory T cells influence tolerance to kidney allografts in nonhuman primates. Sci Transl Med 3:86ra51PubMedPubMedCentralCrossRefGoogle Scholar
  125. Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M, Azuma M, Yagita H, Okumura K (2009) Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood 113:3821–3830PubMedCrossRefGoogle Scholar
  126. Nanji SA, Hancock WW, Anderson CC, Adams AB, Luo B, Schur CD, Pawlick RL, Wang L, Coyle AJ, Larsen CP, Shapiro AM (2004) Multiple combination therapies involving blockade of ICOS/B7RP-1 costimulation facilitate long-term islet allograft survival. Am J Transplant 4:526–536PubMedCrossRefPubMedCentralGoogle Scholar
  127. Nanji SA, Hancock WW, Luo B, Schur CD, Pawlick RL, Zhu LF, Anderson CC, Shapiro AM (2006) Costimulation blockade of both inducible costimulator and CD40 ligand induces dominant tolerance to islet allografts and prevents spontaneous autoimmune diabetes in the NOD mouse. Diabetes 55:27–33PubMedCrossRefPubMedCentralGoogle Scholar
  128. Oura T, Yamashita K, Suzuki T, Fukumori D, Watanabe M, Hirokata G, Wakayama K, Taniguchi M, Shimamura T, Miura T, Okimura K, Maeta K, Haga H, Kubota K, Shimizu A, Sakai F, Furukawa H, Todo S (2012) Long-term hepatic allograft acceptance based on CD40 blockade by ASKP1240 in nonhuman primates. Am J Transplant 12:1740–1754PubMedCrossRefPubMedCentralGoogle Scholar
  129. Ozkaynak E, Gao W, Shemmeri N, Wang C, Gutierrez-Ramos JC, Amaral J, Qin S, Rottman JB, Coyle AJ, Hancock WW (2001) Importance of ICOS-B7RP-1 costimulation in acute and chronic allograft rejection. Nat Immunol 2:591–596PubMedCrossRefPubMedCentralGoogle Scholar
  130. 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 (2002) Programmed death-1 targeting can promote allograft survival. J Immunol 169:6546–6553PubMedCrossRefPubMedCentralGoogle Scholar
  131. Pantenburg B, Heinzel F, Das L, Heeger PS, Valujskikh A (2002) T cells primed by Leishmania major infection cross-react with alloantigens and alter the course of allograft rejection. J Immunol 169:3686–3693PubMedCrossRefPubMedCentralGoogle Scholar
  132. Parker DC, Greiner DL, Phillips NE, Appel MC, Steele AW, Durie FH, Noelle RJ, Mordes JP, Rossini AA (1995) Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand. Proc Natl Acad Sci U S A 92:9560–9564PubMedPubMedCentralCrossRefGoogle Scholar
  133. Pauly S, Broll K, Wittmann M, Giegerich G, Schwarz H (2002) CD137 is expressed by follicular dendritic cells and costimulates B lymphocyte activation in germinal centers. J Leukoc Biol 72:35–42PubMedPubMedCentralGoogle Scholar
  134. Pawar RD, Goilav B, Xia Y, Herlitz L, Doerner J, Chalmers S, Ghosh K, Zang X, Putterman C (2015) B7x/B7-H4 modulates the adaptive immune response and ameliorates renal injury in antibody-mediated nephritis. Clin Exp Immunol 179:329–343PubMedPubMedCentralCrossRefGoogle Scholar
  135. Peach RJ, Bajorath J, Brady W, Leytze G, Greene J, Naemura J, Linsley PS (1994) Complementarity determining region 1 (CDR1)- and CDR3-analogous regions in CTLA-4 and CD28 determine the binding to B7-1. J Exp Med 180:2049–2058PubMedCrossRefPubMedCentralGoogle Scholar
  136. Pearson TC, Alexander DZ, Hendrix R, Elwood ET, Linsley PS, Winn KJ, Larsen CP (1996) CTLA4-Ig plus bone marrow induces long-term allograft survival and donor-specific unresponsiveness in the murine model: evidence for hematopoietic chimerism1. Transplantation 61:997–1004PubMedCrossRefPubMedCentralGoogle Scholar
  137. Pearson TC, Alexander DZ, Corbascio M, Hendrix R, Ritchie SC, Linsley PS, Faherty D, Larsen CP (1997) Analysis of the B7 costimulatory pathway in allograft rejection. Transplantation 63:1463–1469PubMedCrossRefPubMedCentralGoogle Scholar
  138. Pearson TC, Trambley J, Odom K, Anderson DC, Cowan S, Bray R, Lin A, Hollenbaugh D, Aruffo A, Siadak AW, Strobert E, Hennigar R, Larsen CP (2002) Anti-CD40 therapy extends renal allograft survival in rhesus macaques. Transplantation 74:933–940PubMedCrossRefPubMedCentralGoogle Scholar
  139. Pentcheva-Hoang T, Egen JG, Wojnoonski K, Allison JP (2004) B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity 21:401–413PubMedPubMedCentralCrossRefGoogle Scholar
  140. Perez VL (1997) Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity 6:411–417PubMedCrossRefPubMedCentralGoogle Scholar
