There is a general agreement that a preferential accumulation of alloantigens within the liver could induce hyporesponsiveness to the inoculated antigens. Entrapment of antigens in the liver may ...evoke an unique immune response in the organ and play a key role in determination of the fate of the transplanted grafts. To understand the immune response in the liver after inoculation of allogeneic donor antigens, we examined the immune response to systemically inoculated alloantigen in rats whose sensitized liver was replaced with that of naive rats or in naive rats whose liver was replaced with that of sensitized rats.
Using implantation of syngeneic liver (alloantigen-accumulated/naive) in rats (naive/alloantigen-sensitized), we compared the immune responses to alloantigen between rats with hepatic/extrahepatic alloantigen at 24 hr after alloantigen inoculation. This was called sensitized-liver-grafted (SLG)/sensitized-liver-removed (SLR) treatment. The immune response to donor alloantigen in this model was evaluated by survival of skin or heart grafts, complement-dependent cytotoxicity (CDC) titer and delayed-type hypersensitivity (DTH) response.
Compared with the mean survival time (MST) in donor spleen cell inoculated (DSI) rats (skin and heart, MST: 8.2+/-1.1 and 10.7+/-2.3 days), SLG rats rejected allografts in an accelerated fashion (skin and heart, MST: 5.5+/-0.5 and 4.2+/-0.8 days), associated with higher CDC titer and DTH response. In contrast, allograft survival was moderately prolonged in SLR (skin and heart, MST: 16.5+/-2.6 and 29.5+/-3.7 days) associated with suppressed CDC titer and DTH response. The survival of third-party allograft after SLG or SLR treatment (skin, MST: 9.3+/-1.5 or 9.7+/-0.6 days) indicated that immunological hyper/hyporesponsiveness was donor-specific.
A strong anti-donor immune response was induced by the transfer of donor antigen-baring liver to naive rats 24 hr after alloantigen inoculation, whereas removal of the liver suppressed alloimmune response. Our results indicate that vigorous anti-alloimmune response occurred in the liver after systemic inoculation of donor spleen cells.
The mechanism of mucosa-specific formation of DNA adducts, which was found recently in human intestines, was studied in male F344 rats treated with 2-amino-3-methylimidazo4,5-fquinoline (IQ). There ...are three conceivable pathways for p.o. administered IQ to reach the target colonic mucosal cells: pathway 1, through the digestive canal which exposes from the lumenal direction; pathway 2, following enterohepatic circulation re-expose from the lumenal direction; and pathway 3, exposure via blood circulation. To investigate these possible pathways, the following surgical procedures were performed: (a) portal catheterization for IQ administration to eliminate pathway 1 and (b) choledochal catheterization for bile drainage to eliminate pathway 2. When both procedures are combined, only pathway 3 is active. Four types of IQ-DNA adducts were commonly observed in the colons of all experimental groups, with no qualitative difference between the mucosal and muscular layers. When IQ-HCl was administered by p.o. gavage at a dose of 100 mumol/kg body weight, approximately 70% of the IQ-DNA adducts in the colonic mucosa (13.1 +/- 4.3 adducts/10(7) nucleotides) was induced through pathway 1. Pathway 3 induced the remaining 30% of mucosal adducts, producing equal adduct levels in both layers. Pathway 2 did not work for adduct formation. The DNA adduct formation was unaffected in the presence of intestinal flora, indicating that detoxified IQ does not reactivate by floral enzymes. In conclusion, mucosa-specific DNA adduct formation in the colon is caused most likely by the absorption of carcinogens through the lumen.
DNA of normal mucosa and the adjacent muscular layer from 18 adults suffering from colorectal neoplasms was examined by 32P-post-labeling analysis in order to estimate the exposure of the human colon ...and rectum to environmental carcinogens. Colorectal DNA samples obtained from six newborns were also examined as a normal control because they were presumed to have been minimally exposed to environmental carcinogens. One common mucosa-specific DNA adduct was found in the normal colorectal wall in all adults at the level of 0.10-34.13 adducts/10(8) nucleotides (mean +/- SD: 3.64 +/- 7.92 adducts/10(8) nucleotides), however, these were absent from the newborns' colons. Although several common spots were present in the mucosa, muscular layer and newborn tissues, there was no muscular layer-specific DNA adduct. The relationship between the levels of the mucosa-specific DNA adduct in the non-cancerous part and the histological degree of malignancy was not significant. The presence of this mucosa-specific DNA adduct in adult colon suggests that the human colon is commonly exposed mainly to one environmental carcinogen. This carcinogen is supposed to originate from foods, because the incidence of colorectal carcinoma is closely linked to dietary habits and the mucosa-specific DNA adduct was not present in newborns who had never ingested food. The incidence of adult colonic cancer originating from its mucosa is high, while cases of muscular origin or in newborn colon are rare. Therefore, the mucosa-specific DNA adduct is presumably responsible for the development of colonic cancer of epithelial origin.
