Volume 12 Issue 3
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Sun He, Sun Yini, Cheng Ying. Belatacept: a new weapon in anti-rejection battlefield[J]. ORGAN TRANSPLANTATION, 2021, 12(3): 280-287. doi: 10.3969/j.issn.1674-7445.2021.03.005
Citation: Sun He, Sun Yini, Cheng Ying. Belatacept: a new weapon in anti-rejection battlefield[J]. ORGAN TRANSPLANTATION, 2021, 12(3): 280-287. doi: 10.3969/j.issn.1674-7445.2021.03.005
shu

Belatacept: a new weapon in anti-rejection battlefield

doi: 10.3969/j.issn.1674-7445.2021.03.005

  • Department of Organ Transplantation and Hepatobiliary Surgery, the First Hospital of China Medical University, Shenyang 110001, China

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  • Corresponding author: Cheng Ying, Email: chengying75@sina.com
  • Received Date: 2021-01-11
    Available Online: 2021-05-19
  • Publish Date: 2021-05-15
    Abstract
  • As a co-stimulatory blocker against CD28 receptor, belatacept has been approved and applied to the treatment of rejection in organ transplantation in Europe and America. Belatacept has been proven to outperform calcineurin inhibitor (CNI) in improving the long-term survival rate of recipients and grafts, and enhancing graft function. Nevertheless, it might cause a high incidence of rejection. To resolve this issue, transplant workers have attempted to optimize belatacept immunosuppressive regimen and achieved good clinical efficacy. Although belatacept has been proven to exert poor effect on memory T cells, it has potential value in exploring new co-stimulatory molecular targets to optimize immunosuppressive regimes due to its specificity for immune cells and mild adverse effects. In this article, the advent of co-stimulatory blocker, clinical efficacy and application of belatacept, and the causes of belatacept-resistant rejection were reviewed.

     

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  • [1]
    Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients[J]. Am J Transplant, 2009, 9(Suppl 3): S1-S155. DOI: 10.1111/j.1600-6143.2009.02834.x.
    [2]
    HART A, SMITH JM, SKEANS MA, et al. OPTN/SRTR 2015 Annual Data Report: Kidney[J]. Am J Transplant, 2017, 17(Suppl 1): 21-116. DOI: 10.1111/ajt.14124.
    [3]
    MEIER-KRIESCHE HU, SCHOLD JD, SRINIVAS TR, et al. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era[J]. Am J Transplant, 2004, 4(3): 378-383. DOI: 10.1111/j.1600-6143.2004.00332.x.
    [4]
    HAMRAHIAN SM, FÜLÖP T. Hyperkalemia and hypertension post organ transplantation - a management challenge[J]. Am J Med Sci, 2021, 361(1): 106-110. DOI: 10.1016/j.amjms.2020.06.021.
    [5]
    GUETA I, MARKOVITS N, YARDEN-BILAVSKY H, et al. High tacrolimus trough level variability is associated with rejections after heart transplant[J]. Am J Transplant, 2018, 18(10): 2571-2578. DOI: 10.1111/ajt.15016.
    [6]
    JENNINGS DL, BOHN B, ZUVER A, et al. Gut microbial diversity, inflammation, and oxidative stress are associated with tacrolimus dosing requirements early after heart transplantation[J]. PLoS One, 2020, 15(5): e0233646. DOI: 10.1371/journal.pone.0233646.
    [7]
    CASTEDAL M, SKOGLUND C, AXELSON C, et al. Steroid-free immunosuppression with low-dose tacrolimus is safe and significantly reduces the incidence of new-onset diabetes mellitus following liver transplantation[J]. Scand J Gastroenterol, 2018, 53(6): 741-747. DOI: 10.1080/00365521.2018.1463390.
    [8]
    SHRESTHA BM. Two decades of tacrolimus in renal transplant: basic science and clinical evidences[J]. Exp Clin Transplant, 2017, 15(1): 1-9. DOI: 10.6002/ect.2016.0157.