  141. Pfeiffer S, Iii GL, Azimzadeh AM, Atkinson J, Newman R, Pierson RN (2001) Monotherapy with anti-CD40 ligand antibody (IDEC 131) for non-human primate allograft heart transplantation. J Heart Lung Transplant 20:250PubMedCrossRefPubMedCentralGoogle Scholar
  142. Podojil JR, Liu LN, Marshall SA, Chiang MY, Goings GE, Chen L, Langermann S, Miller SD (2013) B7-H4Ig inhibits mouse and human T-cell function and treats EAE via IL-10/Treg-dependent mechanisms. J Autoimmun 44:71–81PubMedPubMedCentralCrossRefGoogle Scholar
  143. Poirier N, Azimzadeh AM, Zhang T, Dilek N, Mary C, Nguyen B, Tillou X, Wu G, Reneaudin K, Hervouet J, Martinet B, Coulon F, Allain-Launay E, Karam G, Soulillou JP, Pierson RN 3rd, Blancho G, Vanhove B (2010) Inducing CTLA-4-dependent immune regulation by selective CD28 blockade promotes regulatory T cells in organ transplantation. Sci Transl Med 2:17ra10PubMedPubMedCentralCrossRefGoogle Scholar
  144. Poirier N, Blancho G, Hiance M, Mary C, Van Assche T, Lempoels J, Ramael S, Wang W, Thepenier V, Braudeau C, Salabert N, Josien R, Anderson I, Gourley I, Soulillou JP, Coquoz D, Vanhove B (2016) First-in-human study in healthy subjects with FR104, a Pegylated monoclonal antibody fragment antagonist of CD28. J Immunol 197:4593–4602PubMedCrossRefPubMedCentralGoogle Scholar
  145. Ponciano VC, Renesto PG, Nogueira E, Rangel EB, Cenedeze MA, Franco MF, Camara NO, Pacheco-Silva A (2007) Tim-3 expression in human kidney allografts. Transpl Immunol 17:215–222PubMedCrossRefPubMedCentralGoogle Scholar
  146. Prasad DV, Richards S, Mai XM, Dong C (2003) B7S1, a novel B7 family member that negatively regulates T cell activation. Immunity 18:863–873PubMedPubMedCentralCrossRefGoogle Scholar
  147. Prasad DVR, Nguyen T, Li Z, Yang Y, Duong J, Wang Y, Dong C (2004) Murine B7-H3 is a negative regulator of T cells. J Immunol 173:2500–2506CrossRefGoogle Scholar
  148. Qian Y, Hong B, Shen L, Wu Z, Yao H, Zhang L (2013) B7-H4 enhances oncogenicity and inhibits apoptosis in pancreatic cancer cells. Cell Tissue Res 353:139–151CrossRefGoogle Scholar
  149. Riella LV, Watanabe T, Sage PT, Yang J, Yeung M, Azzi J, Vanguri V, Chandraker A, Sharpe AH, Sayegh MH, Najafian N (2011) Essential role of PDL1 expression on nonhematopoietic donor cells in acquired tolerance to vascularized cardiac allografts. Am J Transplant 11:832–840PubMedCrossRefPubMedCentralGoogle Scholar
  150. Riella LV, Liu T, Yang J, Chock S, Shimizu T, Mfarrej B, Batal I, Xiao X, Sayegh MH, Chandraker A (2012a) Deleterious effect of CTLA4-Ig on a Treg-dependent transplant model. Am J Transplant 12:846–855PubMedCrossRefPubMedCentralGoogle Scholar
  151. Riella LV, Paterson AM, Sharpe AH, Chandraker A (2012b) Role of the PD-1 pathway in the immune response. Am J Transplant 12:2575–2587PubMedPubMedCentralCrossRefGoogle Scholar
  152. Robles-Carrillo L, Meyer T, Hatfield M, Desai H, Davila M, Langer F, Amaya M, Garber E, Francis JL, Hsu YM, Amirkhosravi A (2010) Anti-CD40L immune complexes potently activate platelets in vitro and cause thrombosis in FCGR2A transgenic mice. J Immunol 185:1577–1583PubMedCrossRefPubMedCentralGoogle Scholar
  153. Rodriguez-Manzanet R, Meyers JH, Balasubramanian S, Slavik J, Kassam N, Dardalhon V, Greenfield EA, Anderson AC, Sobel RA, Hafler DA, Strom TB, Kuchroo VK (2008) TIM-4 expressed on APCs induces T cell expansion and survival. J Immunol 180:4706–4713PubMedPubMedCentralCrossRefGoogle Scholar
  154. Rodriguez-Manzanet R, DeKruyff R, Kuchroo VK, Umetsu DT (2009) The costimulatory role of TIM molecules. Immunol Rev 229:259–270PubMedPubMedCentralCrossRefGoogle Scholar
  155. Ronchese F, Hausmann B, Hubele S, Lane P (1994) Mice transgenic for a soluble form of murine CTLA-4 show enhanced expansion of antigen-specific CD4+ T cells and defective antibody production in vivo. J Exp Med 179:809–817PubMedCrossRefPubMedCentralGoogle Scholar
  156. Rong S, Park JK, Kirsch T, Yagita H, Akiba H, Boenisch O, Haller H, Najafian N, Habicht A (2011) The TIM-1:TIM-4 pathway enhances renal ischemia-reperfusion injury. J Am Soc Nephrol 22:484–495PubMedPubMedCentralCrossRefGoogle Scholar
