Safety and immunogenicity of a polyvalent Pseudomonas aeruginosa O-polysaccharide-toxin A vaccine in humans.
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Animals↗
Biomedical subjects
A S Cross
Publications and source records attributed to A S Cross.
Intravenous immune globulin impairs anti-bacterial defences of a cyclophosphamide-treated host.
Since intravenous immune globulin (i.v.IG) could impair the clearance of autologous IgG-coated erythrocytes by the reticuloendothelial system (RES), we speculated that a patient with leucopenia who died of candida septicaemia following high dose i.v.IG may have had an impairment of his RES function. We therefore studied the ability of intact i.v.IG to impair the clearance of both soluble immune complexes and a relatively avirulent strain of E. coli from the blood of mice made leucopenic with cyclophosphamide. In the presence of leucopenia, 800 micrograms/g i.v.IG prolonged the time to clear 50% of the administered IgG anti-dinitrophenyl immune complex (T1/2) from 2.7 min to 12 min, impaired the clearance of E. coli and lowered the LD50 of the strain five-fold. This impaired clearance of soluble complexes and increased mortality (8/67 versus 37/69, P less than 0.001) following bacterial challenge was present for up to 120 and 60 min, respectively, following the administration of i.v.IG. In contrast, no significant impairment in RES function was noted when 200 micrograms/g i.v.IG was administered to leucopenic mice, or when cyclophosphamide alone was given to mice before challenge with either soluble complexes or bacteria. In addition, no change in LD50 was found when mice were pretreated with 800 micrograms/g i.v.IG alone. These data suggest that high doses of i.v.IG may impair anti-microbial defences of a leucopenic host and thereby convert a relatively avirulent organism into a pathogen.
Animals↗
Human IgG and IgA subclass response following immunization with a polyvalent Klebsiella capsular polysaccharide vaccine.
The human IgG and IgA response was determined after vaccination with an experimental 24-valent Klebsiella capsular polysaccharide vaccine. The majority of natural antibody acquired prior to immunization was found in the IgG1, IgG2 and IgA1 subclasses. The immune response to vaccination was concentrated within the IgG1, IgG2, IgA1 and IgA2 subclasses with greater than or equal to 70% of subjects responding with a significant (greater than or equal to fourfold) rise in titer. The IgG3 and IgG4 response was meager with few volunteers (0%-40%) showing a significant titer rise. Therefore, vaccination with Klebsiella capsular polysaccharide induces a vigorous IgG and IgA response in humans which is not restricted to single antibody class or subclass.
Antibodies, Bacterial↗
A murine monoclonal antibody against Klebsiella capsular polysaccharide is opsonic in vitro and protects against experimental Klebsiella pneumoniae infection.
Murine monoclonal antibodies (mAb) of the immunoglobulin M class specific for the K2 capsular polysaccharide (CPS) of Klebsiella were isolated. One such mAb, termed III/5-1, was selected for further study. This mAb promoted the uptake and killing of Klebsiella pneumoniae K2 strains by human granulocytes and activated complement after contact with the bacteria. The efficiency of mAb-mediated phagocytosis and complement activation was inversely related to the amount of capsular material produced by the test strain. MAb III/5-1 was found to be effective at preventing fatal experimental K. pneumoniae K2 sepsis when administered prophylactically, the degree of protection being dependent upon the amount of CPS produced by the challenge strain.
Animals↗
Functional activities of monoclonal antibodies to the O side chain of Escherichia coli lipopolysaccharides in vitro and in vivo.
Mouse hybridoma antibodies (IgG and IgM) to O side chain determinants of Escherichia coli strain Bort (O18ac:K1:H7) were evaluated for their in vitro and in vivo activities against E. coli strains. Both IgG and IgM were opsonic in vitro and protected newborn rats challenged with a K1 E. coli strain, but their activities were strain specific. The antibodies protected against a K1 strain possessing a homologous O serotype but not against one possessing a heterologous O serotype. These antibodies were not effective against the K5-encapsulated O18 E. coli strain (possessing a homologous O type) but protected against its unencapsulated derivative. The opsonic and protective activities of these antibodies were significantly greater with IgG than IgM. Both IgG and IgM, however, required complement for their activities. When IgM to lipopolysaccharide was given to newborn rats in conjunction with IgM monoclonal antibody to the group B meningococcal polysaccharide, the protective effect was significantly greater than that of either antibody alone. Combinations of two (or more) antibodies to different cell wall components may be more beneficial in preventing and treating E. coli infection.
