Costimulatory Pathways in Kidney Transplantation: Pathogenetic Role, Clinical Significance and New Therapeutic Opportunities

REFERENCES

• Bretscher PA. A two-step: two-signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci USA 1999;96(1):185–190.
   PubMed Web of Science ®Google Scholar
• Schwartz RH. T cell anergy. Annu Rev Immunol 2003;21:305–334.
   PubMed Web of Science ®Google Scholar
• McGrath MM, Najafian N. The role of coinhibitory signaling pathways in transplantation and tolerance. Front Immunol 2012;3:47.
   Google Scholar
• Magee CN, Boenisch O, Najafian N. The role of costimulatory molecules in directing the functional differentiation of alloreactive T helper cells. Am J Transplant 2012;12(10):2588–600.
   PubMed Web of Science ®Google Scholar
• Yamada A, Salama AD, Sayegh MH. The role of novel T cell costimulatory pathways in autoimmunity and transplantation. J Am Soc Nephrol 2002;13(2):559–575.
   PubMed Web of Science ®Google Scholar
• Ansari MJ, Sayegh MH. Costimulation couture: a designer approach to regulating autoimmunity. J Clin Invest 2006;116(8):2080–2083.
   Google Scholar
• Ford ML, Larsen CP. Translating costimulation blockade to the clinic: lessons learned from three pathways. Immunol Rev 2009;229(1):294–306.
   PubMedGoogle Scholar
• Snanoudj R, Zuber J, Legendre C. Co-stimulation blockade as a new strategy in kidney transplantation: benefits and limits. Drugs 2010;70(16):2121–2131.
   Google Scholar
• Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 2005;23:515–548.
   PubMed Web of Science ®Google Scholar
• McAdam AJ, Schweitzer AN, Sharpe AH. The role of B7 co-stimulation in activation and differentiation of CD4+ and CD8+ T cells. Immunol Rev 1998;165:231–247.
   PubMed Web of Science ®Google Scholar
• Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol 2001;1(3):220–228.
   PubMed Web of Science ®Google Scholar
• Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 1995;182:459–465.
   PubMed Web of Science ®Google Scholar
• Linsley PS, Greene JL, Brady W, Human B7–1 (CD80) and B7–2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1994;1(9):793–801.
   PubMed Web of Science ®Google Scholar
• Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 2004;4:762.
   PubMed Web of Science ®Google Scholar
• Coyle AJ, Lehar S, Lloyd C, The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity 2000;13(1):95–105.
   PubMed Web of Science ®Google Scholar
• Yoshinaga SK, Whoriskey JS, Khare SD, T-cell co-stimulation through B7RP-1 and ICOS. Nature 1999;402(6763):827–832.
   PubMed Web of Science ®Google Scholar
• Freeman GJ, Long AJ, Iwai Y, Engagement of the PD-1 immuno-inhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192(7):1027–1034.
   PubMed Web of Science ®Google Scholar
• Yi KH, Chen L. Fine tuning the immune response through B7-H3 and B7-H4. Immunol Rev 2009;229(1):145–151.
   Google Scholar
• Croft M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat Rev Immunol 2003;3(8):609–620.
   PubMed Web of Science ®Google Scholar
• Ha H, Han D, Choi Y. TRAF-mediated TNFR-family signaling. Curr Protoc Immunol 2009;Chapter 11:Unit11 9D.
   PubMedGoogle Scholar
• Bishop GA. The multifaceted roles of TRAFs in the regulation of B-cell function. Nat Rev Immunol 2004;4:775–786.
   PubMed Web of Science ®Google Scholar
• van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc Biol 2000;67:2–17.
   PubMed Web of Science ®Google Scholar
• Mach F, Schonbeck U, Sukhova GK, Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci USA 1997;94:1931–1936.
