The protective effects of hyperimmune anti-murine cytomegalovirus antiserum against lethal viral challenge: the case for passive-active immunization

The administration of 0.2 ml of hyperimmune anti-mouse cytomegalovirus (CMV) antiserum intraperitoneally (ip) or intravenously provided complete protection against lethal challenge (10(5.8) PFU ip) with murine CMV. Antiserum protection was complete when the antiserum was administered as long as 24 hr after viral challenge. The administration of antiserum had little effect on the titers of virus in the organs of these animals. Ammonium sulfate-treated antiserum provided similar complete protection. Animals rechallenged with 10(6)-10(6.5) PFU of murine CMV 1 month after initial challenge, at a time when the administrated antiserum was no longer detectable, all survived. We conclude that hyperimmune antiserum can provide significant protection against otherwise lethal murine CMV infection, that the protecting material lies within the immunoglobulin fraction, and that long-term immunity results from the combined exposure to virus and antiserum. Such passive-active protection could be useful in protecting against human CMV infection.     

Experimental interstitial renal fibrosis in rats: nephritis induced by N-(3,5-dichlorophenyl)succinimide.

The nephrotoxic properties of the chemical N-(3,5-dichlorophenyl)-succinimide were investigated in rats with a view to establishing the usefulness of this chemically-induced nephritis as a model of chronic interstitial renal fibrosis. The compound was synthesized and given daily by gastric intubation as a suspension in arachis oil B.P. to male WAG-strain rats, for periods of up to 108 days. Polydipsia and polyuria resulted rapidly in all treated animals and persisted for the duration of the experiment. There was a progressive increase in the extent of proteinuria in all treated animals and, by the end of the experiment, there was an increase in the plasma levels of urea and creatinine. Short term treatment (up to 3 days) resulted in focal areas of necrosis of some proximal convoluted tubules. Treatment for 28 days resulted in patchy but severe tubular interstitial nephritis with which was associated a moderate interstitial fibrosis. By 108 days, the nephritis was more widespread and the interstitial fibrosis was severe. The activity of proline hydroxylase, a part of the intracellular sequence of collagen synthesis, showed progressive increase in the renal cortex throughout the experiment and there was an associated increase in the cortical hydroxyproline content, a measure of the amount of collagen present. Associated with this biochemical evidence of an active, chronic fibrosis, was an increased water content of the cortical tissue. The results indicate that this chemically-induced, tubular interstitial nephritis is indeed a good and reliable model of interstitial renal fibrosis.     

Transport of methionine in Trypanosoma brucei brucei

African trypanosomes live free in the bloodstream and central nervous system of mammalian hosts and also within the midgut of the tsetse fly vectors which transmit them. The parasite plasma membrane represents the interface between both hosts and parasite, and trypanosomes accumulate many essential metabolites via specific transport processes. L-Methionine uptake by procyclic and bloodstream forms of Trypanosoma brucei has been measured and shown to be mediated by a transporter presenting similar characteristics in both forms of the parasite. The carrier shows, in both forms, a relatively high affinity for methionine (Km ca. 30 microM). The effect of inhibitors of ion gradients across the membrane indicated that the uptake process is likely to be dependent upon a proton motive force. Various methionine analogues were tested against the transporter and these have demonstrated that the recognition depends on the motif common to all amino acids, and an electronegative group at the position of the sulphur atom separated from the alpha-carbon atom by a two carbon spacer.     

Relationships among ragweed skin tests and both allergen specific and nonspecific nasal provocation.

Twenty-six patients with ragweed-induced allergic rhinitis were evaluated prior to the onset of seasonal symptoms. Ragweed skin tests and nasal challenges were performed 2 weeks after histamine nasal provocation. A correlation between ragweed skin tests and nasal challenges was detected (r = .4867, P much less than .01). Histamine challenges did not correlate with either of the other variables. A properly performed skin test predicts nasal reactivity to the same allergen. A clinical role for nonspecific nasal provocation could not be determined.     