Animals↗
Staphylococcal scalded skin syndrome in two immunocompetent adults caused by exfoliatin B-producing Staphylococcus aureus.
An exfoliatin B-producing strain of Staphylococcus aureus was isolated from two adults with typical staphylococcal scalded skin syndrome (SSSS). One patient developed desquamation after a local staphylococcal infection of the hand, and the other developed exfoliation after nosocomially acquired staphylococcal endocarditis. Neither patient was immunocompromised, had evidence of renal insufficiency, or manifested other potential risk factors for SSSS. Purified toxin, isolated from the causative organisms, produced a Nikolsky sign in neonatal mice. The toxins were shown to be exfoliatin B by biochemical and immunologic methods and heretofore had been described only in children with SSSS. Analysis of plasmid DNAs from both strains revealed a 23-megadalton plasmid with identical restriction endonuclease digestion fragments. One isolate belonged to phage group II (3B/3C/6/7/47/54/55), whereas the other isolate belonged to phage groups I and III (7/29/52/52A/53/54/80). The observation that a non-phage group II exfoliatin-producing strain of S. aureus may produce SSSS in adults indicates the need to better define the diagnostic criteria for SSSS. Immunocompetent adults may remain susceptible to some strains of exfoliatin B-producing S. aureus.
Bacterial Toxins↗
The inhibitory effect of sodium alginate on antibiotic activity against mucoid and non-mucoid strains of Pseudomonas aeruginosa.
The exopolysaccharide of mucoid strains of Pseudomonas aeruginosa (MPA) is chemically similar to alginate, a common polysaccharide of seaweeds. Both polymers have been reported to decrease the diameter of the inhibition zones produced in antibiotic disc diffusion assays. In order to determine whether this phenomenon was due to reduced diffusion of the antibiotic in an agar matrix, or to inhibition of antibiotic activity by sodium alginate, we studied the effect of sodium alginate on the susceptibility of P. aeruginosa strains to antibiotics in disc diffusion assays, as well as in broth and agar dilution assays. Sodium alginate decreased the activity of the aminoglycoside antibiotics, amikacin and gentamicin, against two MPA strains and their non-mucoid derivatives in each of the assays. In broth dilution assays, increase of the calcium ion concentration likewise reduced aminoglycoside activity against P. aeruginosa, but not against Escherichia coli and Staphylococcus aureus. Sodium alginate caused no inhibition of the activity of piperacillin and carbenicillin. The reduction of aminoglycoside activity may have implications for the common failure of these antibiotics in the treatment of pulmonary infections caused by MPA in cystic fibrosis patients, but must be considered only an in-vitro phenomenon at present.
Alginates↗
Safety and immunogenicity of a Pseudomonas aeruginosa O-polysaccharide toxin A conjugate vaccine in humans.
Lipid A-free polysaccharide (PS) isolated from Pseudomonas aeruginosa immunotype 5 lipopolysaccharide (LPS) was covalently coupled to toxin A via reductive amination. The PS-toxin A conjugate was comprised of 29.8% PS and 70.2% toxin A, possessed a molecular weight of greater than 1 X 10(6), was nontoxic for animals and was nonpyrogenic for rabbits at a dose of 50 micrograms/kg body wt when administered intravenously. The conjugate evoked only mild, transient reactions upon subcutaneous administration to human volunteers. Vaccination engendered immunoglobulin G (IgG) antibody, which neutralized the cytotoxic effect of toxin A and promoted the uptake and killing of P. aeruginosa in the presence of human polymorphonuclear leukocytes. Passively transferred IgG isolated from the serum of immunized donors was far more effective at preventing fatal P. aeruginosa burn wound sepsis than paired preimmunization serum. These studies establish the potential usefulness of such a PS-toxin A conjugate as a vaccine against P. aeruginosa.
