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Biomedical subjects

B Bizzini

Publications and source records attributed to B Bizzini.

At least 109 records · Page 6Linked to original sources
PubMed1984

[From biotechnology to bacterial toxins and immunomodulators].

The disposal of industrial wastes has been recognized as a serious problem long before the ecological movement gained its present strength. The possibility of using "useful" bacteria for this purpose was considered rather early and numerous studies were made to use them for the biological treatment of industrial wastes. Such attempts have taken advantage of the development of large scale fermentors for the production of bacteria while at the same time they have stimulated progress in the technology of fermentors. The advances made in the technology of fermentors have also made possible the large scale production of pathogenic bacteria. This has made possible the production of bacterial toxins in adequate amounts, enabling investigators to purify them to homogeneity, to characterize the purified toxins physico-chemically and immunologically and to study their structure-function relationships. Similarly, large quantities of bacteria exhibiting specific biological activities could be produced and the constituents responsible for the activities of these bacteria could be isolated and characterized. In this paper, the Author describes the stages of his progress and processes through the fields of the biotechnology and toxinology to that of immunomodulators. His investigations have largely taken advantage of developments in the technology of fermentors. "Ecologic" bacteria have been isolated which are capable of using phenol as the only source of carbon or cyanides as the sole source of carbon and nitrogen. These bacteria have been used for the treatment of industrial wastes enriched either with phenol or with cyanides. Another type of "useful" bacteria investigated was Bifidibacterium bifidus which has a fundamental role in the economy of the breast-fed infant. B. bifidus is present only in the gut of infants fed with mothers-milk. Growth factors for B. bifidus have been isolated from casein hydrolyzates which permitted the implantation of B. bifidus in the gut of infants fed with cows-milk supplemented with these factors. A further development of this type of research has been the large scale production of toxigenic bacteria. As a result large quantities of tetanus toxin have been produced and a method of purification has been devised. The availability of large amounts of purified tetanus toxin made it possible to determine the physico-chemical characteristics of the toxin as well as some of its structure-function relationships. In addition, the mechanism of detoxification of protein toxins by the action of formaldehyde has been clarified. Enzymatically derived toxin fragments have also been purified.(ABSTRACT TRUNCATED AT 400 WORDS)

Adjuvants, Immunologic↗
PubMed1983

Monoclonal antibodies against tetanus toxin and toxoid.

Monoclonal antibodies against tetanus toxin and its toxoid were produced by immunizing mice with toxoid or toxin. They were measured by an enzyme-linked immunosorbent assay (ELISA), by a toxin neutralization test in mice (in vivo prevention test), and by their ability to prevent binding of 125I-toxin to brain membranes or gangliosides (in vitro prevention test). Six monoclonal antibodies obtained by immunization with toxoid (anti-toxoid 1-6) were investigated in more detail. They belonged to IgG class 1. Three of them (anti-toxoid 1, 2 and 3) recognized both toxoid and toxin as well as fragment B and the light chain of toxin, but not fragment C. Two other antibodies (anti-toxoid 4 and 5) were directed against toxoid only. Neither of them prevented toxin action in vitro or in vivo. Anti-toxoid 6 recognized toxin, toxoid and fragment C, but not light chain, and prevented toxin action in vitro and in vivo. Immunization against toxin was initiated with a toxin-antitoxin complex and boosted with toxin. We studied six antibodies in more detail, all of IgG type 2. Their KD against 125I-tetanus toxin varied from 10(-9) to 10(-10) M. Anti-toxin 2 recognized toxin, toxoid, light chain and fragment B, but not fragment C. The others reacted with toxin, toxoid and fragment C, but not with light chain or fragment B. All of them prevented toxin action in vitro and in vivo. As calculated from the maximal extinction achieved in the ELISA, tetanus toxin combined with a maximum of two different antibody molecules from our set. Gel filtration data indicate that tetanus toxin reacts with monoclonal antibodies one by one. Compared with polyclonal antiserum, monoclonal antibodies yield flatter slopes in both in vitro and in vivo prevention tests. Thus, they cannot substitute for the polyclonal antibodies in clinical situations, and cannot be calibrated in international units.

Animals↗
PubMed1983

Neuronal acquisition of tetanus toxin binding sites: relationship with the last mitotic cycle.

In an earlier study on the developing nervous system, the existence of a temporal correlation between the appearance of tetanus toxin-binding cells and neurogenesis was reported (A. Koulakoff, B. Bizzini, and Y. Berwald-Netter (1982). Dev. Brain Res. 5, 139-147). Using a combined approach of immunocytochemistry and [3H]thymidine autoradiography it is shown that, in the fetal mouse central nervous system, dividing cells do not express membrane binding sites for tetanus toxin. A time-course quantitative autoradiography revealed that the toxin-binding sites become apparent within 7 +/- 1 hr, following the last S phase, on cells undergoing the conversion from dividing to postmitotic state. The acquisition of surface binding sites for tetanus toxin may thus be an early property of nascent central neurons, marking the transition from cycling precursor neuroblasts to postmitotic neuronal cells. Parallel studies on in vivo-developing dorsal root ganglia disclosed that at least some peripheral nervous system cells are endowed with tetanus toxin-binding capacity while still capable of DNA synthesis and undergo one or more divisions.