    [9]
    JOUVE T, NOBLE J, ROSTAING L, et al. An update on the safety of tacrolimus in kidney transplant recipients, with a focus on tacrolimus minimization[J]. Expert Opin Drug Saf, 2019, 18(4): 285-294. DOI: 10.1080/14740338.2019.1599858.
    [10]
    OBERBAUER R, BESTARD O, FURIAN L, et al. Optimization of tacrolimus in kidney transplantation: new pharmacokinetic perspectives[J]. Transplant Rev (Orlando), 2020, 34(2): 100531. DOI: 10.1016/j.trre.2020.100531.
    [11]
    JENKINS MK, SCHWARTZ RH. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo[J]. J Exp Med, 1987, 165(2): 302-319. DOI: 10.1084/jem.165.2.302.
    [12]
    SHARMA P, WAGNER K, WOLCHOK JD, et al. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps[J]. Nat Rev Cancer, 2011, 11(11): 805-812. DOI: 10.1038/nrc3153.
    [13]
    LARSEN CP, ELWOOD ET, ALEXANDER DZ, et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways[J]. Nature, 1996, 381(6581): 434-438. DOI: 10.1038/381434a0.
    [14]
    PARDOLL DM. The blockade of immune checkpoints in cancer immunotherapy[J]. Nat Rev Cancer, 2012, 12(4): 252-264. DOI: 10.1038/nrc3239.
    [15]
    FORD ML. T cell cosignaling molecules in transplantation[J]. Immunity, 2016, 44(5): 1020-1033. DOI: 10.1016/j.immuni.2016.04.012.
    [16]
    JUNE CH, LEDBETTER JA, LINSLEY PS, et al. Role of the CD28 receptor in T-cell activation[J]. Immunol Today, 1990, 11(6): 211-216. DOI: 10.1016/0167-5699(90)90085-n.
    [17]
    WEKERLE T. T cell subsets predicting belatacept-resistant rejection: finding the root where the trouble starts[J]. Am J Transplant, 2017, 17(9): 2235-2237. DOI: 10.1111/ajt.14390.
    [18]
    CASTRO-ROJAS CM, ALLOWAY RR, WOODLE ES, et al. High dimensional renal profiling: towards a better understanding or renal transplant immune suppression[J]. Curr Transplant Rep, 2019, 6(1): 60-68. DOI: 10.1007/s40472-019-0225-1.
    [19]
    KHAILAIE S, ROWSHANRAVAN B, ROBERT PA, et al. Characterization of CTLA4 trafficking and implications for its function[J]. Biophys J, 2018, 115(7): 1330-1343. DOI: 10.1016/j.bpj.2018.08.020.
    [20]
    VINCENTI F, LARSEN C, DURRBACH A, et al. Costimulation blockade with belatacept in renal transplantation[J]. N Engl J Med, 2005, 353(8): 770-781. DOI: 10.1056/NEJMoa050085.
    [21]
    VINCENTI F, CHARPENTIER B, VANRENTERGHEM Y, et al. A phase Ⅲ study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study)[J]. Am J Transplant, 2010, 10(3): 535-546. DOI: 10.1111/j.1600-6143.2009.03005.x.
    [22]
    VINCENTI F, LARSEN CP, ALBERU J, et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients[J]. Am J Transplant, 2012, 12(1): 210-217. DOI: 10.1111/j.1600-6143.2011.03785.x.
    [23]
    ROSTAING L, VINCENTI F, GRINYÓ J, et al. Long-term belatacept exposure maintains efficacy and safety at 5 years: results from the long-term extension of the BENEFIT study[J]. Am J Transplant, 2013, 13(11): 2875-2883. DOI: 10.1111/ajt.12460.