Adolescent↗
Safety and immunogenicity of a polyvalent Klebsiella capsular polysaccharide vaccine in humans.
A polyvalent Klebsiella vaccine composed of six serotypes of capsular polysaccharides (K2, K3, K10, K21, K30, and K55) was developed and its safety and immunogenicity evaluated in humans. Highly purified capsular antigens were treated in 0.1 N NaOH in 95% ethanol to detoxify trace amounts of contaminating lipopolysaccharide (LPS). The vaccine was nontoxic and nonpyrogenic for animals. A total of 40 individuals received either 25 or 50 micrograms of each represented antigen subcutaneously. Reactions to vaccination, where noted, were transient and mild in nature. An immunizing dose of 50 micrograms of each antigen (300 micrograms total) elicited a fourfold or greater immunoglobulin G (IgG) response to all vaccine antigens in greater than 80% of vaccinees. Generally, the serospecificity of the antibody response was limited to those capsular antigens included in the vaccine. IgG isolated from the serum of vaccinees was found to be highly protective against fatal experimental Klebsiella K2 burn wound sepsis indicating that the functional antibody is elicited following vaccination.
Adult↗
Role of lipopolysaccharide and capsule in the serum resistance of bacteremic strains of Escherichia coli.
To define the relative roles of capsule and lipopolysaccharide in the virulence of Escherichia coli obtained from blood, we compared the behavior of K1- and K5-encapsulated strains in serum bactericidal and rat virulence assays. Unencapsulated isogenic mutants selected from five parent strains of E. coli O12:K1, but not of O18:K1 or O7:K1 (all rough-specific phage insensitive), were lysed by normal human sera. In contrast, isogenic mutants from strains of serotypes O6:K5 and O18:K5 retained the serum resistance of the parent strains. There was a greater than 10(5) difference in LD50 in newborn rats between K1-positive and K1-negative pairs of E. coli serotypes O18 and O7 and a greater than 1 log difference between isogenic pairs of serotype O12; however, the K5 isogenic pairs had a similar LD50. Some non-O6 O serotypes, however, required the K5 capsule for serum resistance. We conclude that some O serotypes require encapsulation for optimal virulence but that other O serotypes may not.
Animals↗
Monoclonal antibodies reactive with K1-encapsulated Escherichia coli lipopolysaccharide are opsonic and protect mice against lethal challenge.
Seven murine monoclonal antibodies (MAbs) directed against O-side-chain determinants of the K1-encapsulated Bortolussi strain of Escherichia coli (O18:K1:H7) were evaluated for their in vitro and in vivo activities. All the MAbs reacted well in Western blots against E. coli O18 lipopolysaccharide antigens. Two MAbs of the immunoglobulin G (IgG) class promoted in vitro opsonophagocytosis and protected mice lethally challenged with bacteria. Two IgM MAbs showed partial protection, although they had no in vitro opsonic activity, and the remaining three IgM MAbs showed no apparent functional activities. Monoclonal IgG antibodies against bacterial lipopolysaccharide can be opsonic and protective in spite of the presence of the K1 capsule on the bacterium.
Animals↗
Colonization of newly arrived house staff by virulent staphylococcal phage types endemic to a hospital environment.
The acquisition of hospital strains of Staphylococcus aureus by new house officers was studied in an 800-bed referral hospital over a 1-year period. S. aureus isolates, including three strains with characteristic phage patterns that had previously been documented to cause disease in patients and colonize hospital personnel, were recovered from the anterior nares of 35 of 54 newly arrived house officers. There was a significant correlation (r = 0.7475; P less than 0.02) between colonization with the dominant hospital strain (S) and exposure to the hospital environment over 12 months. No hospital-wide increase in infections owing to the S strain was seen during this period, which suggests that house staff acquired this strain from reservoirs within the hospital. The finding of colonization with virulent endemic S. aureus strains in house officers working on every ward of the hospital suggests that new strategies for control of S. aureus nosocomial infections must be considered and evaluated.