Effect of antibody-induced modulation of measles (SSPE) virus membrane proteins on beta-adrenergic receptor-mediated adenylate cyclase activity

The effect of measles virus antiserum on the expression of viral glycoproteins on the membranes of measles (SSPE) persistently infected C6 rat glioma cells was studied. There was a gradual loss of virus membrane antigen from these cells until no antigen was detectable 18 days after initiation of antiserum treatment. At this stage approximately 25% of cells still displayed intracellular virus antigen which was also lost after further cell passages. There was an accompanying recovery of the previously reported disrupted catecholamine-dependent beta-adrenergic receptor-stimulated cAMP synthesis in antiserum-treated cells which coincided with the loss of viral antigen from the membrane. This was determined to be due to a recovery of fluoride-stimulated activity of the cAMP synthesising adenylate cyclase enzyme to normal values. Thus we demonstrate that the impairment of this important cell function was due to insertion of viral antigen in the cell membrane rather than its accumulation in the cytoplasm.     

Comparison of arsenic-induced cell transformation, cytotoxicity, mutation and cytogenetic effects in Syrian hamster embryo cells in culture

Sodium arsenite and sodium arsenate were observed to inducemorphological transformation of Syrian hamster embryo cellsin a dose-dependent manner. A linear dose-dependence with aslope of 1 was observed with both compounds when the data wereplotted on a log-log graph. The trivalent sodium arsenite was> 10-fold more potent than the pentavalent sodium arsenate.The compounds also exhibited toxicity; however, transformationwas observed at non-toxic as well as toxic doses. At low doses,enhanced colony-forming efficiency of the cells was observed.To understand the mechanism of arsenic-induced transformation,the genetic effects of the two arsenicals were examined overthe same doses that induced transformation. No arsenic-inducedgene mutations were detected at two genetic loci. However, celltransformation and cytogenetic effects, including endoreduplication,chromosome aberrations, and sister chromatid exchanges wereinduced by the arsenicals with similar dose-responses. Theseresults support a possible role for chromosomal changes in arsenic-inducedtransformation.     

Changes in stem cell populations of rat tracheal epithelial cell cultures at an early stage in neoplastic progression

The development of transformed colonies and concomitant changes in proliferative and nonproliferative cell compartments were studied in rat tracheal epithelial (RTE) cell cultures following exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Primary RTE cells were plated onto 3T3 feeder layers and treated with MNNG (0.25 micrograms/ml) or solvent. Seven days later, the feeder cells were removed to select for enhanced growth variants, which are the transformants of the RTE cell system, usually scored 5 weeks after carcinogen exposure. Most of the RTE cell colonies, which originally formed during the first 7 days of culture, disappeared within 2 weeks after feeder cell removal in control and MNNG-treated cultures. In control cultures, about 3% of the original colonies persisted, while in MNNG-treated cultures, a larger percentage (approximately 9%) of the colonies persisted. These percentages remained constant from 3 to 7 weeks. Based on colony size, cell density, and cell morphology, the persistent colonies were classified into transformed colonies (large colony size, high cell density, high nuclear:cytoplasmic ratio) and untransformed colonies (small size, low cell density, low nuclear:cytoplasmic ratio). In the MNNG-treated cultures, about 50% of all persistent colonies showed transformed morphology. Their frequency remained unchanged between 3 and 7 weeks of culture. In contrast, only 10 to 15% of the persistent colonies in control cultures showed transformed morphology at 3 weeks, but that proportion increased steadily between 3 and 7 weeks. These data suggest that, in control cultures, transformed colonies developed spontaneously as a function of time within untransformed colonies. Autoradiographic studies with [3H]thymidine showed that labeling indices in the early "normal" RTE cell colonies between Days 4 and 7 of culture were very high, ranging between 75 and 90%. In contrast, the labeling indices of persistent colonies, both those without and those with transformed morphology, were low, i.e., between 18 and 25%, indicating that a major proportion of cells was either noncycling or cycling very slowly. The relative compartment sizes of cells with stem cell characteristics and of cells with characteristics of transformed stem cells were estimated before and after transformed colonies appeared.(ABSTRACT TRUNCATED AT 400 WORDS)