@article {Koparde088831, author = {V Koparde and B Abdul Razzaq and T Suntum and R Sabo and A Scalora and M Serrano and M Jameson-Lee and C Hall and D Kobulnicky and N Sheth and J Sampson and C Roberts and G Buck and M Neale and A Toor}, title = {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}, elocation-id = {088831}, year = {2016}, doi = {10.1101/088831}, publisher = {Cold Spring Harbor Laboratory}, abstract = {The development of alloreactivity following stem cell transplantation (SCT) in HLA matched donor-recipient pairs (DRP) appears to be random. Minor histocompatibility antigens (mHA) are critical in graft versus host disease (GVHD) pathophysiology however, the quantitative relationship between GVHD and the magnitude of mHA in donor-recipient pairs (DRP) is not known. Whole exome sequencing (WES) was performed on 27 HLA matched related donors (MRD), \& 50 unrelated (URD), to identify nonsynonymous single nucleotide polymorphisms (SNPs) with an average 2,490 SNPs were identified in MRD, and 4,287 in URD DRP (p\<0.01). The resulting peptide antigens that may be presented on the relevant 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 3,626 HLA-alloreactive peptide (AP) complexes with an IC50 of \<500 nM and URD, had 5,386 (p\<0.01). To simulate a donor cytotoxic T cell response to these AP, the array of HLA-AP complexes in each patient was considered as an operator matrix modifying a hypothetical cytotoxic T cell clonal vector matrix in which each responding T cell clone{\textquoteright}s proliferation is quantified by the logistic equation of growth. The simulated steady state T cell clonal response to the AP-HLA complexes in each DRP, accounted for the HLA binding affinity and expression of each AP. The resulting simulated organ-specific alloreactive T cell clonal growth revealed marked variability between different DRP. The sum of all T cell clones for common GVHD target organs was: MRD, median 188,821 cytotoxic T cells at steady state (n=26), MUD, 201,176 (n=35), single locus HLA-mismatch MUD: 56,229 (n=10). Despite an estimated, uniform set of constants used in the model for all DRP, and a heterogeneously treated group of patients, overall there was a non-significant trend for higher organ specific T cell counts in patients with GVHD compared to those with none, with weak associations observed for GVHD of the liver. In conclusion, exome wide sequence differences and the variable AP binding affinity to the HLA in each DRP yields a large range of possible alloreactive donor T cell responses possibly explaining the random nature of alloimmune responses observed in clinical practice. Incorporating other quantitative sources of T cell response variability may allow simulations like this to accurately model alloreactivity in SCT in the future.}, URL = {https://www.biorxiv.org/content/early/2016/11/21/088831}, eprint = {https://www.biorxiv.org/content/early/2016/11/21/088831.full.pdf}, journal = {bioRxiv} }