Belatacept and CD28 Costimulation Blockade: Preventing and Reducing Alloantibodies over the Long Term

  • Ronald F. Parsons
  • Christian P. Larsen
  • Thomas C. Pearson
  • I. Raul BadellEmail author
Kidney Transplantation (M Henry and R Pelletier, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Kidney Transplantation


Purpose of Review

Highlight developments in T and B cell biology that are helping elucidate the mechanisms underlying CD28 pathway blockade-mediated inhibition of alloantibodies in transplantation, and discuss recent clinical observations on the impact of belatacept on de novo and established HLA antibodies.

Recent Findings

The identification of T follicular helper cells as the CD4+ T cell subset required for optimal humoral immunity, along with newly identified roles for CD28 and the B7 molecules on B cell lineage cells, has begun to pave the way for improved understanding and discovery of the mechanisms of CD28 costimulation blockade-mediated antibody inhibition. There has been resurgent clinical interest in the ability of belatacept to attenuate alloantibody responses. New reports have continued to document its ability to prevent de novo antibody responses, and more recent studies have surfaced exploring its potential to control nascent or pre-existing HLA antibodies.


A growing understanding of the mechanisms of anti-CD28-mediated alloantibody inhibition and continued clinical successes will guide the clinical optimization of belatacept and next-generation CD28 blockers to prevent and reduce alloantibodies over the long term.


Belatacept Alloantibodies Costimulation blockade Kidney transplantation CD28 pathway CTLA-4-Ig 