  157. Rudd CE (2008) The reverse stop-signal model for CTLA4 function. Nat Rev Immunol 8:153–160PubMedCrossRefGoogle Scholar
  158. Rudd CE, Taylor A, Schneider H (2009) CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev 229:12–26PubMedPubMedCentralCrossRefGoogle Scholar
  159. Salama AD, Yuan X, Nayer A, Chandraker A, Inobe M, Uede T, Sayegh MH (2003) Interaction between ICOS-B7RP1 and B7-CD28 costimulatory pathways in alloimmune responses in vivo. Am J Transplant 3:390–395PubMedCrossRefGoogle Scholar
  160. Salomon B, Bluestone JA (2001) Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 19:225–252PubMedCrossRefPubMedCentralGoogle Scholar
  161. Sanchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, Manlongat N, Bender O, Kamradt T, Kuchroo VK, Gutierrez-Ramos JC, Coyle AJ, Strom TB (2003) Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol 4:1093–1101CrossRefGoogle Scholar
  162. Saoulli K, Lee SY, Cannons JL, Yeh WC, Santana A, Goldstein MD, Bangia N, DeBenedette MA, Mak TW, Choi Y, Watts TH (1998) CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand. J Exp Med 187:1849–1862PubMedPubMedCentralCrossRefGoogle Scholar
  163. Sayegh MH, Akalin E, Hancock WW, Russell ME, Carpenter CB, Linsley PS, Turka LA (1995) CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2. J Exp Med 181:1869–1874PubMedCrossRefGoogle Scholar
  164. Schenk S, Kish DD, He C, El-Sawy T, Chiffoleau E, Chen C, Wu Z, Sandner S, Gorbachev AV, Fukamachi K, Heeger PS, Sayegh MH, Turka LA, Fairchild RL (2005) Alloreactive T cell responses and acute rejection of single class II MHC-disparate heart allografts are under strict regulation by CD4 +CD25+ T cells. J Immunol 174:3741–3748PubMedCrossRefPubMedCentralGoogle Scholar
  165. Schenk AD, Gorbacheva V, Rabant M, Fairchild RL, Valujskikh A (2009) Effector functions of donor-reactive CD8 memory T cells are dependent on ICOS induced during division in cardiac grafts. Am J Transplant 9:64–73PubMedCrossRefPubMedCentralGoogle Scholar
  166. Schuler W, Bigaud M, Brinkmann V, Di Padova F, Geisse S, Gram H, Hungerford V, Kleuser B, Kristofic C, Menninger K, Tees R, Wieczorek G, Wilt C, Wioland C, Zurini M (2004) Efficacy and safety of ABI793, a novel human anti-human CD154 monoclonal antibody, in cynomolgus monkey renal allotransplantation. Transplantation 77:717–726PubMedCrossRefPubMedCentralGoogle Scholar
  167. Seo SK, Park HY, Choi JH, Kim WY, Kim YH, Jung HW, Kwon B, Lee HW, Kwon BS (2003) Blocking 4-1BB/4-1BB ligand interactions prevents herpetic stromal keratitis. J Immunol 171:576–583PubMedCrossRefPubMedCentralGoogle Scholar
  168. Shao W, Chen J, Dai H, Peng Y, Wang F, Xia J, Thorlacius H, Zhu Q, Qi Z (2011a) Combination of monoclonal antibodies with DST inhibits accelerated rejection mediated by memory T cells to induce long-lived heart allograft acceptance in mice. Immunol Lett 138:122–128PubMedCrossRefPubMedCentralGoogle Scholar
  169. Shao W, Yan G, Lin Y, Chen J, Dai H, Wang F, Xi Y, Thorlacius H, Qi Z (2011b) CD44/CD70 blockade and anti-CD154/LFA-1 treatment synergistically suppress accelerated rejection and prolong cardiac allograft survival in mice. Scand J Immunol 74:430–437PubMedCrossRefPubMedCentralGoogle Scholar
  170. Shariff H, Tanriver Y, Brown KL, Meader L, Greenlaw R, Mamode N, Jurcevic S (2010) Intermittent antibody-based combination therapy removes alloantibodies and achieves indefinite heart transplant survival in presensitized recipients. Transplantation 90:270–278PubMedPubMedCentralCrossRefGoogle Scholar
  171. Shi Y, Hu S, Song Q, Yu S, Zhou X, Yin J, Qin L, Qian H (2013) Gene silencing of 4-1BB by RNA interference inhibits acute rejection in rats with liver transplantation. Biomed Res Int 2013:192738PubMedPubMedCentralGoogle Scholar
  172. Shi R, Honczarenko M, Zhang S, Fleener C, Mora J, Lee SK, Wang R, Liu X, Shevell DE, Yang Z, Wang H, Murthy B (2017) Pharmacokinetic, Pharmacodynamic, and safety profile of a novel anti-CD28 domain antibody antagonist in healthy subjects. J Clin Pharmacol 57:161–172PubMedCrossRefPubMedCentralGoogle Scholar
  173. Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3:135–142PubMedPubMedCentralCrossRefGoogle Scholar
  174. Sica GL, Choi IH, Zhu G, Tamada K, Wang SD, Tamura H, Chapoval AI, Flies DB, Bajorath J, Chen L (2003) B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 18:849–861CrossRefGoogle Scholar
