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PubMed2005

Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene.

Glomerular injury and proteinuria in diabetes (types 1 and 2) and IgA nephropathy is related to the degree of podocyte depletion in humans. For determining the causal relationship between podocyte depletion and glomerulosclerosis, a transgenic rat strain in which the human diphtheria toxin receptor is specifically expressed in podocytes was developed. The rodent homologue does not act as a diphtheria toxin (DT) receptor, thereby making rodents resistant to DT. Injection of DT into transgenic rats but not wild-type rats resulted in dose-dependent podocyte depletion from glomeruli. Three stages of glomerular injury caused by podocyte depletion were identified: Stage 1, 0 to 20% depletion showed mesangial expansion, transient proteinuria and normal renal function; stage 2, 21 to 40% depletion showed mesangial expansion, capsular adhesions (synechiae), focal segmental glomerulosclerosis, mild persistent proteinuria, and normal renal function; and stage 3, >40% podocyte depletion showed segmental to global glomerulosclerosis with sustained high-grade proteinuria and reduced renal function. These pathophysiologic consequences of podocyte depletion parallel similar degrees of podocyte depletion, glomerulosclerosis, and proteinuria seen in diabetic glomerulosclerosis. This model system provides strong support for the concept that podocyte depletion could be a major mechanism driving glomerulosclerosis and progressive loss of renal function in human glomerular diseases.

Animals↗
PubMed1976

[Fatal diphtheria in a 26-year-old man. Repetitorium; Known and current aspects of diphtheria].

This paper reports on a 26 year old male who died of toxic diphtheria with all typical features such as: Bullneck, paralysis of the soft palate, renal failure accompanied by proteinuria and--most notably--myocarditis (very typical microscopically) with circulatory disturbances and finally left and right hand failure. The myocarditis hat caused increases of SGOT, SGPT, CPK, LDH and HBDH to values not seen before by us in the course of myocarditis. The patient had been immunized against diphtheria as a child. Initial treatment consisted of the application of ampicillin which caused rapid regression of the local symptoms in the pharyngeal region including the bullneck-symptom; of course the course of intoxication was not influenced, even after the patient had been admitted to the hospital, the disease correctly diagnosed and antitoxin given three days before death.

Adult↗
PubMed1986

Interactions between diphtheria toxin entry and anion transport in Vero cells. II. Inhibition of anion antiport by diphtheria toxin.

When cells with surface-bound diphtheria toxin were exposed to pH 4.5, the toxin became shielded against lactoperoxidase-catalyzed radioiodination, indicating that the toxin was inserted into the membrane. Cells thus treated had strongly reduced ability to take up 36Cl-, 35SO4(2-), and [14C]SCN-. The reduction of chloride uptake was strongest at neutral pH, whereas that of sulfate was strongest at acidic pH. Lineweaver-Burk plots indicated that the toxin treatment reduced the Jmax but not the Km for the anions. The toxin also inhibited the NaCl-stimulated efflux of 35SO4(2-), indicating that the toxin inhibits the antiporter. No inhibition was found when toxin-treated cells were not exposed to low pH, whereas exposure to pH 4.5 for 20 s induced close to maximal inhibition. Half-maximal inhibition was obtained after exposure to pH 5.4. The concentration of diphtheria toxin required to obtain maximal inhibition (0.3 micrograms/ml) was sufficient to ensure close to maximal toxin binding to the cells. Even in ATP-depleted cells and in the absence of permeant anions, low pH induced inhibition of anion antiport in toxin-treated Vero cells. There was no measurable inhibition of anion antiport in cells with little or no ability to bind the toxin.

Adenosine Triphosphate↗
PubMed1975

[The effect of neuraminidase of C. diphtheriae on the functional capacity of the peritoneal exudate cells of guinea pigs to diphtheria bacilli].

A study was made of the effect of neuraminidase preparation containing no diphtheria toxin admixtures and hyaluronidase on the phagocytic activity of macrophages. Neuraminidase produced a stimulating effect on the cells of the developing macrophage culture. The macrophages treated with the enzyme increased their capacity to digestion of nontoxigenic diphtheria bacilli.

Animals↗
PubMedDate not supplied

[Diphtheria in Ukraine. The current aspects of diphtheria epidemiology (1)].

