Do transgenic mice expressing human PiZ α1-Antitrypsin develop liver disease?
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31 DO TRANSGENICMICE EXPRESSINGHUMANPiZ ~:ANTITRYPSIN DEVELOPLIVER DISEASE? &, , Rogers § Hawkins § , negold § J.A. Carlson , R.N. Sifers , B.B. , H.K. M.d. Fi , * * * * &Department S.M. Clift , F.J. DeMayo , D.W. Bullock and S.L.C. Woo , of Medicine, Malm~ General Hospital, Malm~, Sweden, Departments of Cell Biology and §Pathology, Baylor College of Medicine, Houston, Texas, U.S.A. Transgenic mice created by themicroinjection of the human structural genes for normal PiM and variant PiZ ~1-antitrypsin (AAT) into mouse embryos and their non-transgenic littermates were sacrificed at ages from 6 to 18 months. Immunhistochemistryof livers revealed globular aggregates of human AAT immunoreactive substance in hepatocytes and immune electronmicroscopy localized aggregates tothe RER of PiZ mouse hepatocytes. This is t o t a l l y analagousto the human PiZ secretory defect. Hematoxylin-eosin stained biopsies were scored objectively forpathological characteristics. Mean biopsy score in 92 PiZ mice was 5.1 compared to 3.0 for 72 PiM mice and 2.0 for 65non-transgenic littermates (p<O.O01 when comparing PiZ mice to each control group). Chronic lobular inflammation was the most predominant feature and mild fibrosis was frequently seen, but no case of severe fibrosis or cirrhosis was found. Six lysosomal enzymes present in hepatocytes were analyzed in the livers of PiZ and non-transgenic mice at theageof12 months. No differences in levels were found, suggesting that activation of these enzymes for clearance of aggregated protein is not the mechanism of hepatocellular damagein this condition. PiZ transgenic mice produce endogenousmouse protease inhibitors, but in addition mimic the secretory defect found in the human PiZ state. PiZ mice developed more severe liver disease than transgenic PiM or non-transgenic controls. The absence of cirrhosis in PiZ mice may depend on insufficient observation time or physiological differences between mice and men. PiZ mice should provide a helpful model for further studies on factors influencing the developmentof liver disease in AAT deficiency. 32 DIFFERENCES IN MONOCYTE (Mo) FUNCTION BETWEEN SPORADIC(S) AND PARENTERA- LLY-TRANSMITTED (PT) CHRONIC NON-A, NON-B HEPATITIS (CNANBH). A.Castilla, ML. Subir~*, S.Morte, M.Serrano, MP.Civeira y J.Prieto. Dpt. of Internal Medicine and Immunology*. Cllnica Universitarla. University of Na- varra, Pamplona, Spain. In a series of 40 consecutive CNANBH patients, 26 healthy controls, 7 patients with acute liver damage (ALD) (5 viral and 2 toxic) and 8 with inactive cirrhosis (IC) we have investigated in Mo phagocytic activity, the display of surface molecules (DR; CRI and IgGFc receptors) and the expression of vimentln filaments (VF). In the same subjects we also studied the display of CD2, CD3 and CD5 on lymphcytes (Ly). Results: In patients with ALD and IC results were similar to controls indicating that Mo dysfunction is not a nonspecific effect of liver disease. 13 out of 14 patients with PT-CNANB (92.8%) had nor- mal Mo parameters. However in 18 out of 25 patients with S-CNANB (72%) there was a dimi- nished expression of VF and surface molecules and a decreased phagocytic activity (p<0.001). Notably in patients with S-CNANBH without positive HBV serum markers (n = 15) this Mo dysfunction was found in 93.3%. In the S-NANBH group there was an inverse corre- lation between functional parameters of Mo, such as phagocytic activity or VF expression, and the level of serum ALT (p<0.01). In addition S-CNANBH patients exhibited a selective defect in the display of CD3 on Ly (p<0.001); the CD3 expression in these patients di- rectly correlated with the functional state of Mo (p<0.001). Gan~na-interferon (IFN) co- rrected "in vitro" the decreased VF expression (p<0,001) and the other diminished Mo pa- rameters (p<o.o5).Conclusions: I. Unlike the PT-CNANBH patients many cases with S-CNANBH specially those without positive HBV serum markers have a Mo dysfunction reversible with IFN. 2. In sporadic cases of CNANBH there is an inverse relationship between the func- tional state of Mo and the activity of liver disease. S18
Transcript of Do transgenic mice expressing human PiZ α1-Antitrypsin develop liver disease?