  175. Sizing ID, Bailly V, McCoon P, Chang W, Rao S, Pablo L, Rennard R, Walsh M, Li Z, Zafari M, Dobles M, Tarilonte L, Miklasz S, Majeau G, Godbout K, Scott ML, Rennert PD (2007) Epitope-dependent effect of anti-murine TIM-1 monoclonal antibodies on T cell activity and lung immune responses. J Immunol 178:2249–2261PubMedCrossRefPubMedCentralGoogle Scholar
  176. Sonawane SB, Kim JI, Lee MK, Lee SH, Duff PE, Moore DJ, Lian MM, Deng S, Choi Y, Yeh H, Caton AJ, Markmann JF (2009) GITR blockade facilitates Treg mediated allograft survival. Transplantation 88:1169–1177PubMedPubMedCentralCrossRefGoogle Scholar
  177. Stapler D, Lee ED, Selvaraj SA, Evans AG, Kean LS, Speck SH, Larsen CP, Gangappa S (2008) Expansion of effector memory TCR Vbeta4+ CD8+ T cells is associated with latent infection-mediated resistance to transplantation tolerance. J Immunol 180:3190–3200PubMedCrossRefPubMedCentralGoogle Scholar
  178. Suchard SJ, Davis PM, Kansal S, Stetsko DK, Brosius R, Tamura J, Schneeweis L, Bryson J, Salcedo T, Wang H, Yang Z, Fleener CA, Ignatovich O, Plummer C, Grant S, Nadler SG (2013) A monovalent anti-human CD28 domain antibody antagonist: preclinical efficacy and safety. J Immunol 191:4599–4610CrossRefGoogle Scholar
  179. Suchin EJ, Langmuir PB, Palmer E, Sayegh MH, Wells AD, Turka LA (2001) Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J Immunol 166:973–981PubMedCrossRefPubMedCentralGoogle Scholar
  180. Suh WK, Gajewska BU, Okada H, Gronski MA, Bertram EM, Dawicki W, Duncan GS, Bukczynski J, Plyte S, Elia A, Wakeham A, Itie A, Chung S, Da Costa J, Arya S, Horan T, Campbell P, Gaida K, Ohashi PS, Watts TH, Yoshinaga SK, Bray MR, Jordana M, Mak TW (2003) The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat Immunol 4:899–906PubMedPubMedCentralCrossRefGoogle Scholar
  181. Suh WK, Wang SX, Jheon AH, Moreno L, Yoshinaga SK, Ganss B, Sodek J, Grynpas MD, Mak TW (2004) The immune regulatory protein B7-H3 promotes osteoblast differentiation and bone mineralization. Proc Natl Acad Sci U S A 101:12969–12973PubMedPubMedCentralCrossRefGoogle Scholar
  182. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018–1028PubMedPubMedCentralCrossRefGoogle Scholar
  183. Swallow MM, Wallin JJ, Sha WC (1999) B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNFalpha. Immunity 11:423–432PubMedCrossRefPubMedCentralGoogle Scholar
  184. 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 (2001) ICOS is essential for effective T-helper-cell responses. Nature 409:105–109CrossRefGoogle Scholar
  185. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192:303–310PubMedPubMedCentralCrossRefGoogle Scholar
  186. Tan P, Anasetti C, Hansen JA, Melrose J, Brunvand M, Bradshaw J, Ledbetter JA, Linsley PS (1993) Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1. J Exp Med 177:165–173PubMedCrossRefPubMedCentralGoogle Scholar
  187. Tan JT, Ha J, Cho HR, Tucker-Burden C, Hendrix RC, Mittler RS, Pearson TC, Larsen CP (2000) Analysis of expression and function of the costimulatory molecule 4-1BB in alloimmune responses. Transplantation 70:175–183PubMedPubMedCentralGoogle Scholar
  188. Tang Q, Henriksen KJ, Boden EK, Tooley AJ, Ye J, Subudhi SK, Zheng XX, Strom TB, Bluestone JA (2003) Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol 171:3348–3352PubMedPubMedCentralCrossRefGoogle Scholar
  189. Tesselaar K, Xiao Y, Arens R, van Schijndel GM, Schuurhuis DH, Mebius RE, Borst J, van Lier RA (2003) Expression of the murine CD27 ligand CD70 in vitro and in vivo. J Immunol 170:33–40PubMedPubMedCentralCrossRefGoogle Scholar
  190. Thangavelu G, Murphy KM, Yagita H, Boon L, Anderson CC (2011) The role of co-inhibitory signals in spontaneous tolerance of weakly mismatched transplants. Immunobiology 216:918–924PubMedPubMedCentralCrossRefGoogle Scholar
  191. Thornley TB, Fang Z, Balasubramanian S, Larocca RA, Gong W, Gupta S, Csizmadia E, Degauque N, Kim BS, Koulmanda M, Kuchroo VK, Strom TB (2014) Fragile TIM-4-expressing tissue resident macrophages are migratory and immunoregulatory. J Clin Invest 124:3443–3454PubMedPubMedCentralCrossRefGoogle Scholar