Bacteriophage Typing↗
Activity of intravenous immune globulins against Klebsiella.
Seven commercial intravenous immune globulin (IVIG) preparations and an experimental hyperimmune globulin (Klebsiella immune-IVIG) were analyzed for antibody levels to Klebsiella capsular polysaccharides, opsonic activity, and protective capacity against Klebsiella. With one exception, all IVIGs reacted immunologically with the various capsular antigens, although titers between the preparations varied considerably. Klebsiella immune-IVIG possessed substantially higher titers (32-fold to 128-fold) than the commercial preparations. Only the hyperimmune globulin was capable of promoting the phagocytosis and killing of six Klebsiella test strains. When prophylactically administered, a commercial IVIG afforded significant protection (P less than 0.01) against fatal experimental Klebsiella sepsis only at a dose of 500 mg/kg. Klebsiella immune-IVIG provided a similar level of protection at a dose of 5 mg/kg. Whereas the commercial IVIG was ineffective when used therapeutically, the hyperimmune globulin was highly protective. Combined antibiotic-immunoglobulin therapy was most effective at reducing mortality.
Animals↗
Evolving epidemiology of Pseudomonas aeruginosa infections.
The dramatic increase in infections caused by Pseudomonas aeruginosa over the last three decades is examined in this review. By virtue of its unique growth characteristics, this organism occupies a firm niche in the hospital environment where it continues to be a major nosocomial pathogen, with particularly high rates of infection in traditionally susceptible patient subpopulations: the compromised host, patients with malignancy, cystic fibrosis, burn wounds and trauma. In recent years infection with Pseudomonas aeruginosa has become more prominent in other patient subpopulations: for example, post-surgical, pediatric and dialysis patients, as well as the elderly. A more interesting evolution in the epidemiology of infections caused by Pseudomonas aeruginosa is the appearance, often anecdotal, of new manifestations in healthy, non-hospitalized hosts e.g. the water-associated syndromes, puncture wounds, drug addiction. The need for better data on the prevalence of these infections, the required host-organism interactions and their practical impact sets an agenda for future investigation.
Cross Infection↗
A morphological and immunocytochemical study of a distinctive variant of ductal carcinoma in-situ of the breast.
Because so-called 'carcinoid' tumour of the breast has proven to be a difficult entity to define, we studied in-situ carcinoma as there were reasons to believe that this might help clarify the complex problems involved. We studied a consecutive series of 30 cases of ductal carcinoma in-situ (DCIS) by light microscopy and silver impregnation methods and identified a relatively common endocrine variant of DCIS. This variant was studied by immunocytochemical and ultrastructural methods, using conventional DCIS as a control. Endocrine DCIS is identified by its organoid pattern, stromal 'inclusions', festooned structure and a distinctive type of polypoid invagination. It is argyrophilic and rich in neuron-specific enolase. Ultrastructurally it contains abundant dense core granules which are impregnated selectively by Grimelius' method. This tumour type frequently contains peptide hormones of the ACTH family. Three of seven cases contained cells reactive for ACTH and corticotropin-like intermediate lobe peptide CLIP or their precursor, pro-opiomelanocortin. A fourth tumour contained neurotensin, recently identified in a variety of endocrine tumours. Argyrophil invasive carcinomas are a much more heterogeneous group of tumours than argyrophil DCIS and only a minority have an endocrine structure comparable to that described here.
Adrenocorticotropic Hormone↗
Prevention and therapy of experimental Escherichia coli infection with monoclonal antibody.
Mouse hybridoma antibody of immunoglobulin class M prepared with live group B meningococci was evaluated for its ability to protect against and treat Escherichia coli infections in a newborn-rat model. In these studies, antibody was administered intraperitoneally and bacteria were administered subcutaneously to avoid introducing the antibody and bacteria to the same site. The activity of this hybridoma antibody was specific; the antibody provided protection against the K-1 strain, but not against the K-92 strain. In addition, the amount of the antibody required for protection was dependent upon the size of bacterial challenge. With an increase of the bacterial inocula from the 100% lethal dose to 10 times the 100% lethal dose there was a threefold increase in the amount of the antibody required for 50% protection. Similarly, therapeutic efficacy of the antibody was also dependent upon the magnitude of bacteremia before therapy. The antibody successfully cleared the bacteremia only when the pretherapy bacterial counts in blood were less than 10(4) CFU/ml. These findings suggest that the monoclonal immunoglobulin M antibody against the capsular polysaccharide of the group B meningococcus may be useful in the prevention and treatment of K-1 E. coli infections.
