Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

HLA in transplantation

Nature Reviews Nephrology volume 14, pages 558–570 (2018)Cite this article

Subjects

Abstract

The human major histocompatibility complex is a family of genes that encodes HLAs, which have a crucial role in defence against foreign pathogens and immune surveillance of tumours. In the context of transplantation, HLA molecules are polymorphic antigens that comprise an immunodominant alloreactive trigger for the immune response, resulting in rejection. Remarkable advances in knowledge and technology in the field of immunogenetics have considerably enhanced the safety of transplantation. However, access to transplantation among individuals who have become sensitized as a result of previous exposure to alloantigens is reduced proportional to the breadth of their sensitization. New approaches for crossing the HLA barrier in transplantation using plasmapheresis, intravenous immunoglobulin and kidney paired donation have been made possible by the relative ease with which even low levels of anti-HLA antibodies can now be detected and tracked. The development of novel protocols for the induction of tolerance and new approaches to immunomodulation was also facilitated by advances in HLA technology. Here, we review the progress made in understanding HLAs that has enabled organ transplantation to become a life-saving endeavour that is accessible even for sensitized patients. We also discuss novel approaches to desensitization, immunomodulation and tolerance induction that have the potential to further improve transplantation access and outcomes.

Key points

  • HLA molecules are highly polymorphic antigens; antibodies against these antigens can develop as a result of pregnancy, transplantation or blood transfusion.

  • HLA sensitization adversely affects both access to and the outcomes of transplantation.

  • Remarkable advances in HLA typing, HLA antibody screening and crossmatch testing have immensely improved the safety of transplantation.

  • Innovative therapeutic strategies such as desensitization protocols and kidney paired donation have made transplantation possible for patients who are broadly sensitized to HLAs.

  • Novel agents including proteasome inhibitors, complement inhibitors, IL-6 or IL-6 receptor blockers and immunoglobulin-G-degrading enzyme of Streptococcus pyogenes are being tested as add-on therapies to improve the efficacy of desensitization.

  • Achieving long-term immunologic tolerance remains the holy grail of transplantation; the induction of mixed chimaerism through infusion of donor haematopoietic stem cells is an important step in this direction.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: HLA testing.
Fig. 2: Calculated panel reactive antibody sliding scale.
Fig. 3: Kidney paired donation strategies.
Fig. 4: Strategies to overcome HLA sensitization.
Fig. 5: Mechanism of central and peripheral tolerance.
Fig. 6: Regulatory T cell therapy for induction of tolerance in organ transplantation.

Similar content being viewed by others

References

  1. The MHC sequencing consortium. Complete sequence and gene map of a human major histocompatibility complex. Nature 401, 921–923 (1999).

    Article  Google Scholar 

  2. Womer, K. & Rabb, H. in Comprehensive Clinical Nephrology (eds Johnson, R. et al.) 1132–1143 (Elsevier, 2014).

  3. Shiina, T., Inoko, H. & Kulski, J. K. An update of the HLA genomic region, locus information and disease associations: 2004. Tissue Antigens. 64, 631–649 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Zachary, A. A., Hart, J. M., Lucas, D. P. & Leffell, M. S. The co$t of mi$matching. Clin. Transplants. 27, 261–269 (2007).

    Google Scholar 

  5. Zachary, A. A. & Leffell, M. S. HLA mismatching strategies for solid organ transplantation — a balancing act. Front. Immunol. 7, 575 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Gorer, P. A. The detection of antigenic differences in mouse erythrocytes by the employment of immune sera. Br. J. Exp. Pathol. 17, 42–50 (1936).

    CAS  PubMed Central  Google Scholar 

  7. Snell, G. The genetic and antigenic basis of tumor transplantation. J. Pathol. Bacteriol. 44, 691–699 (1937).

    Article  Google Scholar 

  8. Dausset, J. Immuno-hematologie des leucocytes. Bibl Paediatr. 14, 29–56 (1958).

    Google Scholar 

  9. Kissmeyer-Nielsen, F., Olsen, S., Petersen, V. P. & Fjeldborg, O. Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells. Lancet 2, 662–665 (1966).