  192. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541–547PubMedPubMedCentralCrossRefGoogle Scholar
  193. Tone M, Tone Y, Adams E, Yates SF, Frewin MR, Cobbold SP, Waldmann H (2003) Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc Natl Acad Sci U S A 100:15059–15064PubMedPubMedCentralCrossRefGoogle Scholar
  194. Tsai M-K, Ho H-N, Chien H-F, Ou-Yang P, Lee C-J, Lee P-H (2004) The role of b7 ligands (cd80 and cd86) in cd152-mediated allograft tolerance: a crosscheck hypothesis. Transplantation 77:48–54PubMedCrossRefPubMedCentralGoogle Scholar
  195. Turka LA (1992) T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo. Proc Natl Acad Sci U S A 89:11102–11105PubMedPubMedCentralCrossRefGoogle Scholar
  196. Uchida Y, Ke B, Freitas MC, Ji H, Zhao D, Benjamin ER, Najafian N, Yagita H, Akiba H, Busuttil RW, Kupiec-Weglinski JW (2010) The emerging role of T cell immunoglobulin mucin-1 in the mechanism of liver ischemia and reperfusion injury in the mouse. Hepatology 51:1363–1372PubMedPubMedCentralCrossRefGoogle Scholar
  197. Ueda H (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511Google Scholar
  198. Ueno T, Habicht A, Clarkson MR, Albin MJ, Yamaura K, Boenisch O, Popoola J, Wang Y, Yagita H, Hisaya A, Ansari MJ, Yang J, Turka LA, Rothstein DM, Padera RF, Najafian N, Sayegh MH (2008) The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model. J Clin Invest 118:742–751PubMedPubMedCentralCrossRefGoogle Scholar
  199. Ueno T, Yeung MY, McGrath M, Yang S, Zaman N, Snawder B, Padera RF, Magee CN, Gorbatov R, Hashiguchi M, Azuma M, Freeman GJ, Sayegh MH, Najafian N (2012) Intact B7-H3 signaling promotes allograft prolongation through preferential suppression of Th1 effector responses. Eur J Immunol 42:2343–2353PubMedCrossRefPubMedCentralGoogle Scholar
  200. Valujskikh A, Pantenburg B, Heeger PS (2002) Primed allospecific T cells prevent the effects of costimulatory blockade on prolonged cardiac allograft survival in mice. Am J Transplant 2:501–509PubMedCrossRefPubMedCentralGoogle Scholar
  201. Vanhove B, Laflamme G, Coulon F, Mougin M, Vusio P, Haspot F, Tiollier J, Soulillou JP (2003) Selective blockade of CD28 and not CTLA-4 with a single-chain Fv-alpha1-antitrypsin fusion antibody. Blood 102:564–570PubMedCrossRefPubMedCentralGoogle Scholar
  202. Vasu C, Prabhakar BS, Holterman MJ (2004) Targeted CTLA-4 engagement induces CD4+CD25+CTLA-4high T regulatory cells with target (allo)antigen specificity. J Immunol 173:2866–2876PubMedCrossRefPubMedCentralGoogle Scholar
  203. Vergani A, Gatti F, Lee KM, D’Addio F, Tezza S, Chin M, Bassi R, Tian Z, Wu E, Maffi P, Nasr MB, Kim JI, Secchi A, Markmann JF, Rothstein DM, Turka LA, Sayegh MH, Fiorina P (2015) TIM4 regulates the anti-islet Th2 alloimmune response. Cell Transplant 24:1599–1614PubMedCrossRefPubMedCentralGoogle Scholar
  204. Ville S, Poirier N, Branchereau J, Charpy V, Pengam S, Nerriere-Daguin V, Le Bas-Bernardet S, Coulon F, Mary C, Chenouard A, Hervouet J, Minault D, Nedellec S, Renaudin K, Vanhove B, Blancho G (2016) Anti-CD28 antibody and Belatacept exert differential effects on mechanisms of renal allograft rejection. J Am Soc Nephrol 27:3577–3588PubMedPubMedCentralCrossRefGoogle Scholar
  205. Vincenti F, Charpentier B, Vanrenterghem Y, Rostaing L, Bresnahan B, Darji P, Massari P, Mondragon-Ramirez GA, Agarwal M, Di Russo G, Lin CS, Garg P, Larsen CP (2010) A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant 10:535–546PubMedCrossRefPubMedCentralGoogle Scholar
  206. Vincenti F, Dritselis A, Kirkpatrick P (2011) Belatacept. Nat Rev Drug Discov 10:655–656PubMedCrossRefPubMedCentralGoogle Scholar
  207. Vincenti F, Rostaing L, Grinyo J, Rice K, Steinberg S, Gaite L, Moal MC, Mondragon-Ramirez GA, Kothari J, Polinsky MS, Meier-Kriesche HU, Munier S, Larsen CP (2016) Belatacept and long-term outcomes in kidney transplantation. N Engl J Med 374:333–343CrossRefGoogle Scholar
  208. Vu MD, Clarkson MR, Yagita H, Turka LA, Sayegh MH, Li XC (2006) Critical, but conditional, role of OX40 in memory T cell-mediated rejection. J Immunol 176:1394–1401PubMedCrossRefPubMedCentralGoogle Scholar
  209. Vu MD, Xiao X, Gao W, Degauque N, Chen M, Kroemer A, Killeen N, Ishii N, Li XC (2007) OX40 costimulation turns off Foxp3+ Tregs. Blood 110:2501–2510PubMedPubMedCentralCrossRefGoogle Scholar
