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Dynamical System Modeling to Simulate Donor T Cell Response to Whole Exome Sequencing-Derived Recipient Peptides Demonstrates Different Alloreactivity.

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Presentation on theme: "Dynamical System Modeling to Simulate Donor T Cell Response to Whole Exome Sequencing-Derived Recipient Peptides Demonstrates Different Alloreactivity."— Presentation transcript:

1 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  Badar Abdul Razzaq, Allison Scalora, Vishal N. Koparde, Jeremy Meier, Musa Mahmood, Salman Salman, Max Jameson-Lee, Myrna G. Serrano, Nihar Sheth, Mark Voelkner, David J. Kobulnicky, Catherine H. Roberts, Andrea Ferreira-Gonzalez, Masoud H. Manjili, Gregory A. Buck, Michael C. Neale, Amir A. Toor  Biology of Blood and Marrow Transplantation  Volume 22, Issue 5, Pages (May 2016) DOI: /j.bbmt Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

2 Biology of Blood and Marrow Transplantation 2016 22, 850-861DOI: (10
Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

3 Figure 1 Sigmoid growth behavior of simulated individual T cell clonal frequencies under a noncompeting model with different peptide–HLA binding affinities. Proportional growth factors are (A) IC nM, (B) IC nM, and (C) IC nM. Note declining y-axis values in the successive graphs. P# indicates patient number. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

4 Figure 2 Simulated clonal frequency of individual T cell clones accounting for competition between clones. (A) IC nM, (B) IC nM, and (C) IC50 4 nM. Marked early fluctuation can be seen in clonal populations, followed by eventual achievement of steady state at a rate proportional to the binding affinity of the target peptide. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

5 Figure 3 Phase space plots of T cell clonal growth patterns, Nt plotted as a function of Nt−1. Plots A, B, and C are successive clones from P33, and D depicts cumulative clones from P47. Clonal frequency loops have a similar morphology in different patients and tend to evolve toward a limited region of the phase space, an attractor. Attractors may be associated with certain clinical outcomes, like GVHD or tolerance when the entire T cell repertoire is considered. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

6 Figure 4 A. Simulated T cell clonal repertoire configurations (sum of all T cell clones plotted over time), from different HLA-matched patients, fall in 3 broad classes. y-Axis depicts the total T cell number and x-axis, the iterations. (A) Configuration A or α: Rapid average exponential growth with high K. Configuration B or β: Slower exponential growth phase with lower average K. Configuration C or γ: Very slow growth with very low average K value. (B) Range of steady-state values for each vector pattern in the 34 patient cohort: α, n = 10; β, n = 10; and γ, n = 14. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

7 Figure 5 Survival (A) and relapse (B) in patients with TCR vector configuration α, β, and γ, respectively (determination based on the steady-state values). Mantel Cox, test for equality of distribution log-rank P = .03 for survival and P = .47 for relapse. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

8 Figure 6 (A) Cumulative effect of multipliers on K for individual clones to simulate tissue distribution of peptides. Marked slowing of the rate of growth because of a large number of competing clones and significantly larger magnitude of eventual vector. Total clonal frequency plotted against iterations. (B) Vector transformation by the alloreactivity operator. Original T cell vector (gray line) mapped to a new configuration (black line) when iterated through an inverse of the alloreactivity operator. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

9 Figure 7 Multiple different sets of antigens contribute to eventual T cell repertoire formation and competition between clones may alter eventual clinical outcomes. (A) Competing arrays of different antigens encountered by donor T cells after transplantation transform the vector (reversal of the clonal frequencies depicted by the red and orange arrowheads). (B) Depending on the immunogenicity of antigens encountered in the recipients, either alloreactive or nonalloreactive donor-derived T cell clones may becoming dominant. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

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