    Article  CAS  PubMed  Google Scholar 

  10. Patel, R. & Terasaki, P. I. Significance of the positive crossmatch test in kidney transplantation. N. Engl. J. Med. 280, 735–739 (1969).

    Article  CAS  PubMed  Google Scholar 

  11. Williams, G. M. et al. “Hyperacute” renal-homograft rejection in man. N. Engl. J. Med. 279, 611–618 (1968).

    Article  CAS  PubMed  Google Scholar 

  12. Yunis, E. J., Amos, D. B., Eguro, S. Y. & Dorf, M. E. Cross reactions of HL-A antibodies. I. Characterization by absorption and elution. Transplantation 14, 474–479 (1972).

    Article  CAS  PubMed  Google Scholar 

  13. Garovoy, M. R. et al. Flow cytometry analysis: a high technology crossmatch technique facilitation transplantation. Transplant. Proc. 15, 1939–1943 (1983).

    Google Scholar 

  14. Cook, D. J. et al. The flow cytometry crossmatch in kidney transplantation. Clin. Transpl. 409–414 (1987).

  15. Cardella, C. J., Falk, J. A., Nicholson, M. J., Harding, M. & Cook, G. T. Successful renal transplantation in patients with T cell reactivity to donor. Lancet. 2, 1240–1243 (1982).

    Article  CAS  PubMed  Google Scholar 

  16. Goeken, N. E. Outcome of renal transplantation following a positive cross-match with historical sera: the ASHI survey. Hum. Immunol. 14, 77–85 (1985).

    Article  CAS  PubMed  Google Scholar 

  17. Lopes, D. et al. Effect of different sensitization events on HLA alloimmunization in kidney transplantation candidates. Transplant. Proc. 47, 894–897 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Kao, K. J., Scornik, J. C. & Small, S. J. Enzyme-linked immunoassay for anti-HLA antibodies—an alternative to panel studies by lymphocytotoxicity. Transplantation 55, 192–196 (1993).

    Article  CAS  PubMed  Google Scholar 

  19. Olerup, O. & Zetterquist, H. HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens 39, 225–235 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Erlich, H. et al. HLA-DR, DQ and DP typing using PCR amplification and immobilized probes. Eur. J. Immunogenet. 18, 33–55 (1991).

    Article  CAS  PubMed  Google Scholar 

  21. Leffell, M. S., Montgomery, R. A. & Zachary, A. A. The changing role of antibody testing in transplantation. Clin. Transpl. 259–271 (2005).

  22. Segev, D. L., Gentry, S. E., Warren, D. S., Reeb, B. & Montgomery, R. A. Kidney paired donation and optimizing the use of live donor organs. JAMA 293, 1883–1890 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Montgomery, R. A. et al. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients. Transplantation 70, 887–895 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Montgomery, R. A. et al. Domino paired kidney donation: a strategy to make best use of live non-directed donation. Lancet 368, 419–421 (2006).

    Article  PubMed  Google Scholar 

  25. Montgomery, R. A. Renal transplantation across HLA and ABO antibody barriers: integrating paired donation into desensitization protocols. Am. J. Transplant. 10, 449–457 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Ascher, N. L. et al. 100 HLA-identical sibling transplants. Prognostic factors other than histocompatibility. Ann. Surg. 189, 209–216 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cheigh, J. S. et al. Renal transplantation between HLA identical siblings. Comparison with transplants from HLA semi-identical related donors. N. Engl. J. Med. 296, 1030–1034 (1977).

    Article  CAS  PubMed  Google Scholar 

  28. Williams, R. C., Opelz, G., McGarvey, C. J., Weil, E. J. & Chakkera, H. A. The risk of transplant failure with HLA mismatch in first adult kidney allografts from deceased donors. Transplantation 100, 1094–1102 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Opelz, G. Correlation of HLA matching with kidney graft survival in patients with or without cyclosporine treatment. Transplantation 40, 240–243 (1985).

