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N Murase

Publications and source records attributed to N Murase.

At least 163 records · Page 9Linked to original sources
PubMed1993

Humoral and cellular immunopathology of hepatic and cardiac hamster-into-rat xenograft rejection. Marked stimulation of IgM++bright/IgD+dull splenic B cells.

Normal Lewis rat serum contains antibodies (IgM > IgG) that bind to hamster leukocytes and endothelial cells. Transplantation of either the heart or liver from hamster rat results in release of hamster hematolymphoid cells from the graft, which lodge in the recipient spleen (cell migration), where recipient T- and B-cell populations initiate DNA synthesis within one day. There is marked stimulation of splenic IgM++(bright)/IgD+(dull) B cells in the marginal zone and red pulp, which account for 48% of the total splenic blast cell population by 4 days after liver transplantation. CD4+ predominant T-cell proliferation in the splenic periarterial lymphatic sheath and paracortex of peripheral lymph nodes occurs almost simultaneously. The effector phase of rejection in cardiac recipients is dominated by complement-fixing IgM antibodies, which increase daily and result in graft destruction in 3 to 4 days, even in animals treated with FK506. In liver recipients, combined antibody and cellular rejection, associated with graft infiltration by OX8+ natural killer, and fewer W3/25+ (CD4) lymphocytes, are responsible for graft failure in untreated recipients at 6 to 7 days. FK506 inhibits the T-cell response in liver recipients and significantly prolongs graft survival, but does not prevent the rise or deposition of IgM antibodies in the graft. However, a single injection of cyclophosphamide 10 days before transplantation effectively depletes the splenic IgM++(bright)/Ig+(dull) cells and in combination with FK506, results in 100% survival of both cardiac and hepatic xenografts for more than 60 days. Although extrapolation of morphological findings to functional significance is fraught with potential problems, we propose the following mechanisms of xenografts rejection. The reaction initially appears to involve primitive host defense mechanisms, including an IgM-producing subpopulation of splenic B cells and natural killer cells. Based on the reaction and distribution of OX8+ and W3/25+ cells, antibody-dependent cell cytotoxicity and delayed-type hypersensitivity responses seem worthy of further investigation as possible effector mechanisms. Effective control of xenograft rejection is likely to require a dual pharmaceutical approach, one to contain T-cell immunity and another to blunt the primitive B-cell response.

Animals↗
PubMed1993

Hepatocyte growth factor, blood clearance, organ uptake, and biliary excretion in normal and partially hepatectomized rats.

BACKGROUND: Hepatocyte growth factor (HGF) (also known as scatter factor (SF)) is a heterodimeric protein that is the most potent known complete mitogen for hepatocytes in culture. HGF is a mitogen for many epithelial cells including hepatocytes, kidney tubular epithelial cells, mammary epithelial cells, keratinocytes, etc. The protein encoded by the proto-oncogene c-met is the high affinity receptor for HGF. HGF concentration in the plasma dramatically increases after partial hepatectomy and in fulminant hepatic failure. This study describes the pharmacokinetics of HGF in the rat. EXPERIMENTAL DESIGN: Human recombinant HGF (a gift from Genentech) was radioiodinated and shown to retain biologic activity and structure. Approximately 74 ng of [125I]HGF was injected into the penile vein of male Fisher rats 5 minutes after a complete bile fistula and jugular venous catheterization were performed for blood and bile sampling. Half of the rats were subjected to 70% partial hepatectomy. RESULTS: The percentage of injected radioactivity present in the liver of control rats was 29.5% +/- 0.5% at 15 minutes and decreased to 8.6% +/- 1.0% at 120 minutes; the kidneys had 6.2% +/- 0.2% at 15 minutes, decreasing to 1.48% +/- 0.3% at 120 minutes. All the other organs examined had less than 1% of the injected radioactivity. The remaining radioactivity was present in low affinity sites in blood, bone, muscle, and skin. In control rats, radioactivity appeared in the bile within 3 minutes, reached a peak between 40 to 50 minutes, and tapered thereafter for a total 2-hour collection of 2.3% +/- 0.5%. In the partially hepatectomized rats, the HGF blood clearance was decreased (partial hepatectomy = 0.27 +/- 0.03 ml/minute; control = 0.53 +/- 0.06 ml/minute, p < 0.006), and the terminal half-life prolonged (partial hepatectomy = 124 +/- 11 minutes; control = 83 +/- 10 minutes, p < 0.03). The initial half-life for HGF, as extrapolated from the chart, was estimated at 3.8 minutes in control rats. CONCLUSIONS: Liver is the principle organ for initial uptake of [125I]HGF; disappearance from the blood suggests multicompartment kinetics with a rapid phase and a slower phase; only a portion of the hepatic uptake appears in the bile; and partial hepatectomy decreases the blood clearance of [125I]HGF. These results are correlated with previous findings bearing on the role of HGF elevation after partial hepatectomy as a stimulus for transfer of hepatocytes from G0 to G1 early in liver regeneration after partial hepatectomy.