   PubMed Web of Science ®Google Scholar
• Durie FH, Foy TM, Masters SR, The role of CD40 in the regulation of humoral and cell-mediated immunity. Immunol Today 1994;15:406–411.
   PubMedGoogle Scholar
• Klaus SJ, Berberich I, Shu G, Clark EA. CD40 and its ligand in the regulation of humoral immunity. Semin Immunol 1994;6:279–286.
   Google Scholar
• O'Sullivan B, Thomas R. CD40 and dendritic cell function. Crit Rev Immunol 2003;23:83–107.
   Google Scholar
• Acuto O, Michel F. CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol 2003;3(12):939–951.
   PubMed Web of Science ®Google Scholar
• Esposito P, Rampino T, Dal Canton A. Soluble CD40 as a modulator of CD40 pathway. Immunol Lett 2012;147(1–2):85–86.
   Google Scholar
• Stuber E, Neurath M, Calderhead D, Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells. Immunity 1995;2(5):507–521.
   Google Scholar
• Cooper D, Bansal-Pakala P, Croft M. 4–1BB (CD137) controls the clonal expansion and survival of CD8 T cells in vivo but does not contribute to the development of cytotoxicity. Eur J Immunol 2002;32:521–529.
   PubMed Web of Science ®Google Scholar
• Younes A, Consoli U, Zhao S, CD30 ligand is expressed on resting normal and malignant human B lymphocytes. Br J Haematol 1996;93(3):569–571.
   Google Scholar
• Mauri DN, Ebner R, Montgomery RI, LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 1998;8:21–30.
   PubMed Web of Science ®Google Scholar
• Nocentini G, Riccardi C. GITR: a modulator of immune response and inflammation. Adv Exp Med Biol 2009;647:156–173.
   PubMed Web of Science ®Google Scholar
• Bleijs DA, de Waal-Malefyt R, Figdor CG, van Kooyk Y. Co-stimulation of T cells results in distinct IL-10 and TNF-alpha cytokine profiles dependent on binding to ICAM-1, ICAM-2 or ICAM-3. Eur J Immunol 1999;29(7):2248–2258.
   Google Scholar
• Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992;69:11–25.
   PubMed Web of Science ®Google Scholar
• Arnaout MA. Structure and function of the leukocyte adhesion molecules CD11/CD18. Blood 1990;75:1037–1050.
   PubMed Web of Science ®Google Scholar
• Mami-Chouaib F, Franciszkiewicz K, Le Floc'h A, CD103 or LFA-1 engagement at the immune synapse between cytotoxic T cells and tumor cells promotes maturation and regulates T-cell effector functions. Cancer Res 2013;73:617–628.
   Google Scholar
• Kohlmeier JE, Chan MA, Benedict SH. Costimulation of naïve human CD4 T cells through intercellular adhesion molecule-1 promotes differentiation to a memory phenotype that is not strictly the result of multiple rounds of cell division. Immunology 2006;118(4):549–558.
   Google Scholar
• Varga G, Nippe N, Balkow S, LFA-1 contributes to signal I of T-cell activation and to the production of T(h)1 cytokines. J Invest Dermatol 2010;130(4):1005–1012.
   Google Scholar
• Springer TA, Dustin ML, Kishimoto TK, Marlin SD. The lymphocyte function-associated LFA-1, CD2, and LFA-3 molecules: cell adhesion receptors of the immune system. Annu Rev Immunol 1987;5:223–252.
   PubMed Web of Science ®Google Scholar
• Moingeon P, Chang HC, Wallner BP, CD2-mediated adhesion facilitates T lymphocyte antigen recognition function. Nature 1989;339(6222):312–314.
   Google Scholar
• Kuchroo VK, Umetsu DT, DeKruyff RH, Freeman GJ. The TIM gene family: emerging roles in immunity and disease. Nat Rev Immunol 2003;3:454–462.
