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Mathematical Modeling of Early Cellular Innate and Adaptive Immune Responses to Ischemia/Reperfusion Injury and Solid Organ Allotransplantation.

Day JD, Metes DM, Vodovotz Y - Front Immunol (2015)

Bottom Line: We first consider the inflammatory events associated only with the initial surgical procedure and the subsequent ischemia/reperfusion (I/R) events that cause tissue damage to the host as well as the donor graft.These events release damage-associated molecular pattern molecules (DAMPs), thereby initiating an acute inflammatory response.An emergent phenomenon from our simulations is that low-level DAMP release can tolerize the recipient to a mismatched allograft, whereas different restimulation regimens resulted in an exaggerated rejection response, in agreement with published studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Mathematics, University of Tennessee , Knoxville, TN , USA ; National Institute for Mathematical and Biological Synthesis , Knoxville, TN , USA.

ABSTRACT
A mathematical model of the early inflammatory response in transplantation is formulated with ordinary differential equations. We first consider the inflammatory events associated only with the initial surgical procedure and the subsequent ischemia/reperfusion (I/R) events that cause tissue damage to the host as well as the donor graft. These events release damage-associated molecular pattern molecules (DAMPs), thereby initiating an acute inflammatory response. In simulations of this model, resolution of inflammation depends on the severity of the tissue damage caused by these events and the patient's (co)-morbidities. We augment a portion of a previously published mathematical model of acute inflammation with the inflammatory effects of T cells in the absence of antigenic allograft mismatch (but with DAMP release proportional to the degree of graft damage prior to transplant). Finally, we include the antigenic mismatch of the graft, which leads to the stimulation of potent memory T cell responses, leading to further DAMP release from the graft and concomitant increase in allograft damage. Regulatory mechanisms are also included at the final stage. Our simulations suggest that surgical injury and I/R-induced graft damage can be well-tolerated by the recipient when each is present alone, but that their combination (along with antigenic mismatch) may lead to acute rejection, as seen clinically in a subset of patients. An emergent phenomenon from our simulations is that low-level DAMP release can tolerize the recipient to a mismatched allograft, whereas different restimulation regimens resulted in an exaggerated rejection response, in agreement with published studies. We suggest that mechanistic mathematical models might serve as an adjunct for patient- or sub-group-specific predictions, simulated clinical studies, and rational design of immunosuppression.

No MeSH data available.


Related in: MedlinePlus

Preconditioning phenomena: initial surgical IRI allows damaged graft to recover compared to scenario wherein graft failure occurs in the absence of initial surgical damage. (A) Graft functionality with (blue) and without (red) an initial level of host I/R damage, D(0). Initial graft damage [DG(0) = 2] along with a low initial level of host tissue damage [D(0) = 1] results in graft recovery to full functionality (blue); whereas initial graft damage [DG(0) = 2] without the low initial level of host damage [D(0) = 0] leads to graft failure (red). (B) The anti-inflammatory components, A, and (C) anti-inflammatory T cells, TA, with (blue) and without (red) an initial level of host IRI, D(0). Comparing the red and blue time courses for both anti-inflammatory variables (A and TA) in (B,C), one observes a slight increase in levels (blue above red) in the first 24 h or so. This increase in the anti-inflammatory variables (especially of A) induced by the very inflammatory cascade that was due to DAMP release actually allows for graft survival.
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Figure 5: Preconditioning phenomena: initial surgical IRI allows damaged graft to recover compared to scenario wherein graft failure occurs in the absence of initial surgical damage. (A) Graft functionality with (blue) and without (red) an initial level of host I/R damage, D(0). Initial graft damage [DG(0) = 2] along with a low initial level of host tissue damage [D(0) = 1] results in graft recovery to full functionality (blue); whereas initial graft damage [DG(0) = 2] without the low initial level of host damage [D(0) = 0] leads to graft failure (red). (B) The anti-inflammatory components, A, and (C) anti-inflammatory T cells, TA, with (blue) and without (red) an initial level of host IRI, D(0). Comparing the red and blue time courses for both anti-inflammatory variables (A and TA) in (B,C), one observes a slight increase in levels (blue above red) in the first 24 h or so. This increase in the anti-inflammatory variables (especially of A) induced by the very inflammatory cascade that was due to DAMP release actually allows for graft survival.

Mentions: In some simulations, an initial level of host tissue damage can act as a preconditioning factor in promoting graft survival. While the release of DAMPs from injured tissue incites pro-inflammatory components, the cascade also involves induction of anti-inflammatory mediators. If the pro-inflammatory levels from this initial surgical DAMP release are below some threshold, and the corresponding anti-inflammatory cell/mediator levels are above some threshold at the time the additional DAMP release happens from an IR-injured graft, then an attenuated damage response may be possible. We depict one such simulation experiment of this preconditioning phenomenon, shown in Figure 5. This type of preconditioning, in which the response to a second insult is lower than that for the first, is called “tolerance” and has been reported widely in multiple settings of acute inflammation (62, 63). Indeed, a similar tolerance phenomenon was reproduced in a mathematical model of the host immune response to repeated endotoxin challenge (64). That study also demonstrated that repeated endotoxin challenges that were not timed carefully displayed potentiation of the inflammatory response, another manifestation of preconditioning typically known as priming (65). The analogous potentiation feature was seen in the present model in Figure 3D even with no mismatch factor present. We interpret this outcome to be similar to the scenario in which a graft is rejected, and the patient undergoes repeat transplantation. The outcomes in this setting are known to be poor (44, 66). Thus, the timing of the excitatory and inhibitory mechanisms involved in the entire transplant process is important to understand in order for therapeutic strategies to positively synergize with these events.