Compliance with Ethical Standards

Conflict of Interest

Raul Badell reports grants from NIH/NIAID (K08 AI132747) during the conduct of the study. Ronald F. Parsons, Christian P. Larsen, and Thomas C. Pearson declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Lodhi SA, Lamb KE, Meier-Kriesche HU. Solid organ allograft survival improvement in the United States: the long-term does not mirror the dramatic short-term success. Am J Transplant. 2011;11(6):1226–35. Scholar
  2. 2.
    Hart A, Smith JM, Skeans MA, Gustafson SK, Wilk AR, Castro S, et al. OPTN/SRTR 2017 annual data report: kidney. Am J Transplant. 2019;19(Suppl 2):19–123. Scholar
  3. 3.
    Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med. 2003;349(24):2326–33. Scholar
  4. 4.
    Loupy A, Hill GS, Jordan SC. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol. 2012;8(6):348–57. Scholar
  5. 5.
    Lefaucheur C, Loupy A, Hill GS, Andrade J, Nochy D, Antoine C, et al. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol. 2010;21(8):1398–406. Scholar
  6. 6.
    Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ, et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012;12(5):1157–67. Scholar
  7. 7.
    Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M. Diagnosis and management of antibody-mediated rejection: current status and novel approaches. Am J Transplant. 2014;14(2):255–71. Scholar
  8. 8.
    Jordan SC, Ammerman N, Choi J, Huang E, Peng A, Sethi S, et al. Novel therapeutic approaches to allosensitization and antibody-mediated rejection. Transplantation. 2019;103(2):262–72. Scholar
  9. 9.
    Linsley PS, Wallace PM, Johnson J, Gibson MG, Greene JL, Ledbetter JA, et al. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science. 1992;257(5071):792–5.CrossRefGoogle Scholar
  10. 10.
    Larsen CP, Pearson TC, Adams AB, Tso P, Shirasugi N, Strobert E, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant. 2005;5(3):443–53. Scholar
  11. 11.
    Badell IR, Russell MC, Cardona K, Shaffer VO, Turner AP, Avila JG, et al. CTLA4Ig prevents alloantibody formation following nonhuman primate islet transplantation using the CD40-specific antibody 3A8. Am J Transplant. 2012;12(7):1918–23. Scholar
  12. 12.
    Vanrenterghem Y, Bresnahan B, Campistol J, Durrbach A, Grinyo J, Neumayer HH, et al. 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):976–83. Scholar
  13. 13.
    •• Vincenti F, Rostaing L, Grinyo J, Rice K, Steinberg S, Gaite L, et al. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med. 2016;374(4):333–43. Seven year results of phase III BENEFIT Study showing a significant improvement in long-term kidney transplant outcomes with belatacept.CrossRefPubMedGoogle Scholar
  14. 14.
    Ford ML, Kirk AD, Larsen CP. Donor-reactive T-cell stimulation history and precursor frequency: barriers to tolerance induction. Transplantation. 2009;87(9 Suppl):S69–74. Scholar
  15. 15.
    Ford ML, Larsen CP. Translating costimulation blockade to the clinic: lessons learned from three pathways. Immunol Rev. 2009;229(1):294–306. Scholar
  16. 16.
    Badell IR, Karadkhele GM, Vasanth P, Farris AB, 3rd, Robertson JM, Larsen CP. Abatacept as rescue immunosuppression after calcineurin inhibitor treatment failure in renal transplantation. Am J Transplant. 2019;19(8):2342–9. Scholar
  17. 17.
    Vanhove B, Poirier N, Soulillou JP, Blancho G. Selective costimulation blockade with antagonist anti-CD28 therapeutics in transplantation. Transplantation. 2019. Scholar
  18. 18.
    Shahinian A, Pfeffer K, Lee KP, Kundig TM, Kishihara K, Wakeham A, et al. Differential T cell costimulatory requirements in CD28-deficient mice. Science. 1993;261(5121):609–12.CrossRefGoogle Scholar
  19. 19.
    Ferguson SE, Han S, Kelsoe G, Thompson CB. CD28 is required for germinal center formation. J Immunol. 1996;156(12):4576–81.PubMedGoogle Scholar
  20. 20.
    Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity. 2014;41(4):529–42. Scholar
  21. 21.
    Lafferty KJ, Cunningham AJ. A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci. 1975;53(1):27–42.CrossRefGoogle Scholar
  22. 22.
    Badell IR, Ford ML. T follicular helper cells in the generation of alloantibody and graft rejection. Curr Opin Organ Transplant. 2016;21(1):1–6. Scholar
  23. 23.
    Walters GD, Vinuesa CG. T follicular helper cells in transplantation. Transplantation. 2016;100(8):1650–5. Scholar
  24. 24.
    Kim I, Wu G, Chai NN, Klein AS, Jordan SC. Immunological characterization of de novo and recall alloantibody suppression by CTLA4Ig in a mouse model of allosensitization. Transpl Immunol. 2016;38:84–92. Scholar
  25. 25.
    • Kim EJ, Kwun J, Gibby AC, Hong JJ, Farris AB 3rd, Iwakoshi NN, et al. Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection. Am J Transplant. 2014;14(1):59–69. Pre-clinical study demonstrating an association between altered germinal center responses and CD28 costimulation blockade-mediated DSA inhibition in primate transplant model.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ford ML, Adams AB, Pearson TC. Targeting co-stimulatory pathways: transplantation and autoimmunity. Nature Reviews Nephrology. 2014;10(1):14–24. Scholar
  27. 27.
    Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3(5):541–7.CrossRefGoogle Scholar
  28. 28.
    •• Sage PT, Paterson AM, Lovitch SB, Sharpe AH. The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity. 2014;41(6):1026–39. Basic science study identifying intrinsic role of CTLA-4 on T cells to control T cell dependent antibody responses. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    •• Wing JB, Ise W, Kurosaki T, Sakaguchi S. Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4. Immunity. 2014;41(6):1013–25. Basic science study highlighting CTLA-4 mediated control of Tfh cells and humoral response by regulatory T cells.CrossRefPubMedGoogle Scholar
  30. 30.
    • Badell IR, La Muraglia GM 2nd, Liu D, Wagener ME, Ding G, Ford ML. Selective CD28 blockade results in superior inhibition of donor-specific T follicular helper cell and antibody responses relative to CTLA4-Ig. Am J Transplant. 2018;18(1):89–101. Basic science study demonstrating that next generation selective CD28 blockade is superior to CTLA-4-Ig at inhibiting DSA in a murine transplant model.CrossRefPubMedGoogle Scholar