   PubMed Web of Science ®Google Scholar
• de Souza AJ, Oriss TB, O'malley KJ, T cell Ig and mucin 1 (TIM-1) is expressed on in vivo-activated T cells and provides a costimulatory signal for T cell activation. Proc Natl Acad Sci USA 2005;102(47):17113–17118.
   Google Scholar
• Meyers JH, Chakravarti S, Schlesinger D, TIM-4 is the ligand for TIM-1, and the TIM-1-TIM-4 interaction regulates T cell proliferation. Nat Immunol 2005;6(5):455–464.
   Google Scholar
• Freeman GJ, Casasnovas JM, Umetsu DT, TIM genes: a family of cell surface phosphatidyl serine receptors that regulate innate and adaptive immunity. Immunol Rev 2010;235: 172–189.
   PubMedGoogle Scholar
• Anderson AC, Anderson DE, Bregoli L, Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 2007;318(5853):1141–1143.
   PubMed Web of Science ®Google Scholar
• Uchida Y, Ke B, Freitas MC T-cell immunoglobulin mucin-3 determines severity of liver ischemia/reperfusion injury in mice in a TLR4-dependent manner. Gastroenterology 2010;139(6):2195–2206.
   PubMed Web of Science ®Google Scholar
• Lim WH, Kireta S, Leedham E, Uremia impairs monocyte and monocyte-derived dendritic cell function in hemodialysis patients. Kidney Int 2000;72:1138–1148.
   Google Scholar
• Betjes MG. Immune cell dysfunction and inflammation in end-stage renal disease. Nat Rev Nephrol 2013;9(5):255–265.
   PubMed Web of Science ®Google Scholar
• Eleftheriadis T, Antoniadi G, Liakopoulos V, Disturbances of acquired immunity in hemodialysis patients. Semin Dial 2007;20:440–451.
   PubMed Web of Science ®Google Scholar
• Girndt M, Sester M, Sester U, Molecular aspects of T- and B-cell function in uremia. Kidney Int Suppl 2001;78:S206–S211.
   PubMedGoogle Scholar
• Girndt M, Sester M, Sester U, Defective expression of B7–2 (CD86) on monocytes of dialysis patients correlates to the uremia-associated immune defect. Kidney Int 2001;59(4):1382–1389.
   Google Scholar
• Schwabe RF, Engelmann H, Hess S, Fricke H. Soluble CD40 in the serum of healthy donors, patients with chronic renal failure, haemodialysis and chronic ambulatory peritoneal dialysis (CAPD) patients. Clin Exp Immunol 1999;117:153–158.
   PubMed Web of Science ®Google Scholar
• Esposito P, Gabanti E, Bianzina S, CD40/SCD40 imbalance in hemodialysis patients. Clin Biochem 2011;44(2–3):268–269.
   Google Scholar
• Esposito P, Rampino T, Gregorini M, Mechanisms underlying sCD40 production in hemodialysis patients. Cell Immunol 2012;278(1–2):10–15.
   Google Scholar
• Contin C, Lacraz A, de Précigout V. Potential role of the soluble form of CD40 in deficient immunological function of dialysis patients: new findings of its amelioration using polymethylmethacrylate (PMMA) membrane. NDT Plus 2010;3:i20–i27.
   Google Scholar
• Nakao K, Nagake Y, Okamoto A, Serum levels of soluble CD26 and CD30 in patients on hemodialysis. Nephron 2002;91(2):215–221.
   Google Scholar
• Wood KJ, Bushell A, Hester J. Regulatory immune cells in transplantation. Nat Rev Immunol 2012;12(6):417–430.
   PubMed Web of Science ®Google Scholar
• Zhu J, Paul WE. Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev 2010;238(1):247–262. doi: 10.1111/j.1600-065X.2010.00951.x. Review. Erratum in: Immunol Rev. 2011;240(1):317.
   PubMed Web of Science ®Google Scholar
• Li XC, Rothstein DM, Sayegh MH. Costimulatory pathways in transplantation: challenges and new developments. Immunol Rev 2009;229(1):271–293.
