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Increased NK cell lytic activity in chronic HCV infection
Abstracts / Digestive and Liver Disease 40 (2008) A1–A40
HBeAg neg, 73% cirrhotics) started on 10 mg/daily ADV added to ongoing LMV, and were followed-up for a median of 57 months (range 16–81). HBV DNA was assessed every three months by Versant 3.0 (LLQ < 3.3 log cp/ml). Drug resistance was assessed by INNO-LiPA HDR V2 assay in viremic patients every year. Results. Serum HBV–DNA became undetectable in 37/63 (59%), 44/61 (72%), 48/58 (83%) and 45/54 (83%) patients after 1, 2, 3 and 4 years. None of the patients with either persistent viremia or undetectable HBV DNA, experienced a virologic breakthrough, i.e. a >1 log increase of HBV DNA compared to on-treatment nadir. No patient circulated genotypic resistance for rtN236T or rtA181V either at baseline or during follow-up. By converse, the rtA181V mutation was identified as a mixed viral population in six patients (three at baseline and three during treatment at year 1, 2 and 3, respectively). Despite this, HBV DNA progressively declined in all patients to become undetectable in 5 of 6 them. None of 46 cirrhotics clinically decompensated, but 8 (17%) developed hepatocellular carcinoma after 3–38 months (median 24). Three died (2 of liver unrelated causes) and 5 underwent liver transplantation. Conclusions. Adefovir/lamivudine combination prevented ADV resistance and clinical decompensation during 4-year treatment, however without prevention of hepatocellular carcinoma. doi:10.1016/j.dld.2007.12.072 INCREASED NK CELL LYTIC ACTIVITY IN CHRONIC HCV INFECTION B. Oliviero a , S. Varchetta a , A. Cerino a , G. Michelone a , M. Zaramella a , D. Mavilio b , M.U. Mondelli a a
Department of Infectious Diseases, IRCCS Fondazione San Matteo and University of Pavia, Italy b Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD, USA Background/aim. Viral infections are influenced by the quality of innate immune responses, which are thought to control adaptive immunity via interaction with dendritic cells. Little is known on the role of NK cells in HCV infection, the principal effectors of innate immunity, and their ability to lyse virus-infected cells or to produce immunoregulatory cytokines in response to different stimuli. We determined the phenotype and function of NK cells in untreated patients with chronic HCV infection. Material and methods. Peripheral blood mononuclear cells were obtained from 25 patients with chronic HCV infection and controls. NK receptors were identified using mAbs specific for inhibitory (CD94/NKG2A, p75, IRP60, LIR1/ILT2, KIRs) and activating (NKp46, NKp30, NKp44, NKG2D, CD94/NKG2C) receptors. The NK cell cytolytic activity was measured using the CD107a degranulation assay. Functional correlates of inhibitory and activating NK cell receptors were evaluated through re-directed killing assays with FcyR+ P815 target cell lines.
A27
Results. There was a statistically significant increase in the proportion of NK cells expressing the activating receptor NKG2D (p = 0.0092) and, conversely, a significant reduction of cells expressing inhibitory receptors (KIRs and LIR1/ILT2, p = 0.0036) compared with controls. In line with this phenotype, the NK cell-mediated killing of P815 target cells was significantly higher in cells from HCV patient compared to that of uninfected donors. (p = 0.0006). Moreover, redirecting killing experiments confirmed that the increased expression of NKG2D on cells from HCV infected individuals resulted in a higher NKG2D-mediated killing of P815 cells compared to that of uninfected individuals (p = 0.0081). Even the triggering of NKp30 and NKp46 in cells from HCV infected patients induced a significantly higher lysis of P815 compared to that of normal controls (p = 0.0021 for NKp46; p = 0.0032 for NKp30). Conclusions. These data indicate that phenotype and functions of the NK cell compartment in chronic HCV infection are markedly dysfunctional and suggest that this virus is able to enhance NK cytolytic activity mainly through the NKG2D pathway. Therefore, the persistent stimulus given by chronic HCV infection together with the increased NK cell cytotoxicity may contribute to liver injury. doi:10.1016/j.dld.2007.12.073 RISK OF HEPATITIS B AND EFFICACY OF TREATMENT WITH LAMIVUDINE IN PATIENTS UNDERGOING ALLO-SCT L. Mezzabotta a , L. Giaccone b , I. Resta b , A. Marengo a , F. Fiore b , R. Sorasio b , M. Festuccia b , M. Boccadoro b , B. Bruno b , M. Rizzetto a , A. Marzano a a
Gastro-Hepatology, Molinette Hospital, University of Turin Molinette Hospital, University of Turin
b Haematology,
Introduction. HBV+ patients undergoing allogeneic stem cell transplantation (allo-SCT) and recipients of allo-SCT from HBV+ donors are at risk of hepatitis B reactivation (HBR). Patients. Between 1998 and 2007, 98 allo-SCTs were performed and 90 analysed (median follow-up 31 months, range 4–91). Patients (median age 51 years, range 21–66), were transplanted for MM (54), AML (14), CLL (9), lymphoma (7), CMD (5) and AA (1). Three patients received 2 allo-SCT from the same donor for disease progression. SC source was blood in 89 patients and bone marrow in one. Seventy patients had HLA-matched sibling donors and 20 unrelated donors. Since 2005 patients at risk of HBR were treated with LAM prophylaxis. Results. Sixty-four subjects were not considered at risk of HBR (recipients HBsAg/antiHBc− with donors HBsAg−). Four of them received an antiHBc+ donors. None developed HBR. Twenty-six patients were considered at risk: (A) 2 HBsAg− recipients from HBsAg+ donors, treated with LAM before and after SCT. None of them developed HBR 19–22 months after allo-SCT. (B) 2 HBsAg+ recipients from