    Article  CAS  PubMed  Google Scholar 

  30. Doxiadis, I. I. et al. Simpler and equitable allocation of kidneys from postmortem donors primarily based on full HLA-DR compatibility. Transplantation 83, 1207–1213 (2007).

    Article  PubMed  Google Scholar 

  31. Lim, W. H. et al. HLA-DQ mismatches and rejection in kidney transplant recipients. Clin. J. Am. Soc. Nephrol. 11, 875–883 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mytilineos, J., Deufel, A. & Opelz, G. Clinical relevance of HLA-DPB locus matching for cadaver kidney retransplants: a report of the Collaborative Transplant Study. Transplantation 63, 1351–1354 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Youngs, D. HLA-DP alloantibodies. ASHI Quarterly 28, 60 (2004).

    Google Scholar 

  34. Qiu, J., Cai, J., Terasaki, P. I., El-Awar, N. & Lee, J. H. Detection of antibodies to HLA-DP in renal transplant recipients using single antigen beads. Transplantation 80, 1511–1513 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Kosmoliaptsis, V. et al. High-resolution three-dimensional modeling of human leukocyte antigen class I structure and surface electrostatic potential reveals the molecular basis for alloantibody binding epitopes. Hum. Immunol. 72, 1049–1059 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Tambur, A. R. et al. Epitope analysis of HLA-DQ antigens: what does the antibody see? Transplantation 98, 157–166 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Tambur, A. R. & Claas, F. H. HLA epitopes as viewed by antibodies: what is it all about? Am. J. Transplant. 15, 1148–1154 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Locke, J. E. et al. Proinflammatory events are associated with significant increases in breadth and strength of HLA-specific antibody. Am. J. Transplant. 9, 2136–2139 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Cecka, J. M., Kucheryavaya, A. Y., Reinsmoen, N. L. & Leffell, M. S. Calculated PRA: initial results show benefits for sensitized patients and a reduction in positive crossmatches. Am. J. Transplant. 11, 719–724 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Organ Procurement and Transplantation Network. National Data. U.S. Department of Health & Human Services https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/# (2018).

  41. Gibney, E. M. et al. Detection of donor-specific antibodies using HLA-coated microspheres: another tool for kidney transplant risk stratification. Nephrol. Dial. Transplant. 21, 2625–2629 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Lucas, D. P., Leffell, M. S. & Zachary, A. A. Differences in immunogenicity of HLA antigens and the impact of cross-reactivity on the humoral response. Transplantation 99, 77–85 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. EUROSTAM. The Allele Frequency Net Database. EUROSTAM http://www.allelefrequencies.net/default.asp (2018).

  44. Heidt, S., Haasnoot, G. W., van Rood, J. J., Witvliet, M. D. & Claas, F. H. J. Kidney allocation based on proven acceptable antigens results in superior graft survival in highly sensitized patients. Kidney Int. 93, 491–500 (2018).

    Article  PubMed  Google Scholar 

  45. Wilk, A. R., Beck, J. & Kucheryavaya, A. Y. The kidney allocation system (KAS). The first two years. United Network for Organ Sharing https://www.transplantpro.org/wp-content/uploads/sites/3/KAS_First-two-years_041917.pdf (2017).

  46. Baxter-Lowe, L. A., Cecka, M., Kamoun, M., Sinacore, J. & Melcher, M. L. Center-defined unacceptable HLA antigens facilitate transplants for sensitized patients in a multi-center kidney exchange program. Am. J. Transplant. 14, 1592–1598 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Bielmann, D. et al. Pretransplant risk assessment in renal allograft recipients using virtual crossmatching. Am. J. Transplant. 7, 626–632 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Tambur, A. R. et al. Perception versus reality?: virtual crossmatch — how to overcome some of the technical and logistic limitations. Am. J. Transplant. 9, 1886–1893 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Montgomery, R. A. & Zachary, A. A. Transplanting patients with a positive donor-specific crossmatch: a single center’s perspective. Pediatr. Transplant. 8, 535–542 (2004).

