Dynamical System Modeling to Simulate Donor T Cell Response to Whole Exome Sequencing-Derived Recipient Peptides Demonstrates Different Alloreactivity Potential In HLA-Matched and Mismatched Donor-Recipient Pairs

TL;DR

This study models donor T cell responses to recipient peptides derived from exome sequencing, revealing differences in alloreactivity potential between HLA-matched and mismatched donor-recipient pairs, with implications for transplant outcomes.

Contribution

It introduces a dynamical systems approach to simulate T cell responses based on exome sequencing data, highlighting differences in alloreactivity potential.

Findings

Simulated T cell repertoire matches clinical features.

Marked differences in alloreactivity between HLA-matched and mismatched pairs.

Potential correlation between simulated responses and patient survival.

Abstract

Stem cell transplants may be considered as dynamical systems to allow sequence differences across the exomes of the transplant donors and recipients to be used to simulate an alloreactive T cell response. Whole exome sequencing was performed on HLA matched stem cell transplant donor-recipient pairs, and the nucleotide sequence differences translated to peptides. The binding affinity of the peptides to the relevant HLA in each pair was determined. The resulting array of peptide-HLA binding affinity values in each patient was used to simulate an alloreactive donor derived T cell repertoire. This simulated T cell repertoire reproduces a number of features of clinically observed T cell repertoire. The simulated, alloreactive T cell repertoire was markedly different in HLA matched stem cell transplant donors and recipients and demonstrates a possible correlation with survival.