title: The blockade of T-cell co-stimulation as a therapeutic stratagem for immunosuppression: Focus on belatacept.
abstract: The development of immunosuppressive drugs has in recent years been focused on prevention of acute rejection. This has led to an increase in one-year allograft survival. However, these drugs have non-immune effects which contribute to the high incidence of late graft loss, as a consequence of chronic allograft nephropathy, and the death of patients. As an immune-specific alternative to conventional immunosuppressants, new biotechnology tools have been developed; they target the costimulation signal of T-cell activation, particularly by the "classical" B7/CD28 and CD40/CD40L pathways. Here, we review the limitations of current immunosuppressive protocols, the benefits of classical B7/CD28 costimulation blockade, and the first large-scale clinical application of this strategy to human transplantation with belatacept. We will also consider novel costimulatory molecules of the B7/CD28 and TNF/TNF-R families, which appear to be important for the functions of memory and effector T-cells.
authors.affiliation: Service de Néphrologie et Transplantation Rénale, Hôpital du Kremlin Bicêtre, Assistance Publique Hôpitaux de Paris; Le Kremlin-Bicêtre; France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Snanoudj
authors.forename: Carlos
authors.initials: C
authors.lastname: Frangié
authors.forename: Benjamin
authors.initials: B
authors.lastname: Deroure
authors.forename: Hélène
authors.initials: H
authors.lastname: François
authors.forename: Caroline
authors.initials: C
authors.lastname: Créput
authors.forename: Séverine
authors.initials: S
authors.lastname: Beaudreuil
authors.forename: Antoine
authors.initials: A
authors.lastname: Dürrbach
authors.forename: Bernard
authors.initials: B
authors.lastname: Charpentier
references.citation: Am J Transplant. 2007 Mar;7(3):560-70
references.pmid: 17229079
references.citation: N Engl J Med. 2003 Dec 11;349(24):2326-33
references.pmid: 14668458
references.citation: Transplantation. 2001 Nov 15;72(9):1473-8
references.pmid: 11707732
references.citation: Transplantation. 1996 Oct 15;62(7):1029-30
references.pmid: 8878401
references.citation: Am J Transplant. 2004 Mar;4(3):438-43
references.pmid: 14961999
references.citation: Nat Immunol. 2005 Apr;6(4):338-44
references.pmid: 15785759
references.citation: J Immunol. 2000 Jan 1;164(1):265-72
references.pmid: 10605020
references.citation: Arthritis Rheum. 2002 Jun;46(6):1470-9
references.pmid: 12115176
references.citation: Am J Transplant. 2002 Jul;2(6):501-9
references.pmid: 12118893
references.citation: Curr Opin Immunol. 1997 Jun;9(3):330-7
references.pmid: 9203418
references.citation: J Immunol. 2001 Jul 1;167(1):140-6
references.pmid: 11418642
references.citation: Immunity. 2000 Jul;13(1):95-105
references.pmid: 10933398
references.citation: J Immunol. 1999 Feb 15;162(4):1947-51
references.pmid: 9973463
references.citation: Transplantation. 2002 Oct 27;74(8):1192-4
references.pmid: 12438971
references.citation: N Engl J Med. 2002 Feb 21;346(8):580-90
references.pmid: 11856798
references.citation: Immunity. 1994 Dec;1(9):793-801
references.pmid: 7534620
references.citation: Transplantation. 2005 Feb 15;79(3 Suppl):S33-6
references.pmid: 15699745
references.citation: Nat Med. 2002 Mar;8(3):247-52
references.pmid: 11875495
references.citation: Nat Immunol. 2002 Nov;3(11):1097-101
references.pmid: 12368911
references.citation: Transplantation. 1997 Dec 27;64(12):1646-50
references.pmid: 9422396
references.citation: N Engl J Med. 2000 Oct 5;343(14):1020-34
references.pmid: 11018170
references.citation: N Engl J Med. 2005 Aug 25;353(8):770-81
references.pmid: 16120857
references.citation: Transplantation. 2000 Jun 27;69(12):2609-12
references.pmid: 10910284
references.citation: Nat Immunol. 2001 Dec;2(12):1159-66
references.pmid: 11713465
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13230-5
references.pmid: 16150717
references.citation: Nature. 1996 May 30;381(6581):434-8
references.pmid: 8632801
references.citation: Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8789-94