   PubMedGoogle Scholar
• Rulifson IC, Sperling AI, Fields PE, CD28 costimulation promotes the production of Th2 cytokines. J Immunol 1997;158:658–665.
   PubMed Web of Science ®Google Scholar
• Tao X, Constant S, Jorritsma P, Bottomly K. Strength of TCR signal determines the costimulatory requirements for Th1 and Th2 CD4+ T cell differentiation. J Immunol 1997;159:5956–5963.
   PubMed Web of Science ®Google Scholar
• Wing K, Onishi Y, Prieto-Martin P, CTLA-4 control over Foxp3+ regulatory Tcell function. Science 2008; 322:271–275.
   PubMed Web of Science ®Google Scholar
• Zhang R, Huynh A, Whitcher G, An obligate cell-intrinsic function for CD28 in Tregs. J Clin Invest 2013; 123(2):580–593.
   PubMed Web of Science ®Google Scholar
• Sandner SE, Clarkson MR, Salama AD, Role of the programmed death-1 pathway in regulation of alloimmune responses in vivo. J Immunol 2005;174:3408–3415.
   PubMed Web of Science ®Google Scholar
• Francisco LM, Salinas VH, Brown KE, PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 2009;206:3015–3029.
   PubMed Web of Science ®Google Scholar
• Ozkaynak E, Wang L, Goodearl A, Programmed death-1 targeting can promote allograft survival. J Immunol 2002;169(11):6546–6553.
   PubMed Web of Science ®Google Scholar
• Hutloff A, Dittrich AM, Beier KC, ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 1999;397(6716):263–266.
   PubMed Web of Science ®Google Scholar
• Megiovanni AM, Sanchez F, Gluckman JC, Rosenzwajg M. Double-stranded RNA stimulation or CD40 ligation of monocyte-derived dendritic cells as models to study their activation and maturation process. Eur Cytokine Netw 2004;15(2):126–134.
   Google Scholar
• Chan KW, Hopke CD, Krams SM, Martinez OM. CD30 expression identifies the predominant proliferating T lymphocyte population in human alloimmune responses. J Immunol 2002;169:1784–1791.
   Google Scholar
• Lane P. Role of OX40 signals in coordinating CD4 T cell selection, migration, and cytokine differentiation in Th1 and Th2 cells. J Exp Med 2000;191:201–205.
   PubMed Web of Science ®Google Scholar
• Luksch CR, Winqvist O, Ozaki ME, Intercellular adhesion molecule-1 inhibits interleukin 4 production by naive T cells. Proc Natl Acad Sci USA 1999;96:3023–3028.
   PubMedGoogle Scholar
• Hagness M, Henjum K, Landskron J, Kinetics and activation requirements of contact-dependent immune suppression by human regulatory T cells. J Immunol 2012;188(11):5459–5466.
   Google Scholar
• Yeung MY, McGrath M, Najafian N. The emerging role of the TIM molecules in transplantation. Am J Transplant 2011;11(10):2012–2019.
   Google Scholar
• Xiao S, Najafian N, Reddy J, Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function. J Exp Med 2007;204:1691–1702.
   PubMedGoogle Scholar
• Wang F, He W, Yuan J, Activation of Tim-3-galectin-9 pathway improves survival of fully allogeneic skin grafts. Transpl Immunol 2008;19(1):12–19.
   Google Scholar
• Biancone L, Segoloni G, Turello E, Expression of inducible lymphocyte costimulatory molecules in human renal allograft. Nephrol Dial Transplant 1998;13(3):716–722.
   Google Scholar
• Gaweco AS, Mitchell BL, Lucas BA, McClatchey KD. Van Thiel DH. CD40 expression on graft infiltrates and parenchymal CD154 (CD40L) induction in human chronic renal allograft rejection. Kidney Int 1999;55(4):1543–1552.
