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  • Review Article
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HLA in transplantation

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

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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.

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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.

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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

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  1. Robert A. Montgomery
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  2. Vasishta S. Tatapudi
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  3. Mary S. Leffell
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  4. Andrea A. Zachary
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All authors researched the data, discussed the content, wrote the manuscript and reviewed and/or edited the text before submission.

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Correspondence to Robert A. Montgomery.

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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.

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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.

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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

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