    Article  PubMed  Google Scholar 

  50. Bohmig, G. A. et al. Immunoadsorption in severe C4d-positive acute kidney allograft rejection: a randomized controlled trial. Am. J. Transplant. 7, 117–121 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Montgomery, R. A. et al. Desensitization in HLA-incompatible kidney recipients and survival. N. Engl. J. Med. 365, 318–326 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Orandi, B. J. et al. Survival benefit with kidney transplants from HLA-incompatible live donors. N. Engl. J. Med. 374, 940–950 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Vo, A. A. et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N. Engl. J. Med. 359, 242–251 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Burns, J. M. et al. Alloantibody levels and acute humoral rejection early after positive crossmatch kidney transplantation. Am. J. Transplant. 8, 2684–2694 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Montgomery, R. A. et al. Clinical results from transplanting incompatible live kidney donor/recipient pairs using kidney paired donation. JAMA 294, 1655–1663 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Perry, D. K. et al. Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production. Am. J. Transplant. 9, 201–209 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Vo, A. A. et al. A phase I/II trial of the interleukin-6 receptor-specific humanized monoclonal (tocilizumab) + intravenous immunoglobulin in difficult to desensitize patients. Transplantation 99, 2356–2363 (2015).

    Article  CAS  PubMed  Google Scholar 

  58. Stegall, M. D. et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am. J. Transplant. 11, 2405–2413 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Vo, A. A. et al. A phase I/II placebo-controlled trial of C1-inhibitor for prevention of antibody-mediated rejection in HLA sensitized patients. Transplantation 99, 299–308 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Montgomery, R. A. et al. Plasma-derived C1 esterase inhibitor for acute antibody-mediated rejection following kidney transplantation: results of a randomized double-blind placebo-controlled pilot study. Am. J. Transplant. 16, 3468–3478 (2016).

    Article  CAS  PubMed  Google Scholar 

  61. Jordan, S. C. et al. IgG endopeptidase in highly sensitized patients undergoing transplantation. N. Engl. J. Med. 377, 442–453 (2017).

    Article  CAS  PubMed  Google Scholar 

  62. Moreno Gonzales, M. A. et al. 32 doses of bortezomib for desensitization is not well tolerated and is associated with only modest reductions in anti-HLA antibody. Transplantation 101, 1222–1227 (2017).

    Article  CAS  PubMed  Google Scholar 

  63. Everly, M. J. et al. Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection. Transplantation 86, 1754–1761 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Waiser, J. et al. Comparison between bortezomib and rituximab in the treatment of antibody-mediated renal allograft rejection. Nephrol. Dial. Transplant. 27, 1246–1251 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Kwun, J. et al. Humoral compensation after bortezomib treatment of allosensitized recipients. J. Am. Soc. Nephrol. 28, 1991–1996 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Philogene, M. C., Sikorski, P., Montgomery, R. A., Leffell, M. S. & Zachary, A. A. Differential effect of bortezomib on HLA class I and class II antibody. Transplantation 98, 660–665 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Loupy, A. et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N. Engl. J. Med. 369, 1215–1226 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Racusen, L. C. et al. Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection. Am. J. Transplant. 3, 708–714 (2003).

    Article  PubMed  Google Scholar 

  69. Solez, K. et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am. J. Transplant. 8, 753–760 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Sis, B. et al. Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining. Am. J. Transplant. 9, 2312–2323 (2009).

    Article  CAS  PubMed  Google Scholar 

  71. Loupy, A. et al. Outcome of subclinical antibody-mediated rejection in kidney transplant recipients with preformed donor-specific antibodies. Am. J. Transplant. 9, 2561–2570 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Orandi, B. J. et al. Presentation and outcomes of C4d-negative antibody-mediated rejection after kidney transplantation. Am. J. Transplant. 16, 213–220 (2016).