Animals↗
PubMed1983

Naturally acquired antibodies to tetanus toxin in humans and animals from the galápagos islands.

A serologic survey using a highly sensitive enzyme-linked immunosorbent assay confirmed the anticipated finding of naturally acquired antibodies to tetanus toxin both in humans and animals on the Galápagos Islands. In 57 inhabitants (mean age, 31.3 years) who had not been vaccinated against tetanus, antibody to tetanus toxin was detected in the blood in varying titers (geometric mean [reciprocal] titer [GMT], 0.015 international units [IU]/ml). In one individual the titer of antibody was greater than 12.5 IU/ml. Two individuals who had never been vaccinated against tetanus but who had reported having had clinical tetanus had titers of antibody to tetanus toxin of 0.02 IU/ml and 0.3 IU/ml, respectively. All nine of the animals studied showed antibody to tetanus toxin (GMT, 0.028 IU/ml).

Adolescent↗
PubMed1983

Neurotropism of rabies virus. An in vitro study.

The relative susceptibility of neurons and glia, grown as monolayers in vitro, to rabies virus infection was explored. Established cell lines of neuronal or glial phenotype and primary cultures of cells derived from mouse dorsal root ganglia (DRC) or brain were used as homologues of the targets of rabies virus in the nervous system. Fixed rabies virus (CVS) strain was used in most experiments; other fixed rabies strains (PV, HEP, ERA) and a street rabies virus isolate were used in some. Virus-cell tropism was determined by immunofluorescence assay for rabies nucleocapsid antigen and cell permissivity was assessed by titration of virus yields. Neuronal cells always exhibited a much greater susceptibility to infection and a greater propensity to sustain viral growth. By immunofluorescence, 90-100% of neurons commonly had viral inclusion bodies, while doses of the virus three to four orders of magnitude higher still left greater than 99% of astrocytes, in brain cell cultures and 90 +/- 5% of the non-neuronal cells in DRG cultures without any obvious signs of rabies virus. Neuroblastoma cells (95 +/- 5% with viral antigens) produced viral yields about four orders of magnitude higher than glioma cells (10 +/- 5% with viral antigens). Though the overall infectivity of street virus was lower than that of fixed virus strains, a significantly higher viral tropism for neurons than for glia was maintained. Thus, primary neuronal cultures offer a means of exploring molecular events in rabies virus infection and their role in pathogenesis.

Animals↗
PubMed1983

[Anti-tetanus vaccines].

Antitetanus vaccination is the safest and more effective means to eradicate tetanus from the world. The vaccination success will depend on the intrinsic immunogenicity of the vaccine, on the one hand, and on the capacity of a subject to respond to the vaccine stimulation, on the other. To increase the vaccine immunogenicity and to enhance the vaccine immunocompetence, vaccines were potentiated with adjuvants. Mineral adjuvants, so far successfully employed, show some drawbacks. The use of fluid polymerized vaccines might offer an alternative to the use of absorbed vaccines. Another interesting development of the investigations in this field is the attempt to increase and modulate the immunological response to the toxoid favourably, by means of coupling to the toxoid compounds endowed with specific properties. Vaccines made up of subunits of the toxin molecule do not appear to have future development. On the contrary, a future approach to the antitetanus vaccination problem would be the design of a vaccine, made up of a synthetic oligopeptide simulating one of the antigenic determinants of the toxin molecule and involved in eliciting the formation of neutralizing antibodies. Besides, this vaccine should be very suitable for carrying out the oral vaccination.

Humans↗
PubMed1982

[Prevention and therapy of L1210 leukemia in mice, using inactivated and grafted tumor cells, in association with the immunomodulator P40, and Antineoplastic Agents (author's transl)].

The effect on L1210 in Mice of an immunostimulation with P40 fraction isolated from C. granulosum and inactivated L1210 cells coupled with tetanus toxoid, in combination or not with chemotherapy with either daunorubicin or mitomycin, has been looked for using various modalities. Cells partly inactivated by action of the drugs in vitro have also been used for grafting the Mice. The strongest inhibition of tumour growth was observed when the following treatment sequence was applied: Immunostimulation, tumor grafting, chemotherapy, immunostimulation. The significance of the reported results for the treatment of Human neoplasia is discussed.

Adjuvants, Immunologic↗
PubMed1982

Human T cell clones specific for tetanus toxoid: characterization of antigen specificity and HLA restriction.

