Date: Sunday, June 12, 2016
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Halls C&D
Background: Porcine lungs exhibit injury by human blood and are only partially protected in GalTKO organs with additional human membrane cofactor protein (hCD46). Residual injury pathways remain incompletely characterized. Here we analyze perfusate plasma, to describe a luminex assay-defined proteomic profile associated with xenogenic injury of pig lungs.
Methods: Lungs from GalTKO.hCD46 pigs (n=18) or pigs with additional genetic modifications (n=20) were perfused with human blood. Plasma (0, 1 and 4h) was tested with up to 18 human and 13 pig analytes. In addition, pig lungs were transplanted in baboons (n=21) and plasma (0, 1, 4, 6, 8, and 24 h) tested for NHP analytes.
Results: Plasma levels of human IL-4, IL-12/23, IL-13, and IFNG tended to decrease during lung perfusion of GalTKO.CD46+/- (n=7) but did not decrease or change consistently for other pig genetics. All other human cytokines generally increased during lung perfusion. No significant change was detected with addition of hCD55 (n=6) to GalTKO.hCD46 +/+ (n=5) pig lungs. In contrast, the increase in MCP-1 with GalTKO.hCD46+/+ ([Delta] 4h-0': 164±56pg/ml) was blunted with addition of Neu5GcKO (-87±36, p=0.006), and TNFA tended to be lower (p=0.07). Lower sCD40L was associated with protection of EPCR or HLA-E expressing lungs. Inflammatory mediators commonly associated with sepsis (ELA2, LTF, TSP, resistin) and porcine cytokines were also increased in GalTKO.CD46+/-. In vivo, IL-6 (~40x), IL-8 (~10x), IL-10 (~30x), IL-17A (~6x), and sCD40L (~2x) increased after LTX irrespective of whether immunosuppression (IS) was given. IL-1B, IL-2, IFNG, MCP-1, and TNFA increased 3-30-fold after lung transplantation in non-immunosuppressed baboons, but decreased (3-4/7 animals) or remained stable in baboons receiving (IS).
Conclusions: Inflammatory and innate immunity pathway mediators that promote neutrophil and monocyte infiltration in the lung (MCP-1, IL-8) and inflammatory cytokines are upregulated in two preclinical lung models. Neutrophil (elastase) and platelet (sCD40L, TSP) activation are prominent, and likely contribute significantly to residual lung injury. These results justify targeting these pathways (by pathway blockade or genetic manipulation) as a strategy to improve lung xenotransplantation.
CITATION INFORMATION: Azimzadeh A, Cheng N, Cheng X, Schwartz E, Burdorf L, Dahi S, Kubicki N, Parsell D, Zhang T, Cooper D, Phelps C, Ayares D, Pierson III R. Multiplex Profiling of Plasma Proteins After Xenogenic Lung Exposure. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Azimzadeh A, Cheng N, Cheng X, Schwartz E, Burdorf L, Dahi S, Kubicki N, Parsell D, Zhang T, Cooper D, Phelps C, Ayares D, III RPierson. Multiplex Profiling of Plasma Proteins After Xenogenic Lung Exposure. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/multiplex-profiling-of-plasma-proteins-after-xenogenic-lung-exposure/. Accessed March 7, 2021.
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