  210. Walunas TL, Bakker CY, Bluestone JA (1996) CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med 183:2541–2550CrossRefGoogle Scholar
  211. Wang J, Guo Z, Dong Y, Kim O, Hart J, Adams A, Larsen CP, Mittler RS, Newell KA (2003) Role of 4-1BB in allograft rejection mediated by CD8+ T cells. Am J Transplant 3:543–551PubMedCrossRefPubMedCentralGoogle Scholar
  212. Wang G, Feng Y, Hao J, Li A, Gao X, Xie S (2005a) Induction of xenogeneic islet transplantation tolerance by simultaneously blocking CD28-B7 and OX40-OX40L co-stimulatory pathways. Sci China C Life Sci 48:515–522PubMedCrossRefPubMedCentralGoogle Scholar
  213. Wang L, Fraser CC, Kikly K, Wells AD, Han R, Coyle AJ, Chen L, Hancock WW (2005b) B7-H3 promotes acute and chronic allograft rejection. Eur J Immunol 35:428–438PubMedCrossRefPubMedCentralGoogle Scholar
  214. Wang F, He W, Zhou H, Yuan J, Wu K, Xu L, Chen ZK (2007a) The Tim-3 ligand galectin-9 negatively regulates CD8+ alloreactive T cell and prolongs survival of skin graft. Cell Immunol 250:68–74PubMedCrossRefPubMedCentralGoogle Scholar
  215. Wang L, Han R, Hancock WW (2007b) Programmed cell death 1 (PD-1) and its ligand PD-L1 are required for allograft tolerance. Eur J Immunol 37:2983–2990PubMedCrossRefPubMedCentralGoogle Scholar
  216. Wang F, He W, Yuan J, Wu K, Zhou H, Zhang W, Chen ZK (2008) Activation of Tim-3-Galectin-9 pathway improves survival of fully allogeneic skin grafts. Transpl Immunol 19:12–19PubMedCrossRefPubMedCentralGoogle Scholar
  217. Wang X, Hao J, Metzger DL, Mui A, Ao Z, Verchere CB, Chen L, Ou D, Warnock GL (2009) Local expression of B7-H4 by recombinant adenovirus transduction in mouse islets prolongs allograft survival. Transplantation 87:482–490PubMedCrossRefPubMedCentralGoogle Scholar
  218. Wang X, Hao J, Metzger DL, Mui A, Ao Z, Akhoundsadegh N, Langermann S, Liu L, Chen L, Ou D, Verchere CB, Warnock GL (2011) Early treatment of NOD mice with B7-H4 reduces the incidence of autoimmune diabetes. Diabetes 60:3246–3255PubMedPubMedCentralCrossRefGoogle Scholar
  219. Wang X, Hao J, Metzger DL, Mui A, Ao Z, Verchere CB, Chen L, Ou D, Warnock GL (2012) B7-H4 induces donor-specific tolerance in mouse islet allografts. Cell Transplant 21:99–111PubMedCrossRefPubMedCentralGoogle Scholar
  220. Wang H, Zhang Z, Tian W, Liu T, Han H, Garcia B, Li XC, Du C (2014) Memory T cells mediate cardiac allograft vasculopathy and are inactivated by anti-OX40L monoclonal antibody. Cardiovasc Drugs Ther 28:115–122PubMedPubMedCentralCrossRefGoogle Scholar
  221. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985–988PubMedPubMedCentralCrossRefGoogle Scholar
  222. Watts TH (2005) TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 23:23–68PubMedPubMedCentralCrossRefGoogle Scholar
  223. Williams MA, Trambley J, Ha J, Adams AB, Durham MM, Rees P, Cowan SR, Pearson TC, Larsen CP (2000) Genetic characterization of strain differences in the ability to mediate CD40/CD28-independent rejection of skin allografts. J Immunol 165:6849–6857PubMedCrossRefPubMedCentralGoogle Scholar
  224. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322:271–275CrossRefGoogle Scholar
  225. Wojciechowski D, Vincenti F (2016) Current status of costimulatory blockade in renal transplantation. Curr Opin Nephrol Hypertens 25:583–590PubMedCrossRefPubMedCentralGoogle Scholar
  226. Wood KJ, Sakaguchi S (2003) Regulatory T cells in transplantation tolerance. Nat Rev Immunol 3:199–210PubMedCrossRefPubMedCentralGoogle Scholar
  227. Wood KJ, Bushell A, Hester J (2012) Regulatory immune cells in transplantation. Nat Rev Immunol 12:417–430PubMedCrossRefPubMedCentralGoogle Scholar
  228. Wu Z, Bensinger SJ, Zhang J, Chen C, Yuan X, Huang X, Markmann JF, Kassaee A, Rosengard BR, Hancock WW, Sayegh MH, Turka LA (2004) Homeostatic proliferation is a barrier to transplantation tolerance. Nat Med 10:87–92PubMedCrossRefPubMedCentralGoogle Scholar
  229. Xia J, Chen J, Shao W, Lan T, Wang Y, Xie B, Thorlacius H, Tian F, Huang R, Qi Z (2010) Suppressing memory T cell activation induces islet allograft tolerance in alloantigen-primed mice. Transpl Int 23:1154–1163PubMedCrossRefPubMedCentralGoogle Scholar