T cell blasts isolated from six-day cultures of peripheral blood mononuclear cells stimulated with tetanus toxoid (TT) were cloned in a two-layer agar system in the presence of autologous irradiated PBM (iPBM) and TT. Colonies were individually isolated and expanded in interleukin 2-containing medium. The antigen specificity of three T cell clones was attested by their capacity to proliferate under restimulation by TT and not by an unrelated antigen. The clones were specific for either the alpha or the beta chain of the toxin. T cells from these clones expressed Ia determinants and antigens of the helper/inducer T cell subset as defined by anti-T monoclonal antibodies. In the case of the alpha chain-specific clone MA 11 from the donor MA, allogeneic iPBM from HLA-compatible unrelated donors, including seven donors sharing one HLA DR specificity with MA, were found inefficient as antigen-presenting cells. A familial study, however, demonstrated that antigen presentation could be obtained using nonautologous cells. The presenting capability of cells from relatives of the donor MA segregated in association with the HLA-DRw6-bearing maternal haplotype present in MA. Results suggest that MA 11 cells recognized the antigen in the context of a surface determinant closely linked to HLA-DRw6.

Animals↗
PubMed1982

Prenatal and postnatal ontogenesis of neurotransmitter-synthetizing enzymes and [125I]tetanus toxin binding capacity in the mouse hypothalamus.

In order to estimate the early neuronal maturation in the hypothalamus, we followed the development of 3 neurotransmitter-synthetizing enzymes (TH, GAD, ChAT) and a neuronal cell surface marker (tetanus toxin) in the hypothalamus as compared to cerebral hemispheres. This showed that TH, ChAT and GAD activities were present in both structures on the fourteenth fetal day. Yet, before birth, whereas GAD and ChAT activities remained low and followed a similar development in the 2 structures, TH activity was important and higher in hypothalamus than in brain hemispheres. After birth the activities of the 3 enzymes increased rapidly between day 5 and day 20, but their evolution in the hypothalamus always preceded that in the cerebral hemispheres. Tetanus toxin binding capacity was present on the thirteenth fetal day in the 2 structures, but during fetal life in the hypothalamus, the level of toxin binding was always higher than in the cerebral hemispheres. After birth, the toxin binding increased between day 2 and day 10 and reached adult level at the same time in both structures, around day 15. We conclude that neuronal maturation proceeds earlier in the hypothalamus than in brain hemispheres, and that the differentiation of a neuronal surface marker appears concomitantly with that of specific intraneuronal enzymes.

Animals↗
PubMed1982

A correlation between the appearance and the evolution of tetanus toxin binding cells and neurogenesis.

The ontogenesis of cells expressing surface membrane binding sites for tetanus toxin (Tt) was studied in the mouse nervous system. Cells were labeled shortly after the tissue dissociation and the toxin bound was revealed by immunofluorescence. In the brain, spinal cord and dorsal root ganglia the toxin binding cells (TBC) are found as of very early stages of nervous system organogenesis, i.e. at 10 days of gestation. There is a close temporal correlation between the pattern of emergence and accumulation of TBC and the known pattern of appearance of post-mitotic neurons in mouse cerebral cortex, cerebellum and spinal cord. The curves of TBC abundance as a function of fetal age in various nervous system areas are different. They show regional fluctuations in the proportion of TBC that reflect the cumulative changes in the dynamics of neuronal subpopulations. The results indicate that Tt can be used as an ontogenetically early marker of neuronal differentiation and that the acquisition of Tt receptors may represent one of the earliest detectable characteristics of the developing neurons.

Animals↗
PubMed1982

[Effect of an immunomodulator (P40) on Escherichia coli urinary infection in the rat].

The preventive effects of various doses of the immunomodulator P40 on the experimental E. coli infection of the upper and lower urinary tract have been investigated in the rat. Under our experimental conditions, P40 only weakly influenced the bacteriological picture of the infection in rats infected by the upper route. However, the development of nephropathia might be decreased. By contrast, P40 was found to prevent the development of infection in two thirds of cases infected by the lower route. The preventive effect of P40 on infections of the lower urinary tract seems to be mostly medicated by the stimulation of phagocytosis, although both humoral and cellular immunity are likely to be involved. In contrast, the defense is most probably to be ascribed to cellular immunity in infections of the upper urinary tract. For the future, conditions will have to be specified which enable P40 to express predominantly its stimulating effect on cellular immunity. Furthermore, the choice of the minimum active dose together with its fractionated administration will prevent side-effects (prostatitis) while resulting in equally pronounced protective action. Since P40 has already successfully been used in man for the treatment of both infectious and tumoral processes, it could as well be used for the prevention of relapses in recurrent urinary infections.

Adjuvants, Immunologic↗