THERAPEUTIC PLASMA EXCHANGE MODULATES INNATE IMMUNE ACTIVATION AND IMPROVES OUTCOME IN PATIENTS WITH ACUTE LIVER FAILURE

TY - JOUR

T1 - THERAPEUTIC PLASMA EXCHANGE MODULATES INNATE IMMUNE ACTIVATION AND IMPROVES OUTCOME IN PATIENTS WITH ACUTE LIVER FAILURE

AU - Bernsmeier, Christine

AU - Patel, Vishal C.

AU - Singanayagam, A

AU - Yuksel, Muhammed

AU - Huang, X

AU - Willars, Chris

AU - Bernal, William

AU - Auzinger, Georg

AU - Ma, Yun

AU - Larsen, Fin

AU - Wendon, Julia

AU - Antoniades, C

PY - 2015/4

Y1 - 2015/4

N2 - Background and Aims: Acute liver failure (ALF) involves a mortality of >40% despite transplantation. Overwhelming hepatocyte death induces a systemic inflammatory response (SIRS) and confers adverse outcome. Monocytes are key effectors of SIRS in the pathogenesis of ALF. A multicentre study evaluating therapeutic plasma exchange (TPE) demonstrated a 20% survival benefit. TPE has been established for various immunologically driven disorders. Recent data highlight its ability to dampen innate inflammatory responses. We evaluated the effect of TPE on phenotype and function of immune effector cells.Methods: Plasma samples from ALF patients admitted to Rigshospitalet (n = 11) and King’s College Hospital (n = 9) who underwent TPE were taken before and after the first exchange. Healthy peripheral blood mononuclear cells were cultured for 24 hours in medium containing 25% plasma from ALF patients. Theeffect of plasma obtained before/after TPE was compared to plasma from patients who did not receive any therapeutic intervention (natural course, n = 11). Immunophenotyping (CD14, CD16, HLADR, CD86, MERTK, CD163, CD64, CCR7, AnnexinV) and TNF-a/IL-6 production of monocytes in response to lipopolysaccharide (LPS) and phenotyping of lymphocytes (CD4, CD8, CD56, CD127, CD25, FoxP3) and LPS-induced IFN-g/IL-2/TGF-b/IL-10 production wereassessed by flow cytometry.Results: Across TPE, a significant reduction of disease severity markers such as MELD (p = 0.0156), lactate (p = 0.0078) and AST (p = 0.0078) was observed. Monocyte counts (p = 0.8125) and apoptosis rates (AnnexinV; p = 0.1354) before and after TPE were comparable. Monocyte pro-inflammatory response (TNF a) to LPS was significantly reduced in plasma post- compared to pre-TPE (p = 0.004; CD14+16-:p = 0.0003/CD14+16+:p = 0.0014), there was no change following natural course of disease. IL-6 production was unaffected. Immunophenotyping of monocytes in post TPE plasma revealed reduced expression of activation markers CD64 (p = 0.0084), CCR7 (p = 0.0015) and CD163 (p = 0.0479), but no changes following natural course. Numbers of CD4/CD8, regulatory T-cells, NK-cells were unchanged, however CD4-cell secretion of IL-10 (p = 0.0144) and TGF-b (p = 0.0332) was significantly reduced.Conclusions: Clearance of inflammatorymediators from the plasma by TPE reduces disease severity, SIRS activation and extra hepatic organ dysfunction through suppression of innate immune cell activation in ALF; providing a mechanistic explanation for the beneficial effect of TPE on outcome in ALF.

AB - Background and Aims: Acute liver failure (ALF) involves a mortality of >40% despite transplantation. Overwhelming hepatocyte death induces a systemic inflammatory response (SIRS) and confers adverse outcome. Monocytes are key effectors of SIRS in the pathogenesis of ALF. A multicentre study evaluating therapeutic plasma exchange (TPE) demonstrated a 20% survival benefit. TPE has been established for various immunologically driven disorders. Recent data highlight its ability to dampen innate inflammatory responses. We evaluated the effect of TPE on phenotype and function of immune effector cells.Methods: Plasma samples from ALF patients admitted to Rigshospitalet (n = 11) and King’s College Hospital (n = 9) who underwent TPE were taken before and after the first exchange. Healthy peripheral blood mononuclear cells were cultured for 24 hours in medium containing 25% plasma from ALF patients. Theeffect of plasma obtained before/after TPE was compared to plasma from patients who did not receive any therapeutic intervention (natural course, n = 11). Immunophenotyping (CD14, CD16, HLADR, CD86, MERTK, CD163, CD64, CCR7, AnnexinV) and TNF-a/IL-6 production of monocytes in response to lipopolysaccharide (LPS) and phenotyping of lymphocytes (CD4, CD8, CD56, CD127, CD25, FoxP3) and LPS-induced IFN-g/IL-2/TGF-b/IL-10 production wereassessed by flow cytometry.Results: Across TPE, a significant reduction of disease severity markers such as MELD (p = 0.0156), lactate (p = 0.0078) and AST (p = 0.0078) was observed. Monocyte counts (p = 0.8125) and apoptosis rates (AnnexinV; p = 0.1354) before and after TPE were comparable. Monocyte pro-inflammatory response (TNF a) to LPS was significantly reduced in plasma post- compared to pre-TPE (p = 0.004; CD14+16-:p = 0.0003/CD14+16+:p = 0.0014), there was no change following natural course of disease. IL-6 production was unaffected. Immunophenotyping of monocytes in post TPE plasma revealed reduced expression of activation markers CD64 (p = 0.0084), CCR7 (p = 0.0015) and CD163 (p = 0.0479), but no changes following natural course. Numbers of CD4/CD8, regulatory T-cells, NK-cells were unchanged, however CD4-cell secretion of IL-10 (p = 0.0144) and TGF-b (p = 0.0332) was significantly reduced.Conclusions: Clearance of inflammatorymediators from the plasma by TPE reduces disease severity, SIRS activation and extra hepatic organ dysfunction through suppression of innate immune cell activation in ALF; providing a mechanistic explanation for the beneficial effect of TPE on outcome in ALF.

U2 - 10.1016/S0168-8278(15)30125-2

DO - 10.1016/S0168-8278(15)30125-2

M3 - Meeting abstract

SN - 0168-8278

VL - 62

SP - S246-S247

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - Supplement 2

M1 - O106

T2 - 50th The International Liver Congress - European Association for the Study of the Liver

Y2 - 22 April 2015 through 26 April 2015

ER -