C. Jerusalem

Murine malaria: IV. Disturbed immunological responsiveness during Plasmodium berghei infection

Abstract Swiss mice infected with Plasmodium berghei are unable to produce antibodies against rabbit erythrocytes or to develop transplantation immunity against skin heterografts to the same degree as uninfected controls. Mice with a primary infection are capable of producing such antibodies and developing transplantation immunity when parasitemia is prevented or depressed therapeutically, as are immune mice during challenge infection. Mice develop specific resistance to an homologous plasmodial strain when the multiplication in vivo of Plasmodium berghei is limited during the vaccinating or primary infection. At the moment chloroquine therapy is started, some development of the vaccinating infection is necessary for the subsequent development of this protective immunity. When plasmodial growth is limited by long-lasting chloroquine treatment, introduced before the induction of the vaccinating infection, protective immunity develops neither after a single vaccinating dose nor after multiple inoculations of viable plasmodia. On the other hand, mice vaccinated once against viable plasmodia, in which the in vivo growth has been limited by dietary deficiency, develop a protective immunity against the homologous strain. The more the vaccinating disease has progressed at the time treatment is started, the lower the degree of subsequent antimalarial immunity. Multiple vaccinating doses seem to produce the protective immunity under these circumstances. A disturbed immunological responsiveness in Swiss mice during primary infection with Plasmodium berghei is most probably responsible for the deficient immunological defence.

Plasmodium berghei: T cell-dependent autoimmunity

Abstract Plasmodium berghei infection in euthymic mice induced the formation of smooth muscle autoantibodies (SMA) persisting in cured immune mice. Antinuclear antibodies (ANA) were found in challenged hyperimmune mice, but not in acutely infected mice. The autoantibodies were not detected in infected and cured athymic, nude mice, and are therefore T-cell dependent. No evidence for other autoantibodies was obtained. Parallel studies on deposited immune complexes in renal glomeruli served as control for any absence of autoantibodies.

Heterotopic Liver Transplantation

Nine canine and 30 rat-to-rat long surviving heterotopic liver homografts and six canine heterotopic liver autografts were examined for histopathological changes. The picture of a mixed cardiac and po

Patency and morphology of fibrous polyurethane vascular prostheses implanted in the femoral artery of dogs after seeding with subcultivated endothelial cells

A cell culture line was established from enzymatically-derived canine jugular endothelial cells and further cultured. Whenever sufficient cells were present, fibrous polyurethane vascular prostheses, impregnated with gelatin and coated with fibronectin, were seeded with 4.8 x 10(5)/cm2 cells, sufficient to establish a confluent monolayer, and implanted in the femoral arteries of 16 dogs. A non-seeded prosthesis on the contralateral side served as control. Eight dogs received antiplatelet aggregation medication: 250 mg aspirin together with 25 mg dipyridamole, orally three times daily, starting 2 weeks prior to the implantation operation and continued for the duration of the experiment. Results show that in the non-medicated dogs all control prostheses become occluded within 3 weeks after implantation, whereas five out of eight seeded prostheses remained patent. In the medicated group, two out of eight control prostheses occluded and all seeded prostheses remained patent. Scanning and light microscopy revealed that seeded prostheses were completely lined with endothelial cells (Factor VIII positive stain) week 3 (n = 3) and 12 (n = 3) after implantation, while endothelialisation in control prostheses had advanced only 5 mm into the prostheses in 12 weeks. Two dogs of each group were included in long-term patency studies. We conclude that prostheses seeded with a confluent monolayer of endothelial cells result in superior patency rates for both medicated and non-medicated dogs. No immunological reaction against the (allogeneic) seeded endothelial cells were noted.

Auxiliary liver transplantation in jaundiced rats with UDP-glucuronyltransferase deficiency and defective hepatobiliary transport

In this study auxiliary liver transplantation (ALT) has been tested as a means of correcting the UDP-glucuronyltransferase deficiency in Gunn rats and the UDP-glucuronyltransferase deficiency and impaired hepatobiliary bilirubin transport in double mutant rats. In both groups serum bilirubin normalized and remained low until the end of the study at 12 weeks after transplantation in 4 out of 6 rats. Excretion of 99mTc-HIDA in non-transplanted double mutants was considerably slower than in Gunn rats (kel 0.9 x 10(-3) versus 4.3 x 10(-3) s-1). HIDA excretion by transplants in double mutants and Gunn rats was about equal (kel 1.6 x 10(-3) and 1.1 x 10(-3) s-1). Experiments with bile duct-cannulated transplants showed that in double mutants bile flow, bile acid and bilirubin excretion was 2-4 times higher than in Gunn rats. This study shows that auxiliary liver transplants can conjugate and excrete bilirubin when one of these or both functions are lacking in the recipients liver.

Auxiliary Liver Transplantation in the Rat, Influence of the Condition of the Recipient’s Liver on the Fate of the Graft

To evaluate the influence of the functional state of the recipients liver on the fate of an auxiliary liver graft in rats, diverse surgical interventions were carried out on the recipients liver following transplantation of an auxiliary liver. All grafts consisted of 30% of the liver mass, were supplied with portal blood only, and provided with bile drainage. Permanent graft hypertrophy was observed when the recipients liver was resected subtotally, in addition to the ligation of the bile duct. Ligation of the bile duct performed separately has a more pronounced effect on the increase of the weight of the graft than subtotal hepotectomy. If only portal blood was deviated to the graft, grafts atrophied. It is concluded that the functional efficiency and condition of the graft vary directly with the degree of functional impairment of the recipients liver, compair functional hypertrophy. The present results do not seem to indicate the presence of a specific hepatotrophic factor in portal blood.