   Google Scholar
• Kosmaczewska A, Magott-Procelewska M, Frydecka I, CD40L, CD28, and CTLA-4 expression on CD4+ T cells in kidney graft recipients: a relationship with post-transplantation clinical course. Transpl Immunol 2006;16(1):32–40.
   Google Scholar
• Kato M, Matsuguchi T, Ono Y, Characterization of CD28(-)CD4(+) T cells in living kidney transplant patients with long-term allograft acceptance. Hum Immunol 2001;62(12):1335–1345.
   Google Scholar
• Alvarez CM, Paris SC, Arango L, Kidney transplant patients with long-term graft survival have altered expression of molecules associated with T-cell activation. Transplantation 2004;78(10):1541–1547.
   Google Scholar
• Kato M, Ono Y, Kinukawa T, Long time follow up of CD28- CD4 +T cells in living kidney transplant patients. Clin Transplant 2004;18(3):242–246.
   Google Scholar
• Baeten D, Louis S, Braud C, Phenotypically and functionally distinct CD8+ lymphocyte populations in long-term drug-free tolerance and chronic rejection in human kidney graft recipients. J Am Soc Nephrol 2006;17(1):294–304.
   PubMed Web of Science ®Google Scholar
• Giaretta F, Bussolino S, Beltramo S, Different regulatory and cytotoxic CD4(+) T lymphocyte profiles in renal transplants with antibody-mediated chronic rejection or long-term good graft function. Transpl Immunol 2013;28(1):48–56.
   PubMed Web of Science ®Google Scholar
• Haimila K, Turpeinen H, Alakulppi NS, Association of genetic variation in inducible costimulator gene with outcome of kidney transplantation. Transplantation 2009;87(3):393–396.
   PubMedGoogle Scholar
• Wang YL, Fu YX, Zhu ZJ, OX40 mRNA in peripheral blood as a biomarker of acute renal allograft rejection. Chin Med J (Engl) 2012;125(21):3786–3790.
   PubMed Web of Science ®Google Scholar
• Billing H, Sander A, Süsal C, Soluble CD30 and ELISA-detected human leukocyte antigen antibodies for the prediction of acute rejection in pediatric renal transplant recipients. Transpl Int 2013;26(3):331–338.
   Google Scholar
• Afaneh C, Muthukumar T, Lubetzky M, Urinary cell levels of mRNA for OX40, OX40L, PD-1, PD-L1, or PD-L2 and acute rejection of human renal allografts. Transplantation 2010;90(12):1381–1387.
   Google Scholar
• Manfro RC, Aquino-Dias EC, Joelsons G, Non invasive Tim-3 messenger RNA evaluation in renal transplant recipients with graft dysfunction. Transplantation 2008;86:1869–1874.
   Google Scholar
• Ho J, Wiebe C, Gibson IW, Immune monitoring of kidney allografts. Am J Kidney Dis 2012; 60(4):629–640.
   Google Scholar
• Pilat N, Schwarz C, Wekerle T. Modulating T-cell costimulation as new immunosuppressive concept in organ transplantation. Curr Opin Organ Transplant 2012;17(4):368–375.
   Google Scholar
• Poirier N, Blancho G, Vanhove B. A more selective costimulatory blockade of the CD28-B7 pathway. Transpl Int 2011;24(1):2–11.
   PubMed Web of Science ®Google Scholar
• Vincenti F. What's in the pipeline? New immunosuppressive drugs in transplantation. Am J Transplant 2002;2:898–903.
   PubMed Web of Science ®Google Scholar
• Poirier N, Azimzadeh AM, Zhang T, Inducing CTLA-4-dependent immune regulation by selective CD28 blockade promotes regulatory T cells in organ transplantation. Sci Transl Med 2010;2:17ra0.