    [24]
    VINCENTI F, ROSTAING L, GRINYO J, et al. Belatacept and long-term outcomes in kidney transplantation[J]. N Engl J Med, 2016, 374(4): 333-343. DOI: 10.1056/NEJMoa1506027.
    [25]
    DURRBACH A, PESTANA JM, PEARSON T, et al. A phase Ⅲ study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study)[J]. Am J Transplant, 2010, 10(3): 547-557. DOI: 10.1111/j.1600-6143.2010.03016.x.
    [26]
    PESTANA JO, GRINYO JM, VANRENTERGHEM Y, et al. Three-year outcomes from BENEFIT-EXT: a phase Ⅲ study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys[J] Am J Transplant, 2012, 12(3): 630-639. DOI: 10.1111/j.1600-6143.2011.03914.x.
    [27]
    CHARPENTIER B, MEDINA PESTANA JO, DEL C RIAL M, et al. Long-term exposure to belatacept in recipients of extended criteria donor kidneys[J]. Am J Transplant, 2013, 13(11): 2884-2891. DOI: 10.1111/ajt.12459.
    [28]
    DURRBACH A, PESTANA JM, FLORMAN S, et al. Long-term outcomes in belatacept- versus cyclosporine-treated recipients of extended criteria donor kidneys: final results from BENEFIT-EXT, a phase Ⅲ randomized study[J]. Am J Transplant, 2016, 16(11): 3192-3201. DOI: 10.1111/ajt.13830.
    [29]
    DE GRAAV GN, BAAN CC, CLAHSEN-VAN GRONINGEN MC, et al. A randomized controlled clinical trial comparing belatacept with tacrolimus after de novo kidney transplantation[J]. Transplantation, 2017, 101(10): 2571-2581. DOI: 10.1097/TP.0000000000001755.
    [30]
    ADAMS AB, GOLDSTEIN J, GARRETT C, et al. Belatacept combined with transient calcineurin inhibitor therapy prevents rejection and promotes improved long-term renal allograft function[J] Am J Transplant, 2017, 17(11): 2922-2936. DOI: 10.1111/ajt.14353.
    [31]
    BRAY RA, GEBEL HM, TOWNSEND R, et al. De novo donor-specific antibodies in belatacept-treated vs cyclosporine-treated kidney-transplant recipients: post hoc analyses of the randomized phase Ⅲ BENEFIT and BENEFIT-EXT studies[J]. Am J Transplant, 2018, 18(7): 1783-1789. DOI: 10.1111/ajt.14721.
    [32]
    BRAY RA, GEBEL HM, TOWNSEND R, et al. Posttransplant reduction in preexisting donor-specific antibody levels after belatacept- versus cyclosporine-based immunosuppression: post hoc analyses of BENEFIT and BENEFIT-EXT[J]. Am J Transplant, 2018, 18(7): 1774-1782. DOI: 10.1111/ajt.14738.
    [33]
    EVERLY MJ, ROBERTS M, TOWNSEND R, et al. Comparison of de novo IgM and IgG anti-HLA DSAs between belatacept- and calcineurin-treated patients: an analysis of the BENEFIT and BENEFIT-EXT trial cohorts[J]. Am J Transplant, 2018, 18(9): 2305-2313. DOI: 10.1111/ajt.14939.
    [34]
    EVERLY MJ, REBELLATO LM, HAISCH CE, et al. Impact of IgM and IgG3 anti-HLA alloantibodies in primary renal allograft recipients[J]. Transplantation, 2014, 97(5): 494-501. DOI: 10.1097/01.TP.0000441362.11232.48.
    [35]
    BADELL IR, LA MURAGLIA GM 2ND, LIU D, et al. Selective CD28 blockade results in superior inhibition of donor-specific T follicular helper cell and antibody responses relative to CTLA4-Ig[J]. Am J Transplant, 2018, 18(1): 89-101. DOI: 10.1111/ajt.14400.