Animals↗
PubMed1993

Liver allograft rejection in sensitized recipients. Observations in a clinically relevant small animal model.

A sequential analysis of liver allograft rejection in sensitized rats using immunopathological and ultrastructural microscopy is described. Lewis rats were primed with four ACI skin grafts and challenged with an arterialized ACI orthotopic liver allograft 14 to 17 weeks later. The sensitization resulted in a mix of IgG and IgM lymphocytotoxic antibodies at a titer of 1:512 at the time of transplantation. Specificity analysis of pretransplant immune sera revealed a predominance of IgG anti-class I major histocompatibility complex (RT1) antibodies with a minor IgG fraction showing apparent endothelial cell specificity (non-RT1). This level of sensitization was associated with accelerated graft failure in 3 to 5 days from mixed humoral and cellular rejection. Sequential analysis of serial posttransplant graft biopsies revealed diffuse vascular IgG deposition and platelet thrombi in portal veins and periportal sinusoids within 3 minutes after reperfusion. This was followed by endothelial cell hypertrophy and vacuolization, periportal hepatocyte necrosis, arterial spasm, focal large bile duct necrosis, and hilar mast cell infiltration and degranulation. However, the liver allografts did not fail precipitously and hyperacute rejection was not seen. Kupffer cell phagocytosis of the sinusoidal platelets began as early as 30 minutes posttransplant and by 24 hours, the platelet thrombi had decreased. Cholangioles appeared focally at the edge of the limiting plates by 2 to 3 days, apparently in response to earlier periportal hepatocyte damage. A mononuclear portal and perivenular infiltrate became evident at 3 days, and graft failure was attributed to both antibody and cell-mediated rejection (Furuya et al: Preformed lymphocytotoxic antibodies: Hepatology 1992, 16: 1415-1422). The model described resembles observations in crossmatch positive human liver allograft recipients. The mechanisms of hepatic graft resistance to antibody mediated rejection and the possible long term consequences of early damage to the biliary tree are discussed.

Animals↗
PubMed1992

Systemic chimerism in human female recipients of male livers.

We have previously reported data from clinical and laboratory animal observations which suggest that organ tolerance after transplantation depends on a state of balanced lymphodendritic cell chimerism between the host and donor graft. We have sought further evidence to support this hypothesis by investigating HLA-mismatched liver allograft recipients. 9 of 9 female recipients of livers from male donors had chimerism in their allografts and extrahepatic tissues, according to in-situ hybridisation and molecular techniques 10 to 19 years posttransplantation. In 8 women with good graft function, evidence of the Y chromosome was found in the blood (6/8), skin (8/8), and lymph nodes (7/8). A ninth patient whose transplant failed after 12 years from recurrent chronic viral hepatitis had chimerism in her lymph nodes, skin, jejunum, and aorta at the time of retransplantation. Although cell migration is thought to take place after all types of transplantation, the large population of migratory cells in, and the extent of their seeding from, hepatic grafts may explain the privileged tolerogenicity of the liver compared with other organs.

ABO Blood-Group System↗