   Web of Science ®Google Scholar
• Yu XZ, Albert MH, Martin PJ, Anasetti C. CD28 ligation induces transplantation tolerance by IFNgamma-dependent depletion of T cells that recognize alloantigens. J Clin Invest 2004;113:1624–1630.
   Google Scholar
• Lühder F, Huang Y, Dennehy KM, Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists. J Exp Med 2003;197(8):955–966.
   PubMed Web of Science ®Google Scholar
• Suntharalingam G, Perry MR, Ward S, Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006;355:1018–1028.
   PubMed Web of Science ®Google Scholar
• Eastwood D, Findlay L, Poole S, Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells. Br J Pharmacol 2010;161(3):512–526.
   PubMed Web of Science ®Google Scholar
• Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 2001;19:225–252.
   PubMed Web of Science ®Google Scholar
• Sayegh MH, Akalin E, Hancock WW, CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2. J Exp Med 1995;181:1869–1874.
   PubMed Web of Science ®Google Scholar
• Larsen CP, Pearson TC, Adams AB, Rational development of LEA29Y (belatacept): a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant 2005;5(3):443–453.
   PubMed Web of Science ®Google Scholar
• Wekerle T, Grinyo JM. Belatacept: from rational design to clinical application. Transpl Int 2012;25:139–150.
   PubMed Web of Science ®Google Scholar
• Wojciechowski D, Vincenti F. Challenges and opportunities in targeting the costimulation pathway in solid organ transplantation. Semin Immunol 2011;23(3):157–164.
   Google Scholar
• Vincenti F, Larsen C, Durrbach A, Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005;353:770–781.
   PubMed Web of Science ®Google Scholar
• Vincenti F, Charpentier B, Vanrenterghem Y, A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant 2010;10:535–546.
   PubMed Web of Science ®Google Scholar
• Durrbach A, Pestana JM, Pearson T, A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant 2010;10:547–557.
   PubMed Web of Science ®Google Scholar
• Vanrenterghem Y, Bresnahan B, Campistol J, Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation 2011;91(9):976–983.
   PubMed Web of Science ®Google Scholar
• Pilat N, Wekerle T. Belatacept and Tregs: friends or foes? Immunotherapy 2012;4:351–354.
   Google Scholar
• Bouguermouh S, Fortin G, Baba N, CD28 co-stimulation down regulates Th17 development. PloS One 2009;4:e5087.
   PubMed Web of Science ®Google Scholar
• Su VC, Harrison J, Rogers C, Ensom MH. Belatacept: a new biologic and its role in kidney transplantation. Ann Pharmacother 2012;46(1):57–67.
   Google Scholar
• Rizvi M, Pathak D, Freedman JE, Chakrabarti S. CD40-CD40 ligand interactions in oxidative stress, inflammation and vascular disease. Trends Mol Med 2008;14(12):530–538.
   Google Scholar
• Geraldes P, Gagnon S, Hadjadj S, Estradiol blocks the induction of CD40 and CD40L expression on endothelial cells and prevents neutrophil adhesion: an ERalpha-mediated pathway. Cardiovasc Res 2006;71(3):566–573.
   Google Scholar
• Kirk A, Burkly L, Batty D, Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med 1999;5:686–693.
   PubMed Web of Science ®Google Scholar
• Kawai T, Andrews D, Colvin RB, Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 2000;6:114.
   Web of Science ®Google Scholar
• Andre P, Prasad KS, Denis CV, CD40L stabilizes arterial thrombi by a beta3 integral-dependent mechanism. Nat Med 2002;8:247–252.
   PubMed Web of Science ®Google Scholar
• Pearson TC, Trambley J, Odom K, Anti-CD40 therapy extends renal allograft survival in rhesus macaques. Transplantation 2002;74:933–940.
   PubMed Web of Science ®Google Scholar
• Aoyagi T, Yamashita K, Suzuki T, A human anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys: induction and maintenance therapy. Am J Transplant 2009;9:1732–1741.