Animals↗
Mechanism of priming of human neutrophils by a soluble lymphoblastoid cell factor.
Treatment of human neutrophils (PMN) with a cytokine-like factor in the supernatants of human lymphoblastoid cells (Raji) increased the random mobility and enhanced the migration of treated cells in response to other chemoattractants nearly 21/2-fold, although the supernatant itself was not a chemoattractant. Supernatant treatment also increased the adherence of bacteria threefold and the bacterial killing fourfold compared with PMN treated with control media. In examining the metabolic basis for the enhanced bactericidal ability, we observed a significant increase in spontaneous hexose monophosphate shunt activity of Raji cell supernatant (RS)-treated neutrophils even in the absence of additional stimuli. RS-treated PMN also had significantly enhanced production of superoxide anion and chemiluminescence response upon subsequent stimulation with a variety of soluble and particulate stimuli. Unlike other agents that prime neutrophil activation, however, the factor(s) in RS did not cause degranulation. It also differed in its ability to progressively enhance PMN functions with a longer period of preincubation (up to 3 hr). These data suggest that the RS factor(s) primes neutrophils by a unique mechanism. The neutrophil-enhancing activities of RS, which are the opposite of those activities described for leukocyte inhibitory factor, eluted off a Sephacryl S-200 column at approximately 30,000 m.w. This factor expands the relationship between neutrophils and lymphocytes, and may be a useful agent to provide valuable insights into the mechanism of respiratory burst activation and regulation.
B-Lymphocytes↗
Calcium requirements for increased complement receptor expression during neutrophil activation.
It has recently been shown that human neutrophils rapidly increase surface expression of membrane receptors for C3b (CR1) and C3bi (CR3) in response to chemoattractants and other stimuli. In the present studies, we used monoclonal antibodies and flow cytometry to assess the role of Ca2+ in this process. Stimulation with ionophore A23187 in the presence of 1.2 mM Ca2+ increased CR1 330% and CR3 650% compared with unstimulated cells at 37 degrees C. Because this indicated that increasing the cytosolic free Ca2+ caused increased receptor expression, we examined the role of Ca2+ in the response to other stimuli as well. Adding 1.2 mM Ca2+ or 5 mM EDTA to the media in which the polymorphonuclear leukocytes were suspended had no effect on the CR1 response to f-MLP or LTB4, whereas Ca2+ slightly enhanced and EDTA markedly inhibited the CR3 response to these stimuli. The effects of Mg2+-EGTA and EDTA were identical. TMB-8 (200 microM), which inhibits the release of Ca2+ from intracellular stores, completely blocked the increased expression of both receptors induced by fMLP or LTB4. Increased expression of both receptors was also prevented by the calmodulin antagonists chlorpromazine (50 microM) and trifluoperazine (10 microM), but not by chlorpromazine sulfoxide. Phorbol myristate acetate (0.1 ng/ml) increased CR1 230% and CR3 265%. Again Ca2+ and EDTA did not alter the CR1 response, whereas Ca2+ increased CR3 to 287% and EDTA reduced CR3 to 187% of control. TMB-8 (250 microM) completely blocked both CR1 and CR3 responses to this stimulus as well. Thus, release of intracellular Ca2+ is necessary and sufficient for increased CR1 expression in response to diverse stimuli, but maximal increases in CR3 expression require an additional influx of extracellular Ca2+. These results indicate that the mechanisms by which the surface expression of the two different complement receptors increase are different in their requirements for extracellular Ca2+. In comparison with the work of others, we suggest that the processes of increased complement receptor expression and secretion of granular enzymes may also differ.
Calcimycin↗