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Biomedical subjects

E J Ziegler

Publications and source records attributed to E J Ziegler.

35 records · Page 2Linked to original sources
PubMed1982

Induction of immunity against lethal Haemophilus influenzae type b infection by Escherichia coli core lipopolysaccharide.

Efforts to prevent Haemophilus influenzae type b (HIB) infections in infancy have been hampered by the low immunogenicity of capsular polysaccharide vaccines in children younger than 18 mos. In searching for alternate immunogens, we have studied the protective potential of polysaccharide-poor, lipid-rich endotoxin (LPS) core in experimental HIB infections. Because all gram-negative bacteria have similar LPS core structures, we were able to use as vaccine the J5 mutant of Escherichia coli 0111, the LPS of which consists only of core components, and thus to avoid problems in interpretation arising from vaccine contamination with non-LPS HIB immunogens. Mice were given graded inocula of HIB and developed lethal infection analogous to human HIB disease when virulence was enhanced with mucin and hemoglobin. After active immunization with heat-killed E. coli J5, 40/50 (80%) of infected mice survived, compared with 14/50 (28%) of saline-immunized controls (P less than 0.005). Passive immunization with rabbit antiserum against E. coli J5 prevented lethal HIB infection when administered 24 or 72 h before or 3 h after infection. This protection was abolished by adsorption of antiserum with purified J5 LPS, with survival reduced from 14/24 to 0/24 (P less than 0.005). Furthermore, rabbit antiserum to purified J5 LPS gave just as potent protection against death as antiserum to whole J5 cells. These studies demonstrate that immunity to core LPS confers protection against experimental murine HIB infection and provide the framework for a new approach to prevention of human disease from HIB.

Antibody Formation↗
PubMed1981

Immunization against nosocomial infection.

Overwhelming infection with gram-negative bacteremia has become the most serious nosocomial infection in compromised patients. Because gram-negative bacteria share a common core lipopolysaccharide, we tried to develop a single vaccine or antiserum that might control these infections regardless of species. We used a mutant of Escherichia coli 0111 (J5) deficient in uridine diphosphate-galactose (UDP-GAL) epimerase and thus unable to attach "0" side chains, so that core lipopolysaccharide was exposed. A vaccine composed of this mutant produced antibody that gave broad protection against lethal infections by different gram-negative bacteria in immunosuppressed animals. The J5 vaccine protected against 98 percent lethal doses of Pseudomonas aeruginosa, and J5 antiserum improved survival tenfold in animals dying of Esch. coli, Klebsiella and Pseudomonas bacteremia. The protection with vaccine or prophylactic antiserum was undiminished in animals challenged six weeks after immunization. Encouraged by these results, we conducted a double-blind trial in patients with gram-negative bacteremia. In those given J5 antiserum, the mortality rate was cut in half and survival from deep shock increased from 28 percent to 82 percent. Because of these preliminary results in 136 patients, the study has been extended to 300 patients and the double blind code will be examined again to see if the early favorable results are confirmed and extended.

Adult↗
PubMed1979

Pseudomonas aeruginosa vasculitis and bacteremia following conjunctivitis: a simple model of fatal pseudomonas infection in neutropenia.

During attempts to create a realistic model of fatal bacteremia due to Pseudomonas aeruginosa during immunosuppression, it was found that the invasive as well as the disseminated phase of infection could be mimicked by gentle instillation of 10(8) colony-forming units of P. aeruginosa into the intact conjunctival sac of agranulocytic rabbits. Within 48 hr animals developed conjunctivits leading to severe necrotizing vasculitis and fatal bacteremia. Twelve of 26 strains from patients with P. aeruginosa infections were virulent, causing death in 50%--100% of animals. Nine (75%) of 12 isolates from blood but only two (15%) of 13 isolates from sputum and urine were highly lethal. Neither proteolytic enzyme production nor serum resistance alone accounted for virulence. No infection developed in animals and normal leukocyte counts or in neutropenic animals given Escherichia coli, Klebsiella pneumoniae, or non-aeruginosa pseudomonads. A rare vasculitic lesion was observed in animals inoculated with Serratia marcescens. This model, which illustrates the distinctive features of P. aeruginosa infection, is so simple and reproducible that it should be useful for evaluation of the efficacy of drugs and immunization against Pseudomonas in the compromised host.

Agranulocytosis↗
PubMed1978

Antiserum treatment of gram-negative bacteremia.

In order to lower the mortality rate from gram-negative bacteremia, 136 patients were treated with human antiserum against core glycolipid, or with control nonimmune human serum, in a double-blind clinical trial. The antiserum was prepared by immunizing healthy young men with a vaccine composed of heat killed cells of the J5 mutant of E. coli 0111 B4. Since the core glycolipid in this mutant is not encumbered with "O" side chains, it can stimulate antibody against the core glycolipid possessed in common by the different species of gram-negative bacteria responsible for lethal bacteremia in patients. No serious reactions occurred in over 300 men receiving this vaccine, and the J5 antiserum gave striking broad-spectrum protection against experimental gram-negative bacteremia and endotoxemia. When human J5 antiserum was administered to seriously ill bacteremic patients, the mortality rate was virtually cut in half, as compared to controls. The death rate from gram-negative bacteremia was 14% in patients treated with J5 antiserum, and 26% in those given nonimmune control human serum. Among patients in profound gram-negative bacteremic shock, the recovery rate rose from 29% in controls to 82% in those treated with J5 antiserum (p = 0.02). On the basis of these encouraging results we propose to treat more bacteremic patients with J5 antiserum, because larger groups are needed to establish the full significance of the initial findings.