   PubMed Web of Science ®Google Scholar
• Goldwater R, Keirns J, Blahunka P, A phase 1, randomized ascending single-dose study of antagonist anti-human CD40 ASKP1240 in healthy subjects. Am J Transplant 2013;13(4):1040–1046.
   PubMed Web of Science ®Google Scholar
• Adams AB, Shirasugi N, Jones TR, Development of a chimeric anti-CD40 monoclonal antibody that synergizes with LEA29Y to prolong islet allograft survival. J Immunol 2005;174(1):542–550.
   PubMed Web of Science ®Google Scholar
• Gilson CR, Milas Z, Gangappa S, Anti-CD40 monoclonal antibody synergizes with CTLA4-Ig in promoting long-term graft survival in murine models of transplantation. J Immunol 2009;183(3):1625–1635.
   PubMed Web of Science ®Google Scholar
• Ripoll E, Pluvinet R, Torras J, In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection. Gene Ther 2011;18(10):945–952.
   PubMed Web of Science ®Google Scholar
• Sanders ME, Makgoba MW, Sharrow SO, Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-gamma production. J Immunol 1988;140:1401–1407.
   PubMed Web of Science ®Google Scholar
• Nicolls MR, Coulombe M, Beilke J, CD4-dependent generation of dominant transplantation tolerance induced by simultaneous perturbation of CD154 and LFA-1 pathways. J Immunol 2002;169:4831–4839.
   PubMed Web of Science ®Google Scholar
• Kitchens WH, Haridas D, Wagener ME, Integrin antagonists prevent costimulatory blockade-resistant transplant rejection by CD8(+) memory T cells. Am J Transplant 2012;12:69–80.
   PubMed Web of Science ®Google Scholar
• Vincenti F, Mendez R, Pescovitz M, A phase I/II randomized open-label multicenter trial of efalizumab, a humanized anti-CD11a, anti-LFA-1 in renal transplantation. Am J Transplant 2007;7:1770–1777.
   PubMed Web of Science ®Google Scholar
• Major EO. Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Annu Rev Med 2010;61:35–47.
   PubMed Web of Science ®Google Scholar
• Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001;345:248–255.
   PubMed Web of Science ®Google Scholar
• Rostaing L, Mourad M, Charpentier B, Efficacy and Safety of alefacept in combination with tacrolimus, mycophenolate mofetil and steroids in de novo kidney transplantation [Abstract]. Am J Transplant 2011;11(Suppl 2):98.
   Google Scholar
• Bromberg JS, Cibrik D, Steinberg S, A Phase 2 Study to Assess the Safety and Efficacy of Alefacept (ALEF) in De Novo Kidney Transplant Recipients [Abstract]. Am J Transplant 2011;11(Suppl 2):190.
   Google Scholar
• Ueno T, Habicht A, Clarkson MR The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model. J Clin Invest 2008;118(2):742–751.
   Google Scholar
• Wang F, He W, Yuan J, Activation of Tim-3-galectin-9 pathway improves survival of fully allogeneic skin grafts. Transpl Immunol 2008;19:12–19.
   PubMed Web of Science ®Google Scholar
• He W, Fang Z, Wang F, Galectin-9 significantly prolongs the survival of fully mismatched cardiac allografts in mice. Transplantation 2009;88:782–790.
   Google Scholar
• Chapman JR, O'Connell PJ, Nankivell BJ. Chronic renal allograft dysfunction. J Am Soc Nephrol 2005;16(10):3015–3026.
   PubMed Web of Science ®Google Scholar
• Ojo AO, Hanson JA, Wolfe RA, Long-term survival in renal transplant recipients with graft function. Kidney Int 2000;57:307–313.
   PubMed Web of Science ®Google Scholar
• Stoll G, Bendszus M. Inflammation and atherosclerosis: novel insights into plaque formation and destabilization. Stroke 2006;37(7):1923–1932.
