Predicting Humoral Alloimmunity from Differences in Donor and Recipient HLA Surface Electrostatic Potential.

Dermot H Mallon,Craig J Taylor,Eva Ellinghaus,Christiane Kling,Matthew Robb,Vasilis Kosmoliaptsis,Dieter Kabelitz,J Andrew Bradley

doi:10.4049/jimmunol.1800683

Dermot H Mallon, Craig J Taylor + Show 6 more

Open Access

https://doi.org/10.4049/jimmunol.1800683

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Abstract

In transplantation, development of humoral alloimmunity against donor HLA is a major cause of organ transplant failure, but our ability to assess the immunological risk associated with a potential donor–recipient HLA combination is limited. We hypothesized that the capacity of donor HLA to induce a specific alloantibody response depends on their structural and physicochemical dissimilarity compared with recipient HLA. To test this hypothesis, we first developed a novel computational scoring system that enables quantitative assessment of surface electrostatic potential differences between donor and recipient HLA molecules at the tertiary structure level [three-dimensional electrostatic mismatch score (EMS-3D)]. We then examined humoral alloimmune responses in healthy females subjected to a standardized injection of donor lymphocytes from their male partner. This analysis showed a strong association between the EMS-3D of donor HLA and donor-specific alloantibody development; this relationship was strongest for HLA-DQ alloantigens. In the clinical transplantation setting, the immunogenic potential of HLA-DRB1 and -DQ mismatches expressed on donor kidneys, as assessed by their EMS-3D, was an independent predictor of development of donor-specific alloantibody after graft failure. Collectively, these findings demonstrate the translational potential of our approach to improve immunological risk assessment and to decrease the burden of humoral alloimmunity in organ transplantation.

Highlights

Comparisons of electrostatic potential between two HLA molecules of interest were performed in a defined region of space above the HLA molecular surface, and values were expressed as electrostatic similarity distance (ESD), based on the Hodgkin index
The capacity of donor HLA to stimulate alloantibody responses (HLA immunogenicity) is dependent upon their structural recognition by receptors on recipient B cells that initiate the immune response, and previous work has suggested that HLA immunogenicity should be considered in the context of amino acid sequence polymorphisms between donor and recipient HLA molecules [12, 21, 64]
We show that 1) HLA molecules differ widely at the level of electrostatic potential in 3D space, and these differences are not explicable on account of the underlying amino acid sequence polymorphisms; 2) the electrostatic disparity of a donor HLA compared with recipient HLA molecules, as assessed by three-dimensional electrostatic mismatch score (EMS-3D), was strongly associated with the risk of development of donor-specific alloantibody; and 3) electrostatic potential disparities are highest among HLA-DQ molecules, which were the most immunogenic alloantigens in this study and whose immunogenicity conformed best to our EMS-3D algorithm

Summary

Introduction

We hypothesized that the capacity of donor HLA to induce a specific alloantibody response can be predicted by quantitative assessment of their structural and surface electrostatic potential differences compared with recipient HLA molecules.

Results

Conclusion