  230. Xiao S, Najafian N, Reddy J, Albin M, Zhu C, Jensen E, Imitola J, Korn T, Anderson AC, Zhang Z, Gutierrez C, Moll T, Sobel RA, Umetsu DT, Yagita H, Akiba H, Strom T, Sayegh MH, DeKruyff RH, Khoury SJ, Kuchroo VK (2007) Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function. J Exp Med 204:1691–1702PubMedPubMedCentralCrossRefGoogle Scholar
  231. Xiao S, Brooks CR, Zhu C, Wu C, Sweere JM, Petecka S, Yeste A, Quintana FJ, Ichimura T, Sobel RA, Bonventre JV, Kuchroo VK (2012) Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice. Proc Natl Acad Sci U S A 109:12105–12110PubMedPubMedCentralCrossRefGoogle Scholar
  232. Xu H, Montgomery SP, Preston EH, Tadaki DK, Hale DA, Harlan DM, Kirk AD (2003) Studies investigating pretransplant donor-specific blood transfusion, rapamycin, and the CD154-specific antibody IDEC-131 in a nonhuman primate model of skin allotransplantation. J Immunol 170:2776–2782PubMedCrossRefPubMedCentralGoogle Scholar
  233. Yamada A, Kishimoto K, Dong VM, Sho M, Salama AD, Anosova NG, Benichou G, Mandelbrot DA, Sharpe AH, Turka LA, Auchincloss H Jr, Sayegh MH (2001) CD28-independent costimulation of T cells in alloimmune responses. J Immunol 167:140–146PubMedCrossRefPubMedCentralGoogle Scholar
  234. Yamada A, Salama AD, Sho M, Najafian N, Ito T, Forman JP, Kewalramani R, Sandner S, Harada H, Clarkson MR, Mandelbrot DA, Sharpe AH, Oshima H, Yagita H, Chalasani G, Lakkis FG, Auchincloss H Jr, Sayegh MH (2005) CD70 signaling is critical for CD28-independent CD8+ T cell-mediated alloimmune responses in vivo. J Immunol 174:1357–1364CrossRefGoogle Scholar
  235. Yamaura K, Watanabe T, Boenisch O, Yeung M, Yang S, Magee CN, Padera R, Datta S, Schatton T, Kamimura Y, Azuma M, Najafian N (2010) In vivo function of immune inhibitory molecule B7-H4 in alloimmune responses. Am J Transplant 10:2355–2362PubMedCrossRefPubMedCentralGoogle Scholar
  236. 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 (2008) Critical role of donor tissue expression of programmed death ligand-1 in regulating cardiac allograft rejection and vasculopathy. Circulation 117:660–669PubMedCrossRefPubMedCentralGoogle Scholar
  237. Yang J, Riella LV, Boenisch O, Popoola J, Robles S, Watanabe T, Vanguri V, Yuan X, Guleria I, Turka LA, Sayegh MH, Chandraker A (2009) Paradoxical functions of B7: CD28 costimulation in a MHC class II-mismatched cardiac transplant model. Am J Transplant 9:2837–2844PubMedPubMedCentralCrossRefGoogle Scholar
  238. Yang J, Riella LV, Chock S, Liu T, Zhao X, Yuan X, Paterson AM, Watanabe T, Vanguri V, Yagita H, Azuma M, Blazar BR, Freeman GJ, Rodig SJ, Sharpe AH, Chandraker A, Sayegh MH (2011) The novel costimulatory programmed death ligand 1/B7.1 pathway is functional in inhibiting alloimmune responses in vivo. J Immunol 187:1113–1119PubMedPubMedCentralCrossRefGoogle Scholar
  239. Yang Z, Wang H, Salcedo TW, Suchard SJ, Xie JH, Schneeweis LA, Fleener CA, Calore JD, Shi R, Zhang SX, Rodrigues AD, Car BD, Marathe PH, Nadler SG (2015) Integrated pharmacokinetic/Pharmacodynamic analysis for determining the minimal anticipated biological effect level of a novel anti-CD28 receptor antagonist BMS-931699. J Pharmacol Exp Ther 355:506–515CrossRefGoogle Scholar
  240. Yeung MY, Sayegh MH (2009) Regulatory T cells in transplantation: what we know and what we do not know. Transplant Proc 41:S21–S26PubMedCrossRefPubMedCentralGoogle Scholar
  241. Yeung MY, McGrath MM, Nakayama M, Shimizu T, Boenisch O, Magee CN, Abdoli R, Akiba H, Ueno T, Turka LA, Najafian N (2013) Interruption of dendritic cell-mediated TIM-4 signaling induces regulatory T cells and promotes skin allograft survival. J Immunol 191:4447–4455PubMedPubMedCentralCrossRefGoogle Scholar
  242. Yeung MY, Najafian N, Sayegh MH (2014) Targeting CD28 to prevent transplant rejection. Expert Opin Ther Targets 18:225–242PubMedCrossRefPubMedCentralGoogle Scholar
  243. Yeung MY, Ding Q, Brooks CR, Xiao S, Workman CJ, Vignali DAA, Ueno T, Padera RF, Kuchroo VK, Najafian N, Rothstein DM (2015) TIM-1 signaling is required for maintenance and induction of regulatory B cells. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 15:942–953CrossRefGoogle Scholar