   PubMed Web of Science ®Google Scholar
• Andersson J, Libby P, Hansson GK. Adaptive immunity and atherosclerosis. Clin Immunol 2010;134:33–46.
   PubMed Web of Science ®Google Scholar
• Hartvigsen K, Chou MY, Hansen LF, The role of innate immunity in atherogenesis. J Lipid Res 2009;50(Suppl):S388–S393.
   Google Scholar
• Antunes RF, Kaski JC, Dumitriu IE. The role of costimulatory receptors of the tumour necrosis factor receptor family in atherosclerosis. J Biomed Biotechnol 2012;2012:464532.
   Google Scholar
• Gerdes N, Zirlik A. Co-stimulatory molecules in and beyond co-stimulation –tipping the balance in atherosclerosis? Thromb Haemost 2011;106(5):804–813.
   Google Scholar
• Dopheide JF, Sester U, Schlitt A, Monocyte-derived dendritic cells of patients with coronary artery disease show an increased expression of costimulatory molecules CD40, CD80 and CD86 in vitro. Coron Artery Dis 2007;18:523–531.
   Google Scholar
• Lee J, Zhuang Y, Wei X, Contributions of PD-1/PD-L1 pathway to interactions of myeloid DCs with T cells in atherosclerosis. J Mol Cell Cardiol 2009;46:169–176.
   PubMed Web of Science ®Google Scholar
• Danese S, de la Motte C, Reyes BM, Cutting edge: T cells trigger CD40-dependent platelet activation and granular RANTES release: a novel pathway for immune response amplification. J Immunol 2004;172:2011–2015.
   PubMed Web of Science ®Google Scholar
• Lievens D, Zernecke A, Seijkens T, Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood 2010;116(20):4317–27.
   PubMed Web of Science ®Google Scholar
• Schonbeck U, Libby P. CD40 signaling and plaque instability. Circ Res 2001;89:1092–103.
   PubMed Web of Science ®Google Scholar
• Antoniades C, Bakogiannis C, Tousoulis D, The CD40/CD40 ligand system: linking inflammation with atherothrombosis. J Am Coll Cardiol 2009;54:669–677.
   PubMed Web of Science ®Google Scholar
• Heeschen C, Dimmeler S, Hamm CW, Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003:348:1104–1111.
   PubMed Web of Science ®Google Scholar
• Harding SA, Sommerfield AJ, Sarma J Increased CD40 ligand and platelet–monocyte aggregates in patients with type 1 diabetes mellitus. Atherosclerosis 2004;176:321–325.
   PubMed Web of Science ®Google Scholar
• Djamali A, Pietrangeli CE, Gordon RD, Legendre C. Potential of emerging immunosuppressive strategies to improve the posttransplant cardiovascular risk profile. Kidney Int Suppl 2010;(118):S15–S21.
   Google Scholar
• Birsan T, Hausen B, Higgins JP, Treatment with humanized monoclonal antibodies against CD80 and CD86 combined with sirolimus prolongs renal allograft survival in cynomolgus monkeys. Transplantation 2003;75:2106–2113.
   PubMed Web of Science ®Google Scholar
• Laskowski IA, Pratschke J, Wilhelm MJ, Anti-CD28 monoclonal antibody therapy prevents chronic rejection of renal allografts in rats. J Am Soc Nephrol 2002;13:519.
   Google Scholar
• Azuma H, Isaka Y, Li X, Superagonistic CD28 antibody induces donor-specific tolerance in rat renal allografts. Am J Transplant 2008;8:2004.
   PubMed Web of Science ®Google Scholar
• Linsley PS, Nadler SG. The clinical utility of inhibiting CD28-mediated costimulation. Immunol Rev 2009;229:307–321.
   PubMed Web of Science ®Google Scholar
• Sidiropoulos PI, Boumpas DT. Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus 2004;13(5):391–397.
   PubMed Web of Science ®Google Scholar