    Article  CAS  PubMed  Google Scholar 

  73. Wiebe, C. et al. Evaluation of C1q status and titer of de novo donor-specific antibodies as predictors of allograft survival. Am. J. Transplant. 17, 703–711 (2017).

    Article  CAS  PubMed  Google Scholar 

  74. Tambur, A. R. & Wiebe, C. HLA diagnostics: evaluating DSA strength by titration. Transplantation 102, S23–S30 (2018).

    Article  CAS  PubMed  Google Scholar 

  75. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01399593 (2017).

  76. Lefaucheur, C. et al. Complement-activating anti-HLA antibodies in kidney transplantation: allograft gene expression profiling and response to treatment. J. Am. Soc. Nephrol. 29, 620–635 (2018).

    Article  PubMed  Google Scholar 

  77. Levy, J. H., & O’Donnell, P. S. The therapeutic potential of a kallikrein inhibitor for treating hereditary angioedema. Expert Opin. Investigat. Drugs 15, 1077–1090 (2006).

    Article  CAS  Google Scholar 

  78. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02547220 (2017).

  79. Tanaka, T. & Kishimoto, T. The biology and medical implications of interleukin-6. Cancer Immunol. Res. 2, 288–294 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Mease, P. J. et al. The efficacy and safety of clazakizumab, an anti-interleukin-6 monoclonal antibody, in a phase IIb study of adults with active psoriatic arthritis. Arthritis. Rheumatol. 68, 2163–2173 (2016).

    Article  CAS  PubMed  Google Scholar 

  81. Choi, J. et al. Assessment of tocilizumab (anti-interleukin-6 receptor monoclonal) as a potential treatment for chronic antibody-mediated rejection and transplant glomerulopathy in HLA-sensitized renal allograft recipients. Am. J. Transplant. 17, 2381–2389 (2017).

    Article  CAS  PubMed  Google Scholar 

  82. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03380377 (2018).

  83. Wenig, K. et al. Structure of the streptococcal endopeptidase IdeS, a cysteine proteinase with strict specificity for IgG. Proc. Natl Acad. Sci. USA 101, 17371–17376 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02790437 (2018).

  85. Jarnum, S., Bockermann, R., Runstrom, A., Winstedt, L. & Kjellman, C. The bacterial enzyme IdeS cleaves the IgG-type of B cell receptor (BCR), abolishes BCR-mediated cell signaling, and inhibits memory B cell activation. J. Immunol. 195, 5592–5601 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Montgomery, R. A., Lonze, B. E. & Tatapudi, V. S. IgG degrading enzyme of Streptococcus pyogenes: an exciting new development in desensitization therapy. Transplantation 102, 2–4 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Hariharan, S. et al. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N. Engl. J. Med. 342, 605–612 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Salama, A. D., Womer, K. L. & Sayegh, M. H. Clinical transplantation tolerance: many rivers to cross. J. Immunol. 178, 5419–5423 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Fehr, T. & Sykes, M. Clinical experience with mixed chimerism to induce transplantation tolerance. Transpl. Int. 21, 1118–1135 (2008).

    Article  PubMed  Google Scholar 

  90. Pilat, N. & Wekerle, T. Transplantation tolerance through mixed chimerism. Nat. Rev. Nephrol. 6, 594–605 (2010).

    Article  PubMed  Google Scholar 

  91. Denton, M. D., Magee, C. C. & Sayegh, M. H. Immunosuppressive strategies in transplantation. Lancet 353, 1083–1091 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Madariaga, M. L. et al. Effect of tolerance versus chronic immunosuppression protocols on the quality of life of kidney transplant recipients. JCI insight 1, e87019 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Montgomery, R. A. One kidney for life. Am. J. Transplant. 14, 1473–1474 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Cobbold, S. P., Martin, G., Qin, S. & Waldmann, H. Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance. Nature 323, 164–166 (1986).