Altered Portal Pressure Secondary to Portacaval and Portasystemic Shunts in the Rat: The Effect on Liver Function and Intestinal Integrity

Two types of portasystemic shunts were investigated in the rat; low pressure shunts (portacaval shunt, PCS, and portacaval transposition, PCT) and a high pressure shunts (Portasystemic shunt by ligation of the portal vein after splenic transposition, PSSL). liver atrophy was seen in all groups but PCT. Simplification of intestinal villi was observed in all groups and related to the degree of portal pressure alteration. Liver function and clinical status improved if some blood, either systemic or splanchnic, perfused the liver through surgical deviation (PCT) or accidental collateral formation (PSSL + C). In the prevention of the PCS syndromes selective portacaval shunting is advocated, leaving some blood to flow to the liver. A high as possible splanchnic pressure prevents intestinal villi simplification and loss of resorptional surface.

Alcohol-induced liver injury after jejunoileal bypass operation in rats

The objective of this study was to investigate whether alcohol administration exerts a synergistic effect on jejunoileal bypass-induced liver dysfunction in rats. Male Wistar rats were subjected to 90% jejunoileal bypass or sham operation. For 10 weeks, subgroups were pair-fed either an alcohol-containing (36% of total calories) liquid diet or a liquid diet where alcohol was replaced isocalorically by starch. Alcohol feeding in rats with jejunoileal bypass increased hepatic triglyceride content about 6-fold as compared with bypassed rats receiving control diet. Neither jejunoileal bypass nor alcohol feeding led to significant changes in hepatic DNA and protein contents. Alcohol feeding increased cytochrome P-450 levels both in operated and in sham-operated rats. The administration of alcohol-containing diet decreased the activity of succinic dehydrogenase, the decrease being distinctly more pronounced in rats with jejunoileal bypass than in the sham-operated controls. Light microscopy revealed no significant morphological alterations in liver sections of rats fed the control diet after jejunoileal bypass or of rats receiving either the alcohol-containing diet or the control diet after sham operation. Alcohol feeding in bypassed rats, however, produced marked diffuse accumulation of fat, and regularly led to other histological abnormalities in the liver. These abnormalities included ballooning of hepatocytes and disarray of the trabecular structure of the liver lobule, hyalin inclusions resembling megamitochondria, single-cell necrosis and focal clustering of necrosis, increased number of mitotic figures, and infiltrates with inflammatory cells. The histological lesions of the liver of bypassed rats receiving alcohol exhibited no obvious zonal distribution. The results demonstrate that alcohol feeding to rats subjected to jejunoileal bypass leads to marked liver injury which mimics, at least in part, that of alcohol-induced liver disease in man. Rats subjected to jejunoileal bypass may, therefore, provide a new model for the study of alcoholic liver disease.

Plasmodium berghei: influence on granulopoiesis and macrophage production in balb/c mice.

Granulocyte and macrophage progenitor cells forming colonies in vitro (GM-CFC) from bone marrow, spleen, and peripheral blood of BALB/c mice infected with Plasmodium berghei were cultured at various times postinfection in a viscous, 0.8% methylcellulose system. The numbers of GM-CFCs from bone marrow increased gradually during the first week of infection, reaching a maximum around the tenth day of the disease. Subsequently, a rise of GM-CFCs in cultures of nucleated cells from the peripheral blood was observed and, with some delay, in spleen cell cultures also, with a maximum around the end of the second week. After the tenth day of malaria infection a fall of colony frequency in bone marrow-derived cells took place, leading to subnormal values of GM-CFCs during the third week of infection. Subsequently, a decrease in the spleen cell cultures followed, but colony numbers did not fall to normal values. The general increase in GM-CFCs in the different organs was preceded by a rise in serum levels of colony-stimulating activity (CSA), attaining a maximum 1 week after P. berghei inoculation. During the following period the CSA levels fell and reached normal values around the seventeenth day of the disease. Chemotherapy with chloroquine started on the fifteenth day of infection, when GM-CFCs in the bone marrow have dropped to normal values, stopped their further decrease. In the spleen a gradual normalization took more than 2 weeks. A challenge infection evoked an elevation of GM-CFC numbers in the bone marrow and in the spleen during the first 10 days in only about 50% of immune mice. The reaction was immediate in some animals, but generally lower and of shorter duration than during primary infection. The results have indicated that a lethal P. berghei infection in mice caused a transient increase in production of CSA followed by a general recruitment of GM-CFCs in all hemopoietic organs.

Survival of Auxiliary Rat Liver Grafts with Decreased Portal Blood Flow

After auxiliary liver transplantation in the rat, partial liver grafts (30% of the liver) were perfused with mesentericosplenic venous blood. This means a decrease in the total liver blood flow by approximately 34%. Recipient livers retained their arterial and pancreaticoduodenal inflow. Surgical interventions were carried out on the recipients liver to evaluate the effect of the varying induced functional handicap on the fate of the graft in association with a decreased liver blood flow. Graft survival was obtained in all groups, but the conditions of the graft varied inversely with the severity of the functional handicap of the recipients liver. Compared to previous experiments in which the auxiliary grafts were supplied with total portal blood inflow in the same experimental model, the grafts in this study showed a slightly impaired increase in weight. This impairment was attributed to the decreased blood flow. Recipient livers deteriorated or just maintained their size, even after 70% hepatectomy, despite the pancreaticoduodenal venous and arterial inflow. These results suggest that the total liver blood flow in combination with the functional state of the remaining recipient liver, rather than the quality of venous blood deriving from certain splanchnic areas and/or peculiar factor convoyed with it, determines the survival of a liver graft.