A multicenter kidney transplantation study identifies hierarchy and directionality of HLA-DQ alloimmune responses

Nature Communications, vol. 17

Abstract

HLA-incompatibility between recipient and donor is conventionally assessed by counting serologic mismatches. More recently, tools quantifying differences at the amino acid level are advocated to prognosticate risk for generation of de-novo donor-specific antibodies (dnDSA). Using hierarchical clustering based on HLA evolutionary divergence and amino acid physiochemical unique qualities to evaluate HLA-DQ αβ-heterodimers, we demonstrate that HLA-DQ alleles segregate into two main evolutionary clades, and further subdivide into six functional sub-categories. Applying this biologically grounded immune risk-stratification approach to a cohort of 3003 kidney allograft recipients from five transplant centers shows that transplantation across the two evolutionary clades is associated with hierarchy and directionality of humoral immune responses, despite similar values when applying quantitative metrics. Our three-tier risk stratification model identifies patients at higher risk to develop dnDSA (HR:6.77; 95%CI:4.64-9.90), and antibody mediated rejection (HR:4.41; 95%CI:1.44-13.53). This work provides a thoughtful immunologic framework, that outperforms quantitative metrics, for alloimmune risk stratification. Antibody mediated rejection is a main cause of graft rejection in organ transplantation and is often seen as de-novo donor specific antibodies (dnDSA) targeting the donor’s mismatched HLA-DQ molecules. Here the authors use a multi-center cohort to characterise HLA-DQ mismatches in kidney allograft recipients showing hierarchy in generation of dnDSA and antibody mediated rejection and application of these qualitative measures in alloimmune risk stratification.

Authors 15

1. Dennis A. J. van den Broek Aachen Department of Medicine, Leiden Transplant Center

   Northwestern University · Leiden University Medical Center

   Affiliation as printed

   Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA

   Dept of Medicine, Leiden Transplant Center, Leiden University Medical Center (LUMC), Leiden, the Netherlands

2. Akansha Agrawal

   Northwestern University

   Affiliation as printed

   Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA

3. Marta Crespo

   Hospital Del Mar · Hospital del Mar Research Institute

   Affiliation as printed

   Department of Nephrology, Kidney Transplant Unit, Hospital del Mar and Hospital del Mar Research Institute, Barcelona, Spain

4. Marie‐Paule Emonds

   Rode Kruis-Vlaanderen · KU Leuven

   Affiliation as printed

   Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium

   Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross-Flanders, Mechelen, Belgium

5. Sebastiaan Heidt Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center · Erasmus MC

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center (LUMC), Leiden, the Netherlands

   Department of Internal Medicine, Division of Nephrology & Transplantation, University Medical Center Rotterdam, Rotterdam, the Netherlands

6. Danny van der Helm Aachen Department of Medicine, Leiden Transplant Center

   Leiden University Medical Center

   Affiliation as printed

   Dept of Medicine, Leiden Transplant Center, Leiden University Medical Center (LUMC), Leiden, the Netherlands

7. Tobias L. Lenz

   Universität Hamburg

   Affiliation as printed

   Department of Biology, Evolutionary Immunogenomics, University of Hamburg, Hamburg, Germany

8. María Meneghini

   Northwestern University · Vall d'Hebron Hospital Universitari

   Affiliation as printed

   Department of Nephrology, Vall d'Hebron University Hospital, Barcelona, Spain

   Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA

9. Eduard Palou

   Hospital Clínic de Barcelona

   Affiliation as printed

   Department of Immunology, Hospital Clinic, Barcelona, Spain

10. Dolores Redondo Pachón

    Hospital Del Mar · Hospital del Mar Research Institute

    Affiliation as printed

    Department of Nephrology, Kidney Transplant Unit, Hospital del Mar and Hospital del Mar Research Institute, Barcelona, Spain

11. Dave L. Roelen Aachen Department of Medicine, Leiden Transplant Center

    Leiden University Medical Center

    Affiliation as printed

    Dept of Medicine, Leiden Transplant Center, Leiden University Medical Center (LUMC), Leiden, the Netherlands

12. Aleksandar Senev

    Northwestern University · KU Leuven

    Affiliation as printed

    Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium

    Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA

13. Maarten Naesens

    KU Leuven

    Affiliation as printed

    Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium

14. Aiko P. J. de Vries Aachen Department of Medicine, Leiden Transplant Center

    Leiden University Medical Center

    Affiliation as printed

    Dept of Medicine, Leiden Transplant Center, Leiden University Medical Center (LUMC), Leiden, the Netherlands

15. Anat R. Tambur corresponding

    Northwestern University

    Affiliation as printed

    Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA. a-tambur@northwestern.edu