Mathematical Modeling of Early Cellular Innate and Adaptive Immune Responses to Ischemia/Reperfusion Injury and Solid Organ Allotransplantation.

Day JD, Metes DM, Vodovotz Y - Front Immunol (2015)

Preconditioning phenomena: initial surgical IRI allows damaged graft to recover compared to scenario wherein graft failure occurs in the absence of initial surgical damage. (A) Graft functionality with (blue) and without (red) an initial level of host I/R damage, D(0). Initial graft damage [DG(0) = 2] along with a low initial level of host tissue damage [D(0) = 1] results in graft recovery to full functionality (blue); whereas initial graft damage [DG(0) = 2] without the low initial level of host damage [D(0) = 0] leads to graft failure (red). (B) The anti-inflammatory components, A, and (C) anti-inflammatory T cells, TA, with (blue) and without (red) an initial level of host IRI, D(0). Comparing the red and blue time courses for both anti-inflammatory variables (A and TA) in (B,C), one observes a slight increase in levels (blue above red) in the first 24 h or so. This increase in the anti-inflammatory variables (especially of A) induced by the very inflammatory cascade that was due to DAMP release actually allows for graft survival.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4585194&req=5

Figure 5: Preconditioning phenomena: initial surgical IRI allows damaged graft to recover compared to scenario wherein graft failure occurs in the absence of initial surgical damage. (A) Graft functionality with (blue) and without (red) an initial level of host I/R damage, D(0). Initial graft damage [DG(0) = 2] along with a low initial level of host tissue damage [D(0) = 1] results in graft recovery to full functionality (blue); whereas initial graft damage [DG(0) = 2] without the low initial level of host damage [D(0) = 0] leads to graft failure (red). (B) The anti-inflammatory components, A, and (C) anti-inflammatory T cells, TA, with (blue) and without (red) an initial level of host IRI, D(0). Comparing the red and blue time courses for both anti-inflammatory variables (A and TA) in (B,C), one observes a slight increase in levels (blue above red) in the first 24 h or so. This increase in the anti-inflammatory variables (especially of A) induced by the very inflammatory cascade that was due to DAMP release actually allows for graft survival.
Mentions: In some simulations, an initial level of host tissue damage can act as a preconditioning factor in promoting graft survival. While the release of DAMPs from injured tissue incites pro-inflammatory components, the cascade also involves induction of anti-inflammatory mediators. If the pro-inflammatory levels from this initial surgical DAMP release are below some threshold, and the corresponding anti-inflammatory cell/mediator levels are above some threshold at the time the additional DAMP release happens from an IR-injured graft, then an attenuated damage response may be possible. We depict one such simulation experiment of this preconditioning phenomenon, shown in Figure 5. This type of preconditioning, in which the response to a second insult is lower than that for the first, is called “tolerance” and has been reported widely in multiple settings of acute inflammation (62, 63). Indeed, a similar tolerance phenomenon was reproduced in a mathematical model of the host immune response to repeated endotoxin challenge (64). That study also demonstrated that repeated endotoxin challenges that were not timed carefully displayed potentiation of the inflammatory response, another manifestation of preconditioning typically known as priming (65). The analogous potentiation feature was seen in the present model in Figure 3D even with no mismatch factor present. We interpret this outcome to be similar to the scenario in which a graft is rejected, and the patient undergoes repeat transplantation. The outcomes in this setting are known to be poor (44, 66). Thus, the timing of the excitatory and inhibitory mechanisms involved in the entire transplant process is important to understand in order for therapeutic strategies to positively synergize with these events.

Bottom Line: We first consider the inflammatory events associated only with the initial surgical procedure and the subsequent ischemia/reperfusion (I/R) events that cause tissue damage to the host as well as the donor graft.These events release damage-associated molecular pattern molecules (DAMPs), thereby initiating an acute inflammatory response.An emergent phenomenon from our simulations is that low-level DAMP release can tolerize the recipient to a mismatched allograft, whereas different restimulation regimens resulted in an exaggerated rejection response, in agreement with published studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Mathematics, University of Tennessee , Knoxville, TN , USA ; National Institute for Mathematical and Biological Synthesis , Knoxville, TN , USA.

ABSTRACT
A mathematical model of the early inflammatory response in transplantation is formulated with ordinary differential equations. We first consider the inflammatory events associated only with the initial surgical procedure and the subsequent ischemia/reperfusion (I/R) events that cause tissue damage to the host as well as the donor graft. These events release damage-associated molecular pattern molecules (DAMPs), thereby initiating an acute inflammatory response. In simulations of this model, resolution of inflammation depends on the severity of the tissue damage caused by these events and the patient's (co)-morbidities. We augment a portion of a previously published mathematical model of acute inflammation with the inflammatory effects of T cells in the absence of antigenic allograft mismatch (but with DAMP release proportional to the degree of graft damage prior to transplant). Finally, we include the antigenic mismatch of the graft, which leads to the stimulation of potent memory T cell responses, leading to further DAMP release from the graft and concomitant increase in allograft damage. Regulatory mechanisms are also included at the final stage. Our simulations suggest that surgical injury and I/R-induced graft damage can be well-tolerated by the recipient when each is present alone, but that their combination (along with antigenic mismatch) may lead to acute rejection, as seen clinically in a subset of patients. An emergent phenomenon from our simulations is that low-level DAMP release can tolerize the recipient to a mismatched allograft, whereas different restimulation regimens resulted in an exaggerated rejection response, in agreement with published studies. We suggest that mechanistic mathematical models might serve as an adjunct for patient- or sub-group-specific predictions, simulated clinical studies, and rational design of immunosuppression.

No MeSH data available.


Related in: MedlinePlus