From 1991 forth, a diphtheria epidemics has been spreading in Ukraine, the cause of which is decline in the level of collective immunity. The highest incidence rates are registered in large industrial centers. In rural areas, morbidity rates were found to be half as high as those in urban ones, particularly so among the adults. Morbidity and mortality were greater among those children of under school age who did not attend the child's pre-school institutions. Immunization of the adults done on a single-procedure basis does not protect them either against the disease or lethal outcome. The observed decline in mortality is due to the detection of mild forms of the disease, earlier diagnose and, therefore, start of the treatment. But even in 1994 the epidemic situation with respect to diphtheria looks serious in Ukraine, which fact necessitates inaugurating antiepidemic measures on a continuous basis, the mainstay of which is vaccinal prevention.

Adult↗
PubMed1988

Antibody response of children to measles vaccine mixed with diphtheria-pertussis-tetanus or diphtheria-pertussis-tetanus-poliomyelitis vaccine.

The feasibility of giving measles vaccine mixed with either diphtheria-pertussis-tetanus (DPT) or DPT-poliomyelitis (DPTP) vaccine was investigated to simplify the routine immunization schedule. Children 12 to 18 months of age, due for measles immunization, were given measles vaccine alone or mixed with DPT or DPTP. Their prevaccination and four-weeks postvaccination serum samples were tested for the measles virus hemagglutination-inhibition antibody titer. Although 191 children completed the study, only 160 were initially seronegative. The seroconversion rates and geometric mean antibody titers in children given measles vaccine alone, mixed with DPT, or mixed with DPTP were 98%, 96.3%, and 96.4% and 41, 53, and 53, respectively. Local and systemic reactions were no more frequent in children given the mixture of vaccines than in children given DPTP alone. In summary, injecting measles vaccine mixed with DPT or DPTP did not diminish its immunogenic potency or increase adverse reactions. We believe that freshly mixed measles and DPT or DPTP vaccines can be given together, thus avoiding two separate injections.

Antibodies, Viral↗
PubMed2005

Mucosal vaccination against diphtheria using starch microparticles as adjuvant for cross-reacting material (CRM197) of diphtheria toxin.

Mucosal vaccination has the advantage of eliciting a local mucosal immune response as well as a systemic response. In this investigation, polyacryl starch microparticles were conjugated to diphtheria toxin cross-reacting material (CRM197) as a mucosal adjuvant for oral or intranasal immunisation of mice. Various methods of stabilising CRM197 with formaldehyde were investigated. A good systemic and local mucosal immune response was attained with oral immunisation when CRM197 was treated with a relatively low formaldehyde concentration prior to conjugation to the microparticles. No immune response was seen after intranasal immunisation.

Administration, Oral↗
PubMedDate not supplied

Rapid identification of Corynebacterium diphtheriae clonal group associated with diphtheria epidemic, Russian Federation.

We used 199 Corynebacterium diphtheriae isolated from 1995 to 1997 in Russia to evaluate the ability of random amplified polymorphic DNA (RAPD) to identify the unique clonal group that emerged there in 1990. Our data show that RAPD can reliably, reproducibly, and rapidly screen a large number of strains to identify the epidemic clonal group.

Corynebacterium diphtheriae↗
PubMed2001

Update on the supply of tetanus and diphtheria toxoids and of diphtheria and tetanus toxoids and acellular pertussis vaccine.

During the last quarter of 2000, the U.S. Public Health Service learned of a shortage of tetanus and diphtheria toxoids (Td) and tetanus toxoid (TT) resulting from decreased production of these vaccines by the two U.S. manufacturers. Previously published recommendations outlined priorities for use of the limited supply of Td and TT. The shortage was expected to be resolved by early 2001; however, on January 10, 2001, Wyeth Lederle (Pearl River, New York) announced it had stopped production of tetanus toxoid-containing products. Although a small amount of Td is produced by the University of Massachusetts for local distribution, Aventis Pasteur (Swiftwater, Pennsylvania) is now the sole nationwide distributor of Td and TT. Aventis Pasteur is shipping limited quantities of vaccine to assure a wide distribution of available doses.

Diphtheria Toxoid↗
PubMed1995

Localization of a critical diphtheria toxin-binding domain to the C-terminus of the mature heparin-binding EGF-like growth factor region of the diphtheria toxin receptor.

The monkey and human heparin-binding EGF-like growth factor precursors are diphtheria toxin receptors. To investigate which portion of this growth factor precursor is responsible for binding the toxin, the monkey precursor was compared to the mouse precursor which does not bind the toxin. Three clusters of differing residues were identified. The human mature growth factor (residues 63-148), which contains two of three differing clusters, inhibited the binding of radiolabeled toxin to cell-surface receptors, thus narrowing the binding domain to 86 of the 208 residue precursor. To define further the binding domain, chimeric mouse/monkey precursors were expressed and assayed for toxin sensitivity. The third cluster, residues 122-135, was found to be the most important region for toxin binding. Total replacement of monkey residues with mouse residues N-terminal to this region yields a highly toxin-sensitive cell. Collectively, the results suggest that the most critical residues for toxin binding lie between residues 122-148.