31 DO TRANSGENIC MICE EXPRESSING HUMAN PiZ ~:ANTITRYPSIN DEVELOP LIVER DISEASE?
&, , Rogers § Hawkins § , negold § J.A. Carlson , R.N. Sifers , B.B. , H.K. M.d. Fi ,
* * * * &Department S.M. C l i f t , F.J. DeMayo , D.W. Bullock and S.L.C. Woo , of
Medicine, Malm~ General Hospital, Malm~, Sweden, Departments of Cell Biology
and §Pathology, Baylor College of Medicine, Houston, Texas, U.S.A.
Transgenic mice created by themicroinjection of the human structural genes for normal PiM and variant PiZ ~1-antitrypsin (AAT) into mouse embryos and their non-transgenic littermates were sacrificed at ages from 6 to 18 months. Immunhistochemistry of l ivers revealed globular aggregates of human AAT immunoreactive substance in hepatocytes and immune electronmicroscopy localized aggregates tothe RER of PiZ mouse hepatocytes. This is to ta l l y analagous to the human PiZ secretory defect. Hematoxylin-eosin stained biopsies were scored objectively forpathological characteristics. Mean biopsy score in 92 PiZ mice was 5.1 compared to 3.0 for 72 PiM mice and 2.0 for 65non-transgenic littermates (p<O.O01 when comparing PiZ mice to each control group). Chronic lobular inflammation was the most predominant feature and mild fibrosis was frequently seen, but no case of severe fibrosis or cirrhosis was found. Six lysosomal enzymes present in hepatocytes were analyzed in the livers of PiZ and non-transgenic mice at theageof12 months. No differences in levels were found, suggesting that activation of these enzymes for clearance of aggregated protein is not the mechanism of hepatocellular damage in this condition.
PiZ transgenic mice produce endogenous mouse protease inhibitors, but in addition mimic the secretory defect found in the human PiZ state. PiZ mice developed more severe l iver disease than transgenic PiM or non-transgenic controls. The absence of cirrhosis in PiZ mice may depend on insuff icient observation time or physiological differences between mice and men. PiZ mice should provide a helpful model for further studies on factors influencing the development of l iver disease in AAT deficiency.
32 DIFFERENCES IN MONOCYTE (Mo) FUNCTION BETWEEN SPORADIC(S) AND PARENTERA- LLY-TRANSMITTED (PT) CHRONIC NON-A, NON-B HEPATITIS (CNANBH). A.Castilla, ML. Subir~*, S.Morte, M.Serrano, MP.Civeira y J.Prieto. Dpt. of Internal Medicine and Immunology*. Cllnica Universitarla. University of Na- varra, Pamplona, Spain.
In a series of 40 consecutive CNANBH patients, 26 healthy controls, 7 patients with acute liver damage (ALD) (5 viral and 2 toxic) and 8 with inactive cirrhosis (IC) we have investigated in Mo phagocytic activity, the display of surface molecules (DR; CRI and IgGFc receptors) and the expression of vimentln filaments (VF). In the same subjects we also studied the display of CD2, CD3 and CD5 on lymphcytes (Ly). Results: In patients with ALD and IC results were similar to controls indicating that Mo dysfunction is not a nonspecific effect of liver disease. 13 out of 14 patients with PT-CNANB (92.8%) had nor- mal Mo parameters. However in 18 out of 25 patients with S-CNANB (72%) there was a dimi- nished expression of VF and surface molecules and a decreased phagocytic activity (p<0.001). Notably in patients with S-CNANBH without positive HBV serum markers (n = 15) this Mo dysfunction was found in 93.3%. In the S-NANBH group there was an inverse corre- lation between functional parameters of Mo, such as phagocytic activity or VF expression, and the level of serum ALT (p<0.01). In addition S-CNANBH patients exhibited a selective defect in the display of CD3 on Ly (p<0.001); the CD3 expression in these patients di- rectly correlated with the functional state of Mo (p<0.001). Gan~na-interferon (IFN) co- rrected "in vitro" the decreased VF expression (p<0,001) and the other diminished Mo pa- rameters (p<o.o5).Conclusions: I. Unlike the PT-CNANBH patients many cases with S-CNANBH specially those without positive HBV serum markers have a Mo dysfunction reversible with IFN. 2. In sporadic cases of CNANBH there is an inverse relationship between the func- tional state of Mo and the activity of liver disease.
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