RT Journal Article
SR Electronic
T1 Dynamical System Modeling to Simulate Donor T Cell Response to Whole Exome Sequencing-Derived Recipient Peptides: Understanding Randomness In Clinical Outcomes Following Stem Cell Transplantation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 088831
DO 10.1101/088831
A1 V Koparde
A1 B Abdul Razzaq
A1 T Suntum
A1 R Sabo
A1 A Scalora
A1 M Serrano
A1 M Jameson-Lee
A1 C Hall
A1 D Kobulnicky
A1 N Sheth
A1 J Sampson
A1 J Reed
A1 C Roberts
A1 R Qayyum
A1 G Buck
A1 M Neale
A1 A. Toor
YR 2017
UL http://biorxiv.org/content/early/2017/04/06/088831.abstract
AB The quantitative relationship between the magnitude of variation in minor histocompatibility antigens (mHA) and graft versus host disease (GVHD) pathophysiology in stem cell transplant (SCT) donor-recipient pairs (DRP) is not established. In order to elucidate this relationship, whole exome sequencing (WES) was performed on 27 HLA matched related (MRD), & 50 unrelated donors (URD), to identify nonsynonymous single nucleotide polymorphisms (SNPs). An average 2,463 SNPs were identified in MRD, and 4,287 in URD DRP (p<0.01); resulting peptide antigens that may be presented on HLA class I molecules in each DRP were derived in silico (NetMHCpan ver2.0) and the tissue expression of proteins these were derived from determined (GTex). MRD DRP had an average 3,670 HLA-binding-alloreactive peptides, putative mHA (pmHA) with an IC50 of <500 nM, and URD, had 5,386 (p<0.01). To simulate an alloreactive donor cytotoxic T cell response, the array of pmHA in each patient was considered as an operator matrix modifying a hypothetical cytotoxic T cell clonal vector matrix; each responding T cell clone’s proliferation was determined by the logistic equation of growth, accounting for HLA binding affinity and tissue expression of each alloreactive peptide. The resulting simulated organ-specific alloreactive T cell clonal growth revealed marked variability, with the T cell count differences spanning orders of magnitude between different DRP. Despite an estimated, uniform set of constants used in the model for all DRP, and a heterogeneously treated group of patients higher total and organ-specific T cell counts were associated with cumulative incidence of GVHD in recipients in Cox proportional hazard models. In conclusion, exome wide sequence differences and the variable alloreactive peptide binding to HLA in each DRP yields a large range of possible alloreactive donor T cell responses. Our findings also help understand the apparent randomness observed in the development of alloimmune responses.