    Article  CAS  PubMed  Google Scholar 

  95. Kawai, T. et al. CD154 blockade for induction of mixed chimerism and prolonged renal allograft survival in nonhuman primates. Am. J. Transplant. 4, 1391–1398 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Kawai, T. et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N. Engl. J. Med. 358, 353–361 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Scandling, J. D. et al. Tolerance and chimerism after renal and hematopoietic-cell transplantation. N. Engl. J. Med. 358, 362–368 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Leventhal, J. R. et al. HLA identical non-chimeric and HLA disparate chimeric renal transplant tolerance. Clin. Transpl. 145–156 (2013).

  99. Strober, S., Lowsky, R. J., Shizuru, J. A., Scandling, J. D. & Millan, M. T. Approaches to transplantation tolerance in humans. Transplantation 77, 932–936 (2004).

    Article  PubMed  Google Scholar 

  100. Millan, M. T. et al. Mixed chimerism and immunosuppressive drug withdrawal after HLA-mismatched kidney and hematopoietic progenitor transplantation. Transplantation 73, 1386–1391 (2002).

    Article  PubMed  Google Scholar 

  101. Kawai, T., Sachs, D. H., Sykes, M., Cosimi, A. B. & Immune Tolerance Network. HLA-mismatched renal transplantation without maintenance immunosuppression. N. Engl. J. Med. 368, 1850–1852 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Luznik, L. et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol. Blood Marrow Transplant. 14, 641–650 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Bolanos-Meade, J. et al. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood 120, 4285–4291 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Leventhal, J. et al. Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci. Transl Med. 4, 124ra28 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Tang, Q. & Bluestone, J. A. Regulatory T cell therapy in transplantation: moving to the clinic. Cold Spring Harb. Perspect. Med. 3, a015552 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Gregersen, P. K. & Behrens, T. W. Genetics of autoimmune diseases — disorders of immune homeostasis. Nat. Rev. Genet. 7, 917–928 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Muthukumar, T. et al. Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N. Engl. J. Med. 353, 2342–2351 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Zwang, N. A. & Leventhal, J. R. Cell therapy in kidney transplantation: focus on regulatory T cells. J. Am. Soc. Nephrol. 28, 1960–1972 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Roncarolo, M. G. & Battaglia, M. Regulatory T cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat. Rev. Immunol. 7, 585–598 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Bluestone, J. A. et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci. Transl Med. 7, 315ra189 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Jones, A. G. & Hattersley, A. T. The clinical utility of C-peptide measurement in the care of patients with diabetes. Diabet. Med. 30, 803–817 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Leighton, E., Sainsbury, C. A. & Jones, G. C. A practical review of C-peptide testing in diabetes. Diabetes Ther. 8, 475–487 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Trzonkowski, P. et al. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. Clin. Immunol. 133, 22–26 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02129881 (2014).

  116. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02088931 (2016).

  117. Todo, S. et al. A pilot study of operational tolerance with a regulatory T cell-based cell therapy in living donor liver transplantation. Hepatology 64, 632–643 (2016).

    Article  CAS  PubMed  Google Scholar 

  118. Yang, J. et al. Allograft rejection mediated by memory T cells is resistant to regulation. Proc. Natl Acad. Sci. USA 104, 19954–19959 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Korn, T. et al. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat. Med. 13, 423–431 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Li, X. C. & Turka, L. A. An update on regulatory T cells in transplant tolerance and rejection. Nat. Rev. Nephrol. 6, 577–583 (2010).

    Article  PubMed  Google Scholar 

  121. Taylor, C. J., Chapman, J. R., Ting, A. & Morris, P. J. Characterization of lymphocytotoxic antibodies causing a positive crossmatch in renal transplantation. Relationship to primary and regraft outcome. Transplantation 48, 953–958 (1989).

