Aim: To investigate the effect of HIF-1α and -2α activation in myelomonocytic cells during the early phase after ischemia-reperfusion (IRI) injury of mouse allogenic heart transplants.

Methods: We crossed C57 mice carrying a floxed VHL (loxP) allele with C57 mice carrying the lysozyme M promoter (LysMCre) allele, leading to constitutive expression of HIF-1α and -2α in the myeloid cell lineage (VHL knockout, ko). We transplanted hearts from fully MHC-mismatched wild-type Balb/c mice heterotopically into these mice (n=8). C57 VHL littermate mice (LysMCre-) served as control recipients (n=8). Syngenic transplantations were performed between fully MHC-matched Balb/c mice (n=6). Heart transplants were subjected to 2h cold- and 1h warm ischemia prior to reperfusion. We sacrificed recipients at 6h after reperfusion and measured serum cTnT concentrations. Cross-sections from heart transplants were stained for inflammatory cells and tissue samples analyzed for pro- and anti-inflammatory cytokine mRNA expression with real-time RT-PCR.

Results: Serum cTnT concentration was significantly lower in the VHL ko recipients at 6h after reperfusion. The amount of intragraft CD11β, MPO, CD11c, CD4 and CD8 cells was similar. The proinflammatory cytokine IL-1b mRNA expression was significantly lower in the VHL ko hearts, and a trend towards increased immunosuppressive Arg-1 mRNA expression in the VHL ko group was evident.

Conclusions: Constitutive recipient myelomonocyte-specific HIF-1α and -2α expression alleviates cardiac allograft IRI, potentially by modulating the cells towards and immunosuppressive phenotype.

Next, we will investigate the alloantingen recognising and secondary lymphoid tissue homing properties of these myelomonocytic cells. Then, we are going to selectively block monocytes or neutrophils to determine the specific cells that mediate these favorable effects. Lastly, we are going to investigate how those cells behave during the long run.

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