HBeAg neg, 73% cirrhotics) started on 10 mg/daily ADV added to ongoing LMV, and were followed-up for a median of 57 months (range 16–81). HBV DNA was assessed every three months by Versant 3.0 (LLQ < 3.3 log cp/ml). Drug resistance was assessed by INNO-LiPA HDR V2 assay in viremic patients every year. Results. Serum HBV–DNA became undetectable in 37/63 (59%), 44/61 (72%), 48/58 (83%) and 45/54 (83%) patients after 1, 2, 3 and 4 years. None of the patients with either persistent viremia or undetectable HBV DNA, experienced a virologic breakthrough, i.e. a >1 log increase of HBV DNA compared to on-treatment nadir. No patient circulated genotypic resistance for rtN236T or rtA181V either at baseline or during follow-up. By converse, the rtA181V mutation was identified as a mixed viral population in six patients (three at baseline and three during treatment at year 1, 2 and 3, respectively). Despite this, HBV DNA progressively declined in all patients to become undetectable in 5 of 6 them. None of 46 cirrhotics clinically decompensated, but 8 (17%) developed hepatocellular carcinoma after 3–38 months (median 24). Three died (2 of liver unrelated causes) and 5 underwent liver transplantation. Conclusions. Adefovir/lamivudine combination prevented ADV resistance and clinical decompensation during 4-year treatment, however without prevention of hepatocellular carcinoma. doi:10.1016/j.dld.2007.12.072 INCREASED NK CELL LYTIC ACTIVITY IN CHRONIC HCV INFECTION B. Oliviero a , S. Varchetta a , A. Cerino a , G. Michelone a , M. Zaramella a , D. Mavilio b , M.U. Mondelli a a
Department of Infectious Diseases, IRCCS Fondazione San Matteo and University of Pavia, Italy b Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD, USA Background/aim. Viral infections are influenced by the quality of innate immune responses, which are thought to control adaptive immunity via interaction with dendritic cells. Little is known on the role of NK cells in HCV infection, the principal effectors of innate immunity, and their ability to lyse virus-infected cells or to produce immunoregulatory cytokines in response to different stimuli. We determined the phenotype and function of NK cells in untreated patients with chronic HCV infection. Material and methods. Peripheral blood mononuclear cells were obtained from 25 patients with chronic HCV infection and controls. NK receptors were identified using mAbs specific for inhibitory (CD94/NKG2A, p75, IRP60, LIR1/ILT2, KIRs) and activating (NKp46, NKp30, NKp44, NKG2D, CD94/NKG2C) receptors. The NK cell cytolytic activity was measured using the CD107a degranulation assay. Functional correlates of inhibitory and activating NK cell receptors were evaluated through re-directed killing assays with FcyR+ P815 target cell lines.
A27
Results. There was a statistically significant increase in the proportion of NK cells expressing the activating receptor NKG2D (p = 0.0092) and, conversely, a significant reduction of cells expressing inhibitory receptors (KIRs and LIR1/ILT2, p = 0.0036) compared with controls. In line with this phenotype, the NK cell-mediated killing of P815 target cells was significantly higher in cells from HCV patient compared to that of uninfected donors. (p = 0.0006). Moreover, redirecting killing experiments confirmed that the increased expression of NKG2D on cells from HCV infected individuals resulted in a higher NKG2D-mediated killing of P815 cells compared to that of uninfected individuals (p = 0.0081). Even the triggering of NKp30 and NKp46 in cells from HCV infected patients induced a significantly higher lysis of P815 compared to that of normal controls (p = 0.0021 for NKp46; p = 0.0032 for NKp30). Conclusions. These data indicate that phenotype and functions of the NK cell compartment in chronic HCV infection are markedly dysfunctional and suggest that this virus is able to enhance NK cytolytic activity mainly through the NKG2D pathway. Therefore, the persistent stimulus given by chronic HCV infection together with the increased NK cell cytotoxicity may contribute to liver injury. doi:10.1016/j.dld.2007.12.073 RISK OF HEPATITIS B AND EFFICACY OF TREATMENT WITH LAMIVUDINE IN PATIENTS UNDERGOING ALLO-SCT L. Mezzabotta a , L. Giaccone b , I. Resta b , A. Marengo a , F. Fiore b , R. Sorasio b , M. Festuccia b , M. Boccadoro b , B. Bruno b , M. Rizzetto a , A. Marzano a a
Gastro-Hepatology, Molinette Hospital, University of Turin Molinette Hospital, University of Turin
b Haematology,
Introduction. HBV+ patients undergoing allogeneic stem cell transplantation (allo-SCT) and recipients of allo-SCT from HBV+ donors are at risk of hepatitis B reactivation (HBR). Patients. Between 1998 and 2007, 98 allo-SCTs were performed and 90 analysed (median follow-up 31 months, range 4–91). Patients (median age 51 years, range 21–66), were transplanted for MM (54), AML (14), CLL (9), lymphoma (7), CMD (5) and AA (1). Three patients received 2 allo-SCT from the same donor for disease progression. SC source was blood in 89 patients and bone marrow in one. Seventy patients had HLA-matched sibling donors and 20 unrelated donors. Since 2005 patients at risk of HBR were treated with LAM prophylaxis. Results. Sixty-four subjects were not considered at risk of HBR (recipients HBsAg/antiHBc− with donors HBsAg−). Four of them received an antiHBc+ donors. None developed HBR. Twenty-six patients were considered at risk: (A) 2 HBsAg− recipients from HBsAg+ donors, treated with LAM before and after SCT. None of them developed HBR 19–22 months after allo-SCT. (B) 2 HBsAg+ recipients from