    [36]
    LA MURAGLIA GM 2ND, ZENG S, CRICHTON ES, et al. Superior inhibition of alloantibody responses with selective CD28 blockade is CTLA-4 dependent and T follicular helper cell specific[J]. Am J Transplant, 2021, 21(1): 73-86. DOI: 10.1111/ajt.16004.
    [37]
    LEIBLER C, THIOLAT A, HÉNIQUE C, et al. Control of humoral response in renal transplantation by belatacept depends on a direct effect on B cells and impaired T follicular helper-B cell crosstalk[J]. J Am Soc Nephrol, 2018, 29(3): 1049-1062. DOI: 10.1681/ASN.2017060679.
    [38]
    NOBLE J, JOUVE T, JANBON B, et al. Belatacept in kidney transplantation and its limitations[J]. Expert Rev Clin Immunol, 2019, 15(4): 359-367. DOI: 10.1080/1744666X.2019.1574570.
    [39]
    PEREZ CP, PATEL N, MARDIS CR, et al. Belatacept in solid organ transplant: review of current literature across transplant types[J]. Transplantation, 2018, 102(9): 1440-1452. DOI: 10.1097/TP.0000000000002291.
    [40]
    MASSON P, HENDERSON L, CHAPMAN JR, et al. Belatacept for kidney transplant recipients[J]. Cochrane Database Syst Rev, 2014(11): CD010699. DOI: 10.1002/14651858.CD010699.pub2.
    [41]
    ROSTAING L, MASSARI P, GARCIA VD, et al. Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase Ⅱ study[J]. Clin J Am Soc Nephrol, 2011, 6(2): 430-439. DOI: 10.2215/CJN.05840710.
    [42]
    GRINYO J, ALBERU J, CONTIERI FL, et al. Improvement in renal function in kidney transplant recipients switched from cyclosporine or tacrolimus to belatacept: 2-year results from the long-term extension of a phase Ⅱ study[J]. Transpl Int, 2012, 25(10): 1059-1064. DOI: 10.1111/j.1432-2277.2012.01535.x.
    [43]
    GRINYÓ JM, DEL CARMEN RIAL M, ALBERU J, et al. Safety and efficacy outcomes 3 years after switching to belatacept from a calcineurin inhibitor in kidney transplant recipients: results from a phase 2 randomized trial[J]. Am J Kidney Dis, 2017, 69(5): 587-594. DOI: 10.1053/j.ajkd.2016.09.021.
    [44]
    MALVEZZI P, FISCHMAN C, RIGAULT G, et al. Switching renal transplant recipients to belatacept therapy: results of a real-life gradual conversion protocol[J]. Transpl Immunol, 2019, 56: 101207. DOI: 10.1016/j.trim.2019.04.002.
    [45]
    TERREC F, JOUVE T, NACIRI-BENNANI H, et al. Late conversion from calcineurin inhibitors to belatacept in kidney-transplant recipients has a significant beneficial impact on glycemic parameters[J]. Transplant Direct, 2019, 6(1): e517. DOI: 10.1097/TXD.0000000000000964.
    [46]
    BERTRAND D, TERREC F, ETIENNE I, et al. Opportunistic infections and efficacy following conversion to belatacept-based therapy after kidney transplantation: a French multicenter cohort[J]. J Clin Med, 2020, 9(11): 3479. DOI: 10.3390/jcm9113479.
    [47]
    KLINTMALM GB, FENG S, LAKE JR, et al. Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase Ⅱ randomized study[J]. Am J Transplant, 2014, 14(8): 1817-1827. DOI: 10.1111/ajt.12810.
    [48]
    LAMATTINA JC, JASON MP, HANISH SI, et al. Safety of belatacept bridging immunosuppression in hepatitis C-positive liver transplant recipients with renal dysfunction[J]. Transplantation, 2014, 97(2): 133-137. DOI: 10.1097/01.TP.0000438635.44461.2e.