The authors experienced a case with obstruction of the inferior vena cava (IVC) and the common bile duct due to a recurrent hepatocellular carcinoma. In order to improve severe edema of the lower ...extremities and obstructive jaundice, IVC metallic stent as well as biliary stent were applied. A Luminexx stent of 8 cm in length was placed in the bile duct via subcutaneous route after biliary drainage. A spiral zigzag stent of 8 cm in length was also inserted into the IVC through the femoral vein following balloon dilatation of the obstructed portion. Subsequently, jaundice and edema were dramatically improved in a short period of time, which resulted in patient discharge from the hospital. Although the patient died of the cancer in 2 months, the quality of life was well maintained until death.
The presence of several covalent DNA adducts in the human colon was demonstrated by 32P-postlabeling in a previous study. We demonstrated that DNA of all the colonic mucosa tested were selectively ...adducted by a single genotoxic agent and this modification was completely absent in the DNA of muscular layers. In this study, the DNA adducts of the small intestine are compared with those of the colon to understand the role of mucosa-specific DNA adduct (MSA) in intestinal carcinogenesis. The mucosal DNA of the small intestine from 19 adults undergoing surgery due to gastric carcinoma (seven cases), pancreatic carcinoma (four cases), colon carcinoma (four cases), small intestinal tumor (two cases), intestinal trauma (one case) and ectopic pancreas (one cases) were analyzed. The mucosa-adjacent muscular layer DNA of the corresponding samples was examined as a control. Several common DNA adducts were observed in both mucosal and muscular layers of all the adults. Besides these common background DNA adducts, two MSAs (Si1, Si2) were detected in most of the adults as in colon cases. Si1 was present in all adults examined (19/19 cases) at a level of 0.04-0.22 adducts/10(8) nucleotides (average 0.09) and Si2 was found in 13/19 patients at a level of 0.03-0.08 adducts/10(8) nucleotides (average 0.05). Si2 was the same adduct detected in the adult colonic mucosa. However, they were absent in the adjacent muscular layer as well as in the neonatal intestine tested as a control. The total level of the mucosa-specific DNA adducts of the small intestine was approximately 28-fold lower than that of the colon. Considering that the incidence of cancer in the small intestine is rather lower than that in the colon, these results may be relevant to the development of human intestinal cancer.
The present study was conducted to clarify whether endotoxin-induced liver injury could be improved by modulating the function of hepatic macrophages using OK432, an immunostimulant derived from ...Streptococcus. OK432 elevated the capacity of hepatic macrophages to produce superoxide and tumor necrosis factor (TNF), and enhanced the mRNA expression of interleukin-1-alpha, -beta, and TNF-alpha in liver nonparenchymal cells (NPC). However, intravenous (iv) preadministration of OK432 reduced the mRNA expression of TNF-alpha in liver NPC enhanced by the endotoxin injection, decreased the serum level of GOT and lactic dehydrogenase (LDH), and improved the survival rate of endotoxin-injected rats. Histological examination revealed a significant reduction in cell vacuolization and focal necrosis in the livers of the endotoxin-injected rats pretreated with OK432. These results indicate that hepatic macrophages play a crucial role in endotoxin-induced liver injury, and that TNF-alpha is one of the factors most likely to be implicated in the development of endotoxin-induced liver injury. Thus, it is suggested that the administration of OK432 provides liver protection by modulating the responsiveness of hepatic macrophages against endotoxin.
The authors investigated the usefulness of W-Spiral Catheters for adjuvant hepatic arterial infusion (HAI) chemotherapy following curative resection of colorectal liver metastases. The catheter has a ...special shape-memory alloy in its tip, which allows preferable fixation without coils and removal of the catheter if desired. A W-spiral catheter was successfully placed in 13 out of 16 patients who had undergone curative hepatectomy. In the remaining 3 cases in which the hepatic artery was smaller in diameter, a catheter was placed using the conventional GDA coiling method. Removal of the W-Spiral Catheter was attempted in 10 of the 13 patients with a Spiral Catheter after termination of HAI chemotherapy. In all cases, the catheters were easily and uneventfully removed, and 3D-CT angiography revealed that the hepatic artery was well preserved in most cases. These findings suggest that a new approach to prophylactic HAI chemotherapy with W-Spiral Catheters and subsequent removal of the catheters is reasonable and desirable.
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