    Article  CAS  PubMed  Google Scholar 

  122. Tinckam, K. Histocompatibility methods. Transplantat. Rev. 23, 80–93 (2009).

    Article  Google Scholar 

  123. Zangwill, S. D. et al. The virtual crossmatch—a screening tool for sensitized pediatric heart transplant recipients. Pediatr. Transplant. 10, 38–41 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Appel, J. Z. et al. Role of flow cytometry to define unacceptable HLA antigens in lung transplant recipients with HLA-specific antibodies. Transplantation 81, 1049–1057 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Johnson, C. & Ellis, T. Reply to “Allocation Based on Virtual Crossmatch Alone: Not. Yet Ready for Primetime”. Am. J. Transplant. 16, 3578–3579 (2016).

    Article  CAS  PubMed  Google Scholar 

  126. Tait, B. D. et al. Review article: Luminex technology for HLA antibody detection in organ transplantation. Nephrology 14, 247–254 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Tait, B. D. et al. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation 95, 19–47 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Organ Procurement and Transplantation Network. Kidney allocation system webinar — what referring physicians need to know. U.S. Department of Health and Human Services https://optn.transplant.hrsa.gov/news/kidney-allocation-system-webinar-what-referring-physicians-need-toknow/ (2014).

Download references

Author information

Authors and Affiliations

  1. NYU Langone Transplant Institute, NYU Langone Health, New York, NY, USA

    Robert A. Montgomery & Vasishta S. Tatapudi

  2. Department of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Mary S. Leffell & Andrea A. Zachary

Authors
  1. Robert A. Montgomery
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vasishta S. Tatapudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mary S. Leffell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea A. Zachary
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched the data, discussed the content, wrote the manuscript and reviewed and/or edited the text before submission.

Corresponding author

Correspondence to Robert A. Montgomery.

Ethics declarations

Competing interests

R.A.M. has served on advisory boards for Genentech Scientific/ROCHE, True North Therapeutics/iPierian, Alexion, Novartis and Hansa Medical and has received consulting fees from OrbiMed, GuidePoint Global, Sucampo Pharmaceuticals, Astellas Pharma and Shire. He has also received research grants from the Immune Tolerance Network, ViroPharma, Hansa and Alexion. V.S.T., M.S.L. and A.A.Z. declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Tolerance

Defined in the context of transplantation as the clinical state of acceptance of allograft by the recipient without chronic immunosuppression.

Sequence-specific priming

(SSP). A molecular method of HLA typing in which isolated DNA is amplified in the presence of specific primers that are complementary to the HLA alleles of interest.

Reverse sequence-specific oligonucleotide probing

(rSSOP). A molecular method of HLA typing in which amplified DNA is mixed with oligonucleotide probes that are complementary to the unique segments of the DNA that encode the HLA alleles of interest.

Class I and class II antigens

HLA class I (HLA-A, HLA-B and HLA-C) antigens and HLA class II (HLA-DP, HLA-DQ and HLA-DR) antigens are molecules encoded by genes in the major histocompatibility complex and play a key role in antigen presentation to T cells that orchestrate immune responses and tumour surveillance.

Hyperacute rejection

A severe form of rejection that occurs within minutes or hours of allograft reperfusion that is caused by preformed donor-specific antibodies.

Anergic state

A tolerance mechanism in which the lymphocyte is functionally inactivated following an antigen encounter in the absence of co-stimulation.

Co-stimulatory blockade

Inhibition of T cell activation by prevention of interaction between co-stimulatory molecules expressed on T cells and antigen-presenting cells.

Transient chimaerism

Clinical state following haematopoietic cell transplantation in which chimaerism is achieved only transiently.

Full-donor chimaerism

Clinical state following haematopoietic cell transplantation in which the recipient exhibits haematopoietic cells only of donor origin. Full-donor chimaerism has been attempted as a tolerance protocol in experimental transplant models and in humans.

Graft versus host disease

(GVHD). Multisystem disorder that may occur following allogeneic haematopoietic cell transplant owing to immune response directed by donor immune cells against the recipient.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Montgomery, R.A., Tatapudi, V.S., Leffell, M.S. et al. HLA in transplantation. Nat Rev Nephrol 14, 558–570 (2018). https://doi.org/10.1038/s41581-018-0039-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-018-0039-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing