Background: Extended cold preservation contributes to organ ischemia-reperfusion injury (IRI), which stimulates host allo-reactivity, leading to inferior clinical outcomes. We have shown that CD4+ T cells, primarily of T-helper 1 phenotype, are critical for proinflammatory immune responses in IR-stressed mouse livers; and that CD4+ T cell depletion (but not CD4 blockade) prevents hepatocellular damage in warm liver IRI model. Aim: To investigate whether prolonged cold ischemia may affect host alloreactivity in mouse orthotopic liver transplantation (OLT) and to evaluate the effects of anti-CD4 mAb on lymphocyte populations infiltrating MHC-mismatched OLT (allo-OLT). Methods: Livers from B6 or Balb/c mouse donors preserved for 18h at 4[deg] in UW solution were transplanted orthotopically to B6 recipients. Both, donors and recipients were treated with anti-CD4 mAb (GK1.5; 500ug/mouse i.v.) or control Ig at 48h prior to OLT. Results: Compared with iso-OLT, liver allografts suffered more severe hepatocellular damage after cold storage, as evidenced by increased serum ALT levels (p<0.05) and Suzuki's histological score of liver IRI (p<0.05) at 6h post-transplantation (n=5/gr). Compared with Ig-treated controls, depletion of CD4 T cells protected allo-OLT from IR-stress, preserving the hepatocellular function (sALT = 10,846±2,006 and 6,364±2,766 IU/L, respectively; n=5/gr, p<0.05) and OLT histological architecture (Suzuki's score = 6.4±0.8 and 3.1±1.2, respectively; n=5/gr, p<0.05). In parallel, treatment with GK1.5 mAb depressed allo-OLT expression of pro-inflammatory cytokines, such as IL-2 (p<0.05). Flow cytometry analysis of allo-OLT infiltrating T cells has revealed that CD4 depletion decreased the T-bet/Foxp3 T cell ratio (1.3 vs. 0.0;

). Conclusion: This study is the first to document the efficacy of anti-CD4 mAb treatment in a clinically relevant murine model of hepatic IRI in allo-OLT. Depletion of CD4+ T cells reduced the hepatocellular damage and attenuated liver inflammatory response, at least in part by altering OLT-infiltrating T lymphocytes from a pro-inflammatory into regulatory phenotype.

CITATION INFORMATION: Kageyama S, Nakamura K, Busuttil R, Kupiec-Weglinski J, Zhai Y. CD4 T Cell Depletion Mitigates Ischemic Hepatocellular Damage and Promotes Immune Regulation in Mouse Liver Allografts. Am J Transplant. 2017;17 (suppl 3).

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