  244. 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, Senaldi G (1999) T-cell co-stimulation through B7RP-1 and ICOS. Nature 402:827–832CrossRefGoogle Scholar
  245. Yuan X, Salama AD, Dong V, Schmitt I, Najafian N, Chandraker A, Akiba H, Yagita H, Sayegh MH (2003) The role of the CD134-CD134 ligand costimulatory pathway in alloimmune responses in vivo. J Immunol 170:2949–2955PubMedCrossRefPubMedCentralGoogle Scholar
  246. Yuan X, Paez-Cortez J, Schmitt-Knosalla I, D’Addio F, Mfarrej B, Donnarumma M, Habicht A, Clarkson MR, Iacomini J, Glimcher LH, Sayegh MH, Ansari MJ (2008) A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med 205:3133–3144PubMedPubMedCentralCrossRefGoogle Scholar
  247. Yuan CL, Xu JF, Tong J, Yang H, He FR, Gong Q, Xiong P, Duan L, Fang M, Tan Z, Xu Y, Chen YF, Zheng F, Gong FL (2009a) B7-H4 transfection prolongs beta-cell graft survival. Transpl Immunol 21:143–149PubMedCrossRefPubMedCentralGoogle Scholar
  248. Yuan X, Ansari MJ, D’Addio F, Paez-Cortez J, Schmitt I, Donnarumma M, Boenisch O, Zhao X, Popoola J, Clarkson MR, Yagita H, Akiba H, Freeman GJ, Iacomini J, Turka LA, Glimcher LH, Sayegh MH (2009b) Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells. Proc Natl Acad Sci U S A 106:10734–10739PubMedPubMedCentralCrossRefGoogle Scholar
  249. Zaitsu M, Issa F, Hester J, Vanhove B, Wood KJ (2017) Selective blockade of CD28 on human T cells facilitates regulation of alloimmune responses. JCI Insight 2:pii: 89381CrossRefGoogle Scholar
  250. Zang X, Loke P, Kim J, Murphy K, Waitz R, Allison JP (2003) B7x: a widely expressed B7 family member that inhibits T cell activation. Proc Natl Acad Sci U S A 100:10388–10392PubMedPubMedCentralCrossRefGoogle Scholar
  251. Zhang G, Hou J, Shi J, Yu G, Lu B, Zhang X (2008) Soluble CD276 (B7-H3) is released from monocytes, dendritic cells and activated T cells and is detectable in normal human serum. Immunology 123:538–546PubMedPubMedCentralCrossRefGoogle Scholar
  252. Zhang T, Fresnay S, Welty E, Sangrampurkar N, Rybak E, Zhou H, Cheng XF, Feng Q, Avon C, Laaris A, Whitters M, Nagelin AM, O’Hara RM Jr, Azimzadeh AM (2011) Selective CD28 blockade attenuates acute and chronic rejection of murine cardiac allografts in a CTLA-4-dependent manner. Am J Transplant 11:1599–1609PubMedPubMedCentralCrossRefGoogle Scholar
  253. Zhang L, Wu H, Lu D, Li G, Sun C, Song H, Li J, Zhai T, Huang L, Hou C, Wang W, Zhou B, Chen S, Lu B, Zhang X (2013a) The costimulatory molecule B7-H4 promote tumor progression and cell proliferation through translocating into nucleus. Oncogene 32:5347–5358PubMedPubMedCentralCrossRefGoogle Scholar
  254. Zhang Y, Ji H, Shen X, Cai J, Gao F, Koenig KM, Batikian CM, Busuttil RW, Kupiec-Weglinski JW (2013b) Targeting TIM-1 on CD4 T cells depresses macrophage activation and overcomes ischemia-reperfusion injury in mouse orthotopic liver transplantation. Am J Transplant 13:56–66PubMedCrossRefPubMedCentralGoogle Scholar
  255. Zhang T, Pierson RN 3rd, Azimzadeh AM (2015) Update on CD40 and CD154 blockade in transplant models. Immunotherapy 7:899–911PubMedPubMedCentralCrossRefGoogle Scholar
  256. Zheng XX, Markees TG, Hancock WW, Li Y, Greiner DL, Li XC, Mordes JP, Sayegh MH, Rossini AA, Strom TB (1999) CTLA4 signals are required to optimally induce allograft tolerance with combined donor-specific transfusion and anti-CD154 monoclonal antibody treatment. J Immunol 162:4983–4990Google Scholar
  257. Zheng XX, Sanchez-Fueyo A, Sho M, Domenig C, Sayegh MH, Strom TB (2003) Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance. Immunity 19:503–514PubMedCrossRefPubMedCentralGoogle Scholar
  258. Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK (2005) The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 6:1245–1252PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Melissa Y. Yeung
    • 1
    • 2
    Email author
  • Tanja Grimmig
    • 3
  • Mohamed H. Sayegh
    • 1
    • 2
    • 4
  1. 1.Department of Medicine, Renal DivisionBrigham and Women’s HospitalBostonUSA
  2. 2.Harvard Medical SchoolBostonUSA
  3. 3.Department of Surgery, Molecular Oncology and ImmunologyUniversity of WuerzburgWuerzburgGermany
  4. 4.Department of Medicine and ImmunologyAmerican University of BeirutBeirutLebanon

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