    [49]
    SCHWARZ C, RASOUL-ROCKENSCHAUB S, SOLIMAN T, et al. Belatacept treatment for two yr after liver transplantation is not associated with operational tolerance[J]. Clin Transplant, 2015, 29(1): 85-89. DOI: 10.1111/ctr.12483.
    [50]
    VALLEJO AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence[J]. Immunol Rev, 2005, 205: 158-169. DOI: 10.1111/j.0105-2896.2005.00256.x.
    [51]
    SHABIR S, SMITH H, KAUL B, et al. Cytomegalovirus-associated CD4(+) CD28(null) cells in NKG2D-dependent glomerular endothelial injury and kidney allograft dysfunction[J]. Am J Transplant, 2016, 16(4): 1113-1128. DOI: 10.1111/ajt.13614.
    [52]
    MOU D, ESPINOSA JE, STEMPORA L, et al. Viral-induced CD28 loss evokes costimulation independent alloimmunity[J]. J Surg Res, 2015, 196(2): 241-246. DOI: 10.1016/j.jss.2015.02.033.
    [53]
    ENGELA AU, BAAN CC, LITJENS NH, et al. Mesenchymal stem cells control alloreactive CD8(+) CD28(-) T cells[J]. Clin Exp Immunol, 2013, 174(3): 449-458. DOI: 10.1111/cei.12199.
    [54]
    LO DJ, ANDERSON DJ, WEAVER TA, et al. Belatacept and sirolimus prolong nonhuman primate renal allograft survival without a requirement for memory T cell depletion[J]. Am J Transplant, 2013, 13(2): 320-328. DOI: 10.1111/j.1600-6143.2012.04342.x.
    [55]
    LO DJ, WEAVER TA, STEMPORA L, et al. Selective targeting of human alloresponsive CD8+ effector memory T cells based on CD2 expression[J]. Am J Transplant, 2011, 11(1): 22-33. DOI: 10.1111/j.1600-6143.2010.03317.x.
    [56]
    MATHEWS DV, WAKWE WC, KIM SC, et al. Belatacept-resistant rejection is associated with CD28+ memory CD8 T cells[J]. Am J Transplant, 2017, 17(9): 2285-2299. DOI: 10.1111/ajt.14349.
    [57]
    CORTES-CERISUELO M, LAURIE SJ, MATHEWS DV, et al. Increased pretransplant frequency of CD28+ CD4+ TEM predicts belatacept-resistant rejection in human renal transplant recipients[J]. Am J Transplant, 2017, 17(9): 2350-2362. DOI: 10.1111/ajt.14350.
    [58]
    ESPINOSA J, HERR F, THARP G, et al. CD57(+) CD4 T cells underlie belatacept-resistant allograft rejection[J]. Am J Transplant, 2016, 16(4): 1102-1112. DOI: 10.1111/ajt.13613.
    [59]
    KRUMMEY SM, CHEESEMAN JA, CONGER JA, et al. High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept[J]. Am J Transplant, 2014, 14(3): 607-614. DOI: 10.1111/ajt.12600.
    [60]
    KRUMMEY SM, FLOYD TL, LIU D, et al. Candida-elicited murine Th17 cells express high CTLA-4 compared with Th1 cells and are resistant to costimulation blockade[J]. J Immunol, 2014, 192(5): 2495-2504. DOI: 10.4049/jimmunol.1301332.
    [61]
    VANHOVE B, POIRIER N, SOULILLOU JP, et al. Selective costimulation blockade with antagonist anti-CD28 therapeutics in transplantation[J]. Transplantation, 2019, 103(9): 1783-1789. DOI: 10.1097/TP.0000000000002740.
    [62]
    SUN H, HARTIGAN CR, CHEN CW, et al. TIGIT regulates apoptosis of risky memory T cell subsets implicated in belatacept-resistant rejection[J]. Am J Transplant, 2021, DOI: 10.1111/ajt.16571[Epub ahead of print].
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