Animals↗
PubMed1978

Neutralization of meningococcal endotoxin by antibody to core glycolipid.

Antibodies to Escherichia coli J5, a uridine 5'-diphosphate-galactose epimerase-less mutant of E. coli 0111, neutralized meningococcal endotoxemia from all three major capsular serogroups. We chose the dermal necrosis of the local Shwartzman phenomenon and the renal cortical necrosis of the general Shwartzman phenomenon as assays because these are the hallmarks of meningococcemia, and because meningococcal lipopolysaccharide (LPS) is a uniquely potent cause of dermal purpura and necrosis. Meningococcal antisera raised against LPS from MGC A, B, and C also provided good protection against endotoxemia from the homologous capsular groups, but it was inconsistent against the heterologous serogroups. The superiority of J5 antibodies (purified IgG as well as antiserum) is probably due to the fact that J5 LPS contains only the endotoxin core. Consequently, immunization with this mutant stimulates production of antibodies to core LPS without interference by the "0" antigenic determinants of the side chains. These observations indicate that the endotoxin core is the toxic moiety of meningococcal LPS, that the core LPS of meningococcus (MGC) is immunologically similar to enteric LPS, and that the antigenically variable "0" side chains of MGC LPS interfere with antibody production against the common core. They also suggest that antibodies prepared against this E. coli mutant could interrupt the devastating course of meningococcal endotoxemia in man, regardless of the capsular serogroup of the infecting strain.

Animals↗
PubMed1977

Antibody to cell wall glycolipid of Gram-negative bacteria: induction of immunity to bacteremia and endotoxemia.

Antiserum to the core glycolipid of gram-negative bacteria was prepared by immunization of rabbits with vaccine composed of killed cells of the uridine diphosphate galactose-deficient mutant (J5) of Escherichia coli O:111. Antiserum to J5 not only prevented death of animals from endotoxin but also prevented the local and generalized Shwartzman reactions. Antiserum to endotoxin also prevented renal cortical necrosis and disseminated intravascular coagulation during the evolution of the generalized Shwartzman reaction. Antiserum to be J5 mutant was successful in the treatment of overwhelming bacteremia produced by other gram-negative bacteria; in addition to bacteremia cause by coliform organism, antiserum to J5 was dramatically effective in treatment of bacteremia due to Pseudomonas aeruginosa. One injection of rabbit antiserum to J5 improved the survival rate from 15% in controls to 59% in treated animals (P less than 0.002). Active immunization with J5 vaccine was even more effective against pseudomonas bacteremia: such immunization improved the survival rate from 13% in controls to 92% in vaccinated rabbits. Since an antiserum effective against the J5 mutant of E. coli can be prepared safely in human subjects, such immunotherapy should be considered for patients with gram-negative bacteremia.

Animals↗
PubMed1975

Prevention of lethal pseudomonas bacteremia with epimerase-deficient E. coli antiserum.

All of these experiments demonstrate that despite many microbiologic differences between Pseudomonas and the enteric rods, there is a close immunologic relationship between their endotoxin cores. These studies also show that by genetic manipulation we can unmask a protective antigen for preparing antiserum with a broad range of activity, even in the face of neutropenia. Production of potent human J5 antiserum is a safe, simple procedure, making it possible to consider endotoxin core antibody treatment of all Gram negative bacteremia in patients regardless of the causative organism.

Agranulocytosis↗
PubMed1973

Human antiserum for prevention of the local shwartzman reaction and death from bacterial lipopolysaccharides.

Bacterial lipopolysaccharides from dead bacteria have been blamed for the continuing high mortality from gram-negative infections despite antibiotic treatment. Because animal antiserum against these lipopolysaccharides has been shown to protect against several of the effects of endotoxin, we undertook the development of antiserum in human subjects. 21 men were immunized with a single injection of Salmonclla typhimurium or Escherichia coli 0:111 heat-killed cells and immune serum was collected at 2 wk. Preimmune serum was obtained as a control in all animal experiments. 1 ml antiserum given intravenously protected mice against a lethal intravenous dose of homologous endotoxin (P < 0.005 for both antisera). E. coli antiserum reduced the incidence of positive local Shwartzman reactions with E. coli endotoxin from 100 to 38%; S. typhimurium antiserum reduced the incidence from 92 to 35%. (P < 0.0005 for both antisera). There was no protection against heterologous endotoxin in either animal model. These experiments demonstrate for the first time that human antiserum confers exceedingly potent passive immunity to the effects of endotoxin.

Antitoxins↗
PubMedDate not supplied

Lethal Haemophilus influenzae type b infection in mice.

Previous animal models of invasive Haemophilus influenzae type b (HITB) infection are characterized by a low mortality rate. We produced a highly lethal infection in CF1 mice using mouse passage, mucin, and hemoglobin to enhance infectivity. Infection by the intraperitoneal route was followed by progressive peritonitis and bacteremia with subsequent HITB infection of the brain and meninges, and death. Death occurred between eight and 72 hours after infection and was associated with 10(6) to 10(9) HITB per ml of blood and with 10(2) to 10(5) HITB per g of brain. Mucin-hemoglobin did not augment HITB growth, but impaired macrophage adherence to glass in vitro, without decreasing cellular viability. In vivo, mucin-hemoglobin decreased the rate of disappearance of 51Cr-labelled HITB from the blood by impairment of hepatic clearance. This technically simple and inexpensive model is useful for the study of HITB infections in which bacterial multiplication, invasion and host lethality are desired features.

Animals↗