title: 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.
abstract: Immune reconstitution kinetics and subsequent clinical outcomes in HLA-matched recipients of allogeneic stem cell transplantation (SCT) are variable and difficult to predict. Considering SCT as a dynamical system may allow sequence differences across the exomes of the transplant donors and recipients to be used to simulate an alloreactive T cell response, which may allow better clinical outcome prediction. To accomplish this, whole exome sequencing was performed on 34 HLA-matched SCT donor-recipient pairs (DRPs) and the nucleotide sequence differences translated to peptides. The binding affinity of the peptides to the relevant HLA in each DRP was determined. The resulting array of peptide-HLA binding affinity values in each patient was considered as an operator modifying a hypothetical T cell repertoire vector, in which each T cell clone proliferates in accordance with the logistic equation of growth. Using an iterating system of matrices, each simulated T cell clone's growth was calculated with the steady-state population being proportional to the magnitude of the binding affinity of the driving HLA-peptide complex. Incorporating competition between T cell clones responding to different HLA-peptide complexes reproduces a number of features of clinically observed T cell clonal repertoire in the simulated repertoire, including sigmoidal growth kinetics of individual T cell clones and overall repertoire, Power Law clonal frequency distribution, increase in repertoire complexity over time with increasing clonal diversity, and alteration of clonal dominance when a different antigen array is encountered, such as in SCT. The simulated, alloreactive T cell repertoire was markedly different in HLA-matched DRPs. The patterns were differentiated by rate of growth and steady-state magnitude of the simulated T cell repertoire and demonstrate a possible correlation with survival. In conclusion, exome wide sequence differences in DRPs may allow simulation of donor alloreactive T cell response to recipient antigens and may provide a quantitative basis for refining donor selection and titration of immunosuppression after SCT.
authors.affiliation: Virginia Commonwealth University School of Engineering, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Badar
authors.initials: B
authors.lastname: Abdul Razzaq
authors.affiliation: Bone Marrow Transplant Program, Massey Cancer Center & Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Allison
authors.initials: A
authors.lastname: Scalora
authors.affiliation: Center for Biological Complexity, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Vishal N
authors.initials: VN
authors.lastname: Koparde
authors.affiliation: Bone Marrow Transplant Program, Massey Cancer Center & Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Meier
authors.affiliation: Virginia Commonwealth University School of Engineering, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Musa
authors.initials: M
authors.lastname: Mahmood
authors.affiliation: Virginia Commonwealth University School of Engineering, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Salman
authors.initials: S
authors.lastname: Salman
authors.affiliation: Bone Marrow Transplant Program, Massey Cancer Center & Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Max
authors.initials: M
authors.lastname: Jameson-Lee
authors.affiliation: Center for Biological Complexity, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Myrna G
authors.initials: MG
authors.lastname: Serrano
authors.affiliation: Center for Biological Complexity, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Nihar
authors.initials: N
authors.lastname: Sheth
authors.affiliation: Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Mark
authors.initials: M
authors.lastname: Voelkner
authors.affiliation: Bone Marrow Transplant Program, Massey Cancer Center & Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kobulnicky
authors.affiliation: Bone Marrow Transplant Program, Massey Cancer Center & Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Roberts
authors.affiliation: Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ferreira-Gonzalez
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
authors.affiliation: Center for Biological Complexity, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Buck
authors.affiliation: Department of Psychiatry and Statistical Genomics, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Neale
authors.affiliation: Bone Marrow Transplant Program, Massey Cancer Center & Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298. Electronic address: amir.toor@vcuhealth.org.
authors.forename: Amir A
authors.initials: AA
authors.lastname: Toor
mesh_terms: D000328:Adult; D064591:Allografts; D059472:Exome; D005260:Female; D055106:Genome-Wide Association Study; D006680:HLA Antigens / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes; D014019:Tissue Donors
chemical_list: D006680:HLA Antigens; D011948:Receptors, Antigen, T-Cell
keywords: Dynamic system; GVHD; HLA; Histocompatibility; Logistic equation; Operators; Stem cell transplantation; Vectors; Whole exome sequencing