references.pmid: 9238056
references.citation: J Clin Invest. 2005 Jul;115(7):1896-902
references.pmid: 15951837
references.citation: J Immunol. 2002 Oct 1;169(7):3744-51
references.pmid: 12244168
references.citation: Transplantation. 2001 Sep 27;72(6):1128-37
references.pmid: 11579312
references.citation: J Immunol. 2005 Nov 1;175(9):5774-82
references.pmid: 16237069
references.citation: Transplantation. 1998 Jun 15;65(11):1422-8
references.pmid: 9645796
references.citation: Am J Transplant. 2002 Sep;2(8):701-11
references.pmid: 12243491
references.citation: J Immunol. 2005 Jun 1;174(11):6648-56
references.pmid: 15905503
references.citation: Transpl Immunol. 2004 Sep-Oct;13(2):87-99
references.pmid: 15380539
references.citation: N Engl J Med. 2000 Mar 2;342(9):605-12
references.pmid: 10699159
references.citation: Nat Med. 1999 Jun;5(6):686-93
references.pmid: 10371508
references.citation: Nat Med. 1999 Nov;5(11):1298-302
references.pmid: 10545997
references.citation: Nat Rev Immunol. 2006 Sep;6(9):671-81
references.pmid: 16932752
references.citation: Transplantation. 2007 Mar 15;83(5):663-7
references.pmid: 17353791
references.citation: Science. 1992 Aug 7;257(5071):789-92
references.pmid: 1323143
references.citation: Am J Transplant. 2004 Aug;4(8):1289-95
references.pmid: 15268730
references.citation: Science. 1990 Jun 15;248(4961):1349-56
references.pmid: 2113314
references.citation: Transplantation. 2005 Oct 15;80(7):883-9
references.pmid: 16249734
references.citation: Immunol Res. 1996;15(1):38-49
references.pmid: 8739564
references.citation: Annu Rev Immunol. 2005;23:515-48
references.pmid: 15771580
references.citation: Am J Transplant. 2007 Mar;7(3):495-6
references.pmid: 17286614
references.citation: J Immunol. 2002 Jun 1;168(11):5558-65
references.pmid: 12023351
references.citation: Nat Rev Immunol. 2003 Aug;3(8):609-20
references.pmid: 12974476
references.citation: J Exp Med. 1995 May 1;181(5):1869-74
references.pmid: 7536798
references.citation: Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9560-4
references.pmid: 7568172
references.citation: J Immunol. 2001 Jan 1;166(1):322-9
references.pmid: 11123308
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13967-72
references.pmid: 8943044
references.citation: Science. 1994 Jun 10;264(5165):1587-9
references.pmid: 8202711
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10398-403
references.pmid: 15235129
references.citation: J Immunol. 2005 Jan 1;174(1):542-50
references.pmid: 15611281
references.citation: Transplantation. 1999 Oct 27;68(8):1200-3
references.pmid: 10551652
references.citation: Am J Transplant. 2002 Nov;2(10):898-903
references.pmid: 12482141
references.citation: Am J Transplant. 2005 Mar;5(3):443-53
references.pmid: 15707398
references.citation: N Engl J Med. 2005 Dec 1;353(22):2342-51
references.pmid: 16319383
references.citation: J Clin Invest. 1999 Dec;104(12):1715-22
references.pmid: 10606625
references.citation: J Clin Invest. 1999 May;103(9):1243-52
references.pmid: 10225967
references.citation: Lancet. 1999 Mar 27;353(9158):1083-91
references.pmid: 10199367
references.citation: Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):11102-5
references.pmid: 1332070
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12439-44
references.pmid: 8901600
references.citation: Am J Transplant. 2006;6(5 Pt 2):1153-69
references.pmid: 16613593
references.citation: N Engl J Med. 2004 Dec 23;351(26):2715-29
references.pmid: 15616206
references.citation: Transplantation. 1997 Dec 27;64(12):1641-5
references.pmid: 9422395
references.citation: Nat Immunol. 2002 Nov;3(11):1056-7
references.pmid: 12407416
references.citation: N Engl J Med. 2003 Nov 13;349(20):1907-15
references.pmid: 14614165
references.citation: N Engl J Med. 1999 Jun 3;340(22):1704-14
references.pmid: 10352162
references.citation: Transpl Immunol. 2007 Jun;17(4):243-8
references.pmid: 17493526
references.citation: Nat Med. 2000 Feb;6(2):114
references.pmid: 10655073
references.citation: J Immunol. 2002 Feb 1;168(3):1080-6
references.pmid: 11801641
references.citation: J Immunol. 1997 Aug 15;159(4):1711-7
references.pmid: 9257832