Amino Acid Sequence↗
PubMed2001

Extension of juxtamembrane domain of diphtheria toxin receptor arrests translocation of diphtheria toxin fragment A into cytosol.

Diphtheria toxin (DT) binds to the EGF-like domain of the DT receptor (DTR), followed by internalization and translocation of the enzymatically active fragment A into the cytosol. The juxtamembrane domain (JM) of the DTR is the linker domain connecting the transmembrane and EGF-like domains. We constructed mutants of DTRs with altered JMs and studied their abilities for DT intoxication. Although DTR mutants with extended JMs showed normal DT binding activity, the cells expressing the mutants showed both reduced translocation of DT fragment A into the cytosol and reduced sensitivity to DT, when compared with cells expressing wild-type DTR. These results indicate that the JM contributes to DT intoxication by providing a space appropriate for the interaction of DT with the cell membrane. The present study also indicates that consideration of epitopes of an immunotoxins would be an important factor in the design of potent immunotoxins.

Animals↗
PubMed1999

The effects of inhibitors upon pore formation by diphtheria toxin and diphtheria toxin T domain.

The formation of pores by membrane-inserted diphtheria toxin is closely linked to the translocation of its catalytic chain across membranes. In this report a number of aromatic polyanionic molecules were identified that inhibit toxin-induced leakage of molecules from model membrane vesicles. One inhibitor, Cibacron blue, totally blocked pore formation. Aniline blue and Fast Green decreased the size of the molecule released by a given concentration of toxin. Amaranth appeared to reduce the maximal amount of leakage, without greatly affecting the size of the molecule released at a given toxin concentration. Finally, Ponceau S and Cibacron brilliant red appeared to exhibit a mixture of these various types of inhibition. The inhibitors neither prevented the conformational transition of the toxin to form a hydrophobic state at low pH, nor (with the exception of Cibacron Brilliant Red) appeared to strongly inhibit toxin binding to model membranes. Additional experiments showed release of trapped materials from model membranes by isolated T domain of the toxin was similar to that by whole toxin. The effects of inhibitors on T domain induced release was also similar to that they have on whole toxin. Therefore, it is likely that the inhibition of pore formation by whole toxin involves inhibitor interaction with the T domain. The inhibitors identified in this study may be helpful for development of agents that interfere with toxin action in vivo.

Aniline Compounds↗
PubMed2006

Fresh frozen plasma and platelet concentrates may increase plasma anti-diphtheria toxin IgG concentrations: Implications for diphtheria fusion protein therapy.

We are developing two fusion proteins consisting of a diphtheria toxin (DT) linked to either granulocyte macrophage colony stimulating factor (DT388-GMCSF) or interleukin-3 (DT388-IL3). In trials, patients with anti-DT IgG concentrations >2.5 microg/ml had significantly lower concentrations of either fusion protein. DT389-IL2 is currently FDA approved for the treatment of cutaneous T-cell lymphomas. We noted increased concentrations of anti-DT IgG after administration of platelet concentrates (PC). Because many of these patients require transfusions, we measured the anti-DT IgG content of FFP and PC. We assayed 14 bags of FFP and 12 bags of single-donor PCs for anti-DT IgG by an enzymoimmunoassay against DT389-IL2, DT388-IL3, DT388-GMCSF. The median (percent of samples positive) of anti-DT IgG concentrations in PC against DT388-GMCSF, DT388-IL3, DT389-IL2 was 0.8 microg/ml (83%), 0.7 microg/ml (83%), and 0.3 microg/ml (58%), respectively. The median (percent of samples positive) anti-DT IgG concentration in FFP against DT388-GMCSF, DT388-IL3, and DT389-IL2 was 2.1 microg/ml (86%), 1.9 microg/ml (93%), and 1.4 microg/ml (86%), respectively. There was a strong association between anti-DT389IL2 IgG, anti-DT388IL3 IgG, and anti-DT388GMCSF IgG concentrations in both the FFP (95.6%) and PC (76.3%). Assuming a plasma volume of 3 l in a 70 kg patient, a single FFP unit would increase the plasma anti-DT389IL2 IgG, anti-DT388IL3 IgG, and anti-DT388GMCSF IgG by 0.13 microg/ml, 0.17 microg/ml, and 0.19 microg/ml, respectively. For PC, a single unit would increase plasma anti-DT389-IL2 IgG, anti-DT388-IL3 IgG, and anti-DT388-GMCSF IgG by 0.03 microg/ml, 0.06 microg/ml, and 0.07 microg/ml, respectively. In conclusion, a single FFP or PC appears to minimally increase anti-DT IgG concentrations, but multiple units may significantly do such.