  31. 31.
    Ville S, Poirier N, Branchereau J, Charpy V, Pengam S, Nerriere-Daguin V, et al. Anti-CD28 antibody and belatacept exert differential effects on mechanisms of renal allograft rejection. J Am Soc Nephrol. 2016;27(12):3577–88. Scholar
  32. 32.
    La Muraglia GM 2nd, Wagener M, Ford ML, Badell IR. ICOS+PD-1+ circulating T follicular helper cells are a biomarker of humoral alloreactivity and predict donor-specific antibody generation following transplantation. Am J Transplant. 2019;19(S3).Google Scholar
  33. 33.
    Chen J, Yin H, Xu J, Wang Q, Edelblum KL, Sciammas R, et al. Reversing endogenous alloreactive B cell GC responses with anti-CD154 or CTLA-4Ig. Am J Transplant. 2013;13(9):2280–92. Scholar
  34. 34.
    • Chen J, Wang Q, Yin D, Vu V, Sciammas R, Chong AS. Cutting edge: CTLA-4Ig inhibits memory B cell responses and promotes allograft survival in sensitized recipients. J Immunol. 2015;195(9):4069–73. Pre-clinical study showing that CTLA-4-Ig capable of abrogating memory B cell responses and heart allograft rejection in sensitized mice.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Young JS, Chen J, Miller ML, Vu V, Tian C, Moon JJ, et al. Delayed cytotoxic T lymphocyte-associated protein 4-immunoglobulin treatment reverses ongoing alloantibody responses and rescues allografts from acute rejection. Am J Transplant. 2016;16(8):2312–23. Scholar
  36. 36.
    Leibler C, Thiolat A, Henique C, Samson C, Pilon C, Tamagne M, 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 Am Soc Nephrol. 2018;29(3):1049–62. Scholar
  37. 37.
    •• Rozanski CH, Arens R, Carlson LM, Nair J, Boise LH, Chanan-Khan AA, et al. Sustained antibody responses depend on CD28 function in bone marrow-resident plasma cells. J Exp Med. 2011;208(7):1435–46. Elegant study demonstrating that long-lived plasma cells and sustained antibody responses are dependent on CD28-mediated pro-survival signals. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Rozanski CH, Utley A, Carlson LM, Farren MR, Murray M, Russell LM, et al. CD28 promotes plasma cell survival, sustained antibody responses, and BLIMP-1 upregulation through its distal PYAP proline motif. J Immunol. 2015;194(10):4717–28. Scholar
  39. 39.
    Halliley JL, Tipton CM, Liesveld J, Rosenberg AF, Darce J, Gregoretti IV, et al. Long-lived plasma cells are contained within the CD19(-)CD38(hi)CD138(+) subset in human bone marrow. Immunity. 2015;43(1):132–45. Scholar
  40. 40.
    Njau MN, Kim JH, Chappell CP, Ravindran R, Thomas L, Pulendran B, et al. CD28-B7 interaction modulates short- and long-lived plasma cell function. J Immunol. 2012;189(6):2758–67. Scholar
  41. 41.
    Njau MN, Jacob J. The CD28/B7 pathway: a novel regulator of plasma cell function. Advances in experimental medicine and biology. 2013;785:67–75. Scholar
  42. 42.
    La Muraglia GM 2nd, Ford ML, Badell IR. Selective CD28 blockade-mediated inhibition of T follicular helper cell and DSA responses is CTLA-4 dependent. Am J Transplant. 2019;19(S3).Google Scholar
  43. 43.
    Heher E, Markmann JF. The clearer BENEFITS of belatacept. N Engl J Med. 2016;374(4):388–9. Scholar
  44. 44.
    • Adams AB, Goldstein J, Garrett C, Zhang R, Patzer RE, Newell KA, et al. Belatacept combined with transient calcineurin inhibitor therapy prevents rejection and promotes improved long-term renal allograft function. Am J Transplant. 2017;17(11):2922–36. Largest off-trial clinical experience reporting superior renal allograft function and DSA reduction with belatacept-based immunosuppression following kidney transplantation.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Bray RA, Gebel HM, Townsend R, Roberts ME, Polinsky M, Yang L, 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. Am J Transplant. 2018;18(7):1783–9. Scholar
  46. 46.
    Everly MJ, Roberts M, Townsend R, Bray RA, Gebel HM. 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. Am J Transplant. 2018;18(9):2305–13. Scholar
  47. 47.
    Badell IR, Elbein R, Bray RA, Gebel HM, Adams AB, Larsen CP. Belatacept monotherapy in kidney transplant recipients with failed allografts reduces humoral sensitization in a single center randomized controlled trial. Am J Transplant. 2019;19(S3).Google Scholar
  48. 48.
    Bray RA, Gebel HM, Townsend R, Roberts ME, Polinsky M, Yang L, et al. Posttransplant reduction in preexisting donor-specific antibody levels after belatacept- versus cyclosporine-based immunosuppression: post hoc analyses of BENEFIT and BENEFIT-EXT. Am J Transplant. 2018;18(7):1774–82. Scholar
  49. 49.
    Parsons RF, Zahid A, Bumb S, Decker H, Sullivan HC, Eun-Hyung Lee F et al. The impact of belatacept on third-party HLA alloantibodies in highly sensitized kidney transplant recipients. Am J Transplant. 2019.
  50. 50.
    • Ulloa CE, Anglicheau D, Snanoudj R, Scemla A, Martinez F, Timsit MO, et al. Conversion from calcineurin inhibitors to belatacept in HLA- sensitized kidney-transplant recipients with low-level donor specific antibodies. Transplantation. 2019. Retrospective analysis of sensitized kidney transplant recipients safely converted to belatacept post-transplant.CrossRefGoogle Scholar
  51. 51.
    • Leibler C, Matignon M, Moktefi A, Samson C, Zarour A, Malard S, et al. Belatacept in renal transplant recipient with mild immunologic risk factor: a pilot prospective study (BELACOR). Am J Transplant. 2019;19(3):894–906. Prospective pilot clinical trial examining the use of belatacept-based immunosuppression in lowly sensitized kidney transplant recipients with pre-formed DSA. CrossRefPubMedGoogle Scholar
  52. 52.
    • Burghuber CK, Manook M, Ezekian B, Gibby AC, Leopardi FV, Song M, et al. Dual targeting: combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients. Am J Transplant. 2019;19(3):724–36. Pre-clinical study utilizing belatacept-based immunosuppression as a desensitization strategy in sensitized nonhuman primates to faciliate kidney transplantation. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Ronald F. Parsons
    • 1
  • Christian P. Larsen
    • 1
  • Thomas C. Pearson
    • 1
  • I. Raul Badell
    • 1
    Email author
  1. 1.Emory Transplant CenterAtlantaUSA

Personalised recommendations