Date: Sunday, June 12, 2016
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Halls C&D
Concurrent infections have been shown to increase risk of transplant rejection via enhanced innate immune activation and increased T cell alloreactivity. In some cases, these infections can progress to sepsis, a dysregulated immune response to infection associated with concomitant pro- and anti-inflammatory changes, lymphocyte apoptosis, monocyte deactivation, and increased T cell inhibitory markers. Importantly, the impact of this dysregulation on T cell alloreactivity and graft rejection has not been studied. We hypothesized that sepsis-induced immune dysregulation would exhibit a differential effect on alloreactivity relative to non-septic infections. To test this, mice received a fully allogeneic skin graft without immunosuppression and either no infection (control), or an intratracheal instillation of Pseudomonas aeruginosa with morbidity titrated to model either nonfatal infection or severe sepsis. Consistent with published reports of other bacterial infections, infection with Pseudomonas did accelerate graft rejection relative to uninfected controls. In survival analysis of time to graft failure, control versus pneumonia groups showed significantly different graft survival curves by log-rank test (p=0.04), with a hazard ratio for graft failure of 0.45, CI 0.21-0.98. In contrast, sepsis-inducing infection did not accelerate allograft rejection as compared to uninfected controls (p=0.29, hazard ratio 0.63, CI 0.26-1.48). To investigate the impact of sepsis on T cell alloreactivity, donor-reactive CD4+ OT-II and CD8+ OT-I T cells were adoptively transferred into mice, followed by allogeneic BALB/c OVA-expressing skin graft, and subsequent intratracheal instillation of Pseudomonas with morbidity titrated to model nonfatal infection or severe sepsis as above. Sepsis resulted in fewer graft-specific cells in the spleen at day 5 post-infection relative to non-septic infection (196047±62076 cells vs 573765±140625 cells, p=0.04). Furthermore, sepsis resulted in an increased number of donor-specific CD8+ T cells expressing the inhibitory marker 2B4 in the spleen as early as 24 hours post-infection, as compared with non-septic infection (31841±4687 vs 17632±2238, p=0.004). Taken together, these data suggest that the immune dysregulation of sepsis may result in altered T cell alloreactivity and increased expression of exhaustion markers, mitigating the impact of infection on allograft rejection.
CITATION INFORMATION: Margoles L, Laurie S, Coopersmith C, Ford M. Sepsis Prolongs Allograft Survival Compared with Non-Septic Infection in a Murine Model of Skin Transplantation and Pseudomonas aeruginosa Pneumonia. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Margoles L, Laurie S, Coopersmith C, Ford M. Sepsis Prolongs Allograft Survival Compared with Non-Septic Infection in a Murine Model of Skin Transplantation and Pseudomonas aeruginosa Pneumonia. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/sepsis-prolongs-allograft-survival-compared-with-non-septic-infection-in-a-murine-model-of-skin-transplantation-and-pseudomonas-aeruginosa-pneumonia/. Accessed May 18, 2021.
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