Blood Platelets↗
PubMed1996

Targeted delivery of diphtheria toxin via immunoliposomes: efficient antitumor activity in the presence of inactivating anti-diphtheria toxin antibodies.

Diphtheria toxin (DT) has attracted considerable attention for anti-cancer therapy. However, its extensive use is prohibited by (i) its non-specific action which can result in substantial toxicity, (ii) most patients have low serum levels of anti-DT antibodies (AT antibodies) which can inactivate DT and (iii) its immunogenicity will boost the circulating AT antibody level, thereby further compromising the antitumor activity. To overcome these limitations, we have developed a new approach for targeted delivery of DT utilizing immunoliposomes. In this approach, protection against the non-specific action of DT is combined with efficient antitumor activity even in the presence of inactivating AT antibodies.

Animals↗
PubMed1997

Feasibility study of a combined diphtheria-tetanus-acellular pertussis-hepatitis B (DTPa-HBV) vaccine, and comparison of clinical reactions and immune responses with diphtheria-tetanus-acellular pertussis (DTPa) and hepatitis B vaccines applied as mixed or injected into separate limbs.

The feasibility of a combined diphtheria-tetanus-acellular pertussis-hepatitis B (DTPa-HBV) vaccine was assessed and a comparison made of immunogenicity and reactogenicity to DTPa and HBV vaccines mixed in one syringe and to concomitant but separate injections as a primary vaccination course in three groups of infants at 3, 4.5 and 6 months of age. All subjects attained protective levels of anti-HBs antibodies 1 month after the primary course with higher geometric mean titres (GMTs) in the combined or mixed vaccinations. GMTs for pertussis toxin (PT), filamentous haemagglutinin (FHA) and pertactin (PRN) were as good or better in the groups administered the combined formulation and the extemporaneously mixed vaccines than the separate administration. No serious adverse event related to the vaccination was reported in this study. Neither the combined formulation of DTPa and HBV vaccines nor the extemporaneous mixture increased the incidence or severity of adverse reactions compared with the separate administration of DTPa. This study shows the feasibility of a combined DTPa-HBV vaccine and the data support, in the interim, the mixing of DTPa and HBV vaccines which are tested in clinical trials for infant immunization.

Antibodies, Bacterial↗
PubMed1999

In vitro-translated diphtheria toxin A chain inhibits translation in wheat germ extracts: analysis of biologically active, caspase-3-resistant diphtheria toxin mutants.

The diphtheria toxin A chain (DTA) is a potent cytocidal agent that inactivates elongation factor 2. This activity of DTA inhibits protein synthesis and rapidly leads to cell death through apoptosis. In this paper, we have developed a simple in vitro assay for DTA activity in which in vitro-translated DTA is used to inhibit the translation of proteins in wheat germ extracts. Inhibition of translation by DTA is dependent on cofactor NAD+, and the analysis of an attenuated DTA mutant indicates that this in vitro assay accurately reflects the in vivo activity of DTA. We have also identified aspartic acid at residue 8 (Asp-8) of DTA as a site of cleavage by the cell-death protease caspase-3. Cleavage of DTA by caspase-3 inactivates its ability to inhibit translation in wheat germ extracts. Conservative mutations at Asp-8 render DTA resistant to cleavage by caspase-3, but only slightly affect the ability of DTA to inhibit translation in vitro. Moreover, caspase-3-resistant DTA mutants are toxic in cells in tissue culture. The in vitro assay that we describe here will be useful for the rapid analysis of DTA activity and the development of DTA mutants with altered biological properties that may be of therapeutic value. Lastly, these studies serve as a prototype for the creation of caspase-resistant effector molecules.

Amino Acid Sequence↗
PubMed1992

Quantitative estimation of diphtheria and tetanus toxoids. 6. Use of different antibody titration methods for evaluation of immunogenicity in animals during potency assay of diphtheria toxoid.

Two diphtheria toxoid preparations were compared in potency assays in guinea-pigs using different methods for evaluation of the responses to vaccination. The methods used were the direct skin challenge (Schick test) and ELISA and VERO cell titration of antibodies. The different evaluation methods resulted in the same relative potencies between the toxoids. It was observed that when first-vaccination sera were compared with a second-vaccination serum, the relative antibody concentration depended on whether ELISA or VERO cell titration was used.

Animals↗