Predicting HLA Class I Alloantigen Immunogenicity From the Number and Physiochemical Properties of Amino Acid Polymorphisms

Kosmoliaptsis, Vasilis; Chaudhry, Afzal; Sharples, Linda D.; Halsall, David; Dafforn, Timothy R.; Bradley, J. Andrew; Taylor, Craig

doi:10.1097/tp.0b013e3181b4a9ff

Cited by 84 publications

(98 citation statements)

References 43 publications

(39 reference statements)

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“…Both position (specific positions, a helices, or b sheet) (26) and physicochemical properties (size, polarity, and charge) of the amino acids involved may play a role (27)(28)(29). We aim to develop an algorithm in which we incorporate all aspects of the amino acid differences to predict T cell alloreactivity against single MHC class I mismatches and to use this as a tool for single HLA class Imismatched unrelated or related donor selection in HSCT.…”

mentioning

confidence: 99%

A Proposed Algorithm Predictive for Cytotoxic T Cell Alloreactivity

Jöris

Rood

Roelen

et al. 2012

The Journal of Immunology

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Previously, we showed that with an increasing number of amino acid differences in single HLA class I-mismatched molecules, the probability of T cell alloreactivity decreases. It is unlikely that every amino acid difference will affect T cell alloreactivity in a similar way; we hypothesized that the effect of an amino acid difference may be dependent on its position and/or physicochemical properties. We selected 131 patient/donor pairs with either a single HLA-A or -C mismatch in the graft-versus-host direction and that were compatible for HLA-B, -DRB1, and -DQB1. The alloreactive CTL precursor (CTLp) frequency was determined and associated with the amino acid differences between the single HLA class I mismatches. In the β sheet, only amino acids that are noncompatible in their physicochemical properties affect T cell alloreactivity, whereas in the α helices, both compatible and noncompatible amino acids affect CTLp outcome. Positions 62, 63, 73, 76, 77, 80, 99, 116, 138, 144, 147, and 163 were bivariately associated with CTLp outcome, irrespective of the total number of amino acid differences. In multivariate analysis, positions 62, 63, 73, 80, 116, 138, 144, and 163 were found to be most predictive for negative CTLp outcome. These results formed the basis for a weighted predictive mismatch score; pairs with the highest mismatch scores are estimated to be 13 times more likely to have a negative CTLp. This new algorithm may be a tool in donor selection for hematopoietic stem cell transplantation.

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confidence: 99%

A Proposed Algorithm Predictive for Cytotoxic T Cell Alloreactivity

Jöris

Rood

Roelen

et al. 2012

The Journal of Immunology

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“…We recently reported a novel approach to defining HLA immunogenicity based on the number and physiochemical properties of aa mismatches (incorporating intralocus and interlocus subtraction) [25]. The occurrence and magnitude of the humoral response in highly sensitized patients correlated independently with the number of mismatched aa and the total electrostatic and hydrophobicity mismatch scores of mismatched HLA class I alloantigens.…”

Section: Introductionmentioning

confidence: 99%

HLA class I amino acid sequence-based matching after interlocus subtraction and long-term outcome after deceased donor kidney transplantation

et al. 2010

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“…For each donor-recipient HLA class I mismatch combination, the individual AA physiochemical disparity scores were summed to give a total hydrophobicity mismatch score (HMS) and a total electrostatic mismatch score (EMS). 7 End points and competing risks Primary end point for the HSCT analysis was incidence of ⩾ grade II aGVHD. Peak severity of aGVHD after HSCT defined according to grade (no, I, II, III or IV) was available for 317 patients.…”

Section: Donor-recipient Pairsmentioning

confidence: 99%

“…9 The AA sequence comparisons between mismatched HLA class I specificities at the graft-versus-host direction were performed using a previously described computer program 7 (available on request). The program allows identification of the position and nature of all disparate AAs in the entire 1 Department of Surgery, University of Cambridge, and NIHR Cambridge Biomedical Research Centre, Cambridge, UK; α1 and α2 domains.…”

Section: Donor-recipient Pairsmentioning

confidence: 99%

“…6 In the context of solid-organ transplantation, the immunogenicity of HLA class I and class II alloantigens relates not only to the number of AA polymorphisms between mismatched HLA molecules but also to their physiochemical differences. 7,8 In this report, we describe an analysis of fully matched and single HLA class I-mismatched grafts and show that the physiochemical disparity between mismatched HLA alloantigens is predictive of the risk of developing aGVHD following HSCT.…”

Section: Introductionmentioning

confidence: 99%

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Physiochemical disparity of mismatched HLA class I alloantigens and risk of acute GVHD following HSCT

Kosmoliaptsis

Jöris

Mallon

et al. 2015

Bone Marrow Transplant

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We determined whether assessment of the immunogenicity of individual donor-recipient HLA mismatches based on differences in their amino-acid sequence and physiochemical properties predicts clinical outcome following haematopoietic SCT (HSCT). We examined patients transplanted with 9/10 single HLA class I-mismatched grafts (n = 171) and 10/10 HLA-A-, -B-, -C-, -DRB1-and -DQB1-matched grafts (n = 168). A computer algorithm was used to determine the physiochemical disparity (electrostatic mismatch score (EMS) and hydrophobic mismatch score (HMS)) of mismatched HLA class I specificities in the graft-versus-host direction. Patients transplanted with HLA-mismatched grafts with high EMS/HMS had increased incidence of ⩾ grade II acute GVHD (aGVHD) compared with patients transplanted with low EMS/HMS grafts; patients transplanted with low and medium EMS/HMS grafts had similar incidence of aGVHD to patients transplanted with 10/10 HLA-matched grafts. Mortality was higher following single HLAmismatched HSCT but was not correlated with HLA physiochemical disparity. Assessment of donor-recipient HLA incompatibility based on physiochemical HLA disparity may enable better selection of HLA-mismatched donors in HSCT.

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Predicting HLA Class I Alloantigen Immunogenicity From the Number and Physiochemical Properties of Amino Acid Polymorphisms

Abstract: Differences in AA number, hydrophobicity, and electrostatic charge between HLA class I specificities enable prediction of donor HLA class I types with low immunogenicity for a given recipient.

Cited by 84 publications

References 43 publications

A Proposed Algorithm Predictive for Cytotoxic T Cell Alloreactivity

A Proposed Algorithm Predictive for Cytotoxic T Cell Alloreactivity

HLA class I amino acid sequence-based matching after interlocus subtraction and long-term outcome after deceased donor kidney transplantation

Physiochemical disparity of mismatched HLA class I alloantigens and risk of acute GVHD following HSCT

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