Oral priming followed by parenteral immunization with HIV-immunosomes induce HIV-1-specific salivary and circulatory IgA in mice and rabbits.
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Administration, Oral↗
Biomedical subjects
L Thibodeau
Publications and source records attributed to L Thibodeau.
[Oral and parenteral immunization with HIV immunosome induce the secretion of IgA specific of HIV-1 in the salivary and the production of circulatory IgA in mice and rabbits].
Given the sexual transmission of HIV, the establishment of a genital mucosal immunity through secretory IgA may be necessary to achieve protection. We have investigated if repeated stimulations of oral mucosa with HIV-Immunosomes would lead to the production of secretory IgA in saliva and also, if such an oral immunization could prime the immune system to an early systemic immune response following a parenteral immunisation with a low dose of the antigen. HIV-1 gp 160-specific secretory IgA were detected in the saliva of all rabbits orally immunized with HIV-Immunosomes. As early as one week after the parenteral immunization, high titers of serum IgA, IgM and IgG were detected both in mice and rabbits that had been orally stimulated with the antigen. These antibodies could neutralize HIV infectivity in vitro. Animals that were immunized only parenterally showed a very weak humoral immune response.
Administration, Oral↗
Insert earphones for speech recognition testing.
Performance-intensity functions for PB word lists were run on 19 normal-hearing subjects and 15 subjects with sensorineural hearing losses. Comparisons were made between standard supra-aural earphones (TDH-49P) and insert phones (ER-3A). Results showed that, at least for the higher sensation levels where word recognition tests are usually performed, the phones may be used interchangeably. Using insert earphones for word recognition tests can have several beneficial effects with respect to cross hearing and masking.
Adult↗
Use of electrophysiologic tests to measure disease progression in ALS therapeutic trials.
A battery of electrophysiologic tests was developed to assess the relative degree of lower and upper motor neuron (spasticity) deficit in a group of ALS patients enrolled in a therapeutic trial. Test results were correlated with strength in the tibialis anterior muscle as determined by measurement of maximum voluntary isometric contraction (MVIC), using strain gauge tensiometers, and were also correlated with a clinical spasticity rating scale. Patients were tested every 6 to 8 weeks over more than 1 year. Compound muscle action potential amplitude (CMAPa) from tibialis anterior correlated best with MVIC and also showed a strong linear correlation with time, as did MVIC. Other tests correlated poorly with MVIC on the average, although individual patients did show high correlations. In those patients where correlation between CMAPa and MVIC was low, MVIC did not show a high linear correlation with time and was also highly variable. This study suggests that the addition of CMAPa should be considered in ALS therapeutic trials if MVIC is not available. In addition, CMAPa can be useful in study samples where MVIC deterioration is not linear over time or is highly variable.
Action Potentials↗
5-azacytidine and 5-azadeoxycytidine inhibit human immunodeficiency virus type 1 replication in vitro.
Chemotherapeutic agents which affect the integration, stability, or inducibility of the human immunodeficiency virus (HIV) provirus would have considerable value in treating acquired immunodeficiency syndrome. Two nucleoside analogs of cytosine, 5-azacytidine and 5-azadeoxycytidine, which seem to have such value because of their capabilities to affect both the stability and the methylation patterns of the nucleic acids into which they are incorporated, were tested for their ability to inhibit the replication of HIV type 1 (HIV-1) in human CEM T cells in vitro. 5-Azadeoxycytidine (1 microM) completely inhibited HIV replication in CEM cells, by the criteria of reduced viral antigen expression and decreased supernatant reverse transcriptase activity, with little toxicity for the treated cells. 5-azacytidine (1 microM) also inhibited HIV replication, but less effectively. When added 2 or more h after CEM cells were infected with HIV-1, both 5-azacytosine derivatives were less effective than they were when added at the time of infection. Even 2 h of exposure to 5-azadeoxycytidine was sufficient for inhibition of HIV replication. Although long exposure to either analog at concentrations of 1 microM would result in pronounced cellular cytotoxicity, the the fact that short exposures to the same dose of drug inhibit HIV replication but are not toxic for the cells implies that cellular toxicity itself is not an important mechanism of the antiviral action of the analogs.
Antineoplastic Agents↗
Production and characterization of neutralizing monoclonal antibodies against poliovirus type 1, 2, and 3.
Neutralizing monoclonal antibodies were produced against a reference vaccine or a reference wild strain of poliovirus type 1, 2, and 3. After 26 fusions, 55 monoclonal antibodies were obtained with serotype 1 as the immunizing antigen, 180 with serotype 2, and 115 with serotype 3. The neutralizing activity of these monoclonal antibodies was tested first with the two reference strains and then if reactive, against a panel of 10 well-characterized strains of each serotype, 5 vaccinelike (VL) and 5 nonvaccinelike (NVL). All monoclonal antibodies were type specific without reactivity with any of the heterologous strains. There was a wide range of reactivity within the strains of each serotype. Several monoclonal antibodies to serotype 1 reacted with all type 1 strains, while several neutralized strongly all VL strains and weakly one or more of the NVL strains. Most of the 180 monoclonal antibodies to serotype 2 neutralized to various degrees all strains of this serotype and about half reacted very strongly with all homologous strains whether VL or NVL. None could differentiate all VL and NVL homologous strains. Of the 115 monoclonal antibodies to serotype 3, several monoclonal antibodies neutralize to various levels all homologous strains and some can differentiate VL and NVL strains.
Animals↗
[Role of liposomes in the presentation of HIV envelope glycoprotein and the immune response in mice].
The role of antigen presentation in the induction of humoral as well as cell-mediated immune responses has been investigated by anchoring HIV-1 envelope glycoprotein (gp 160/120) into the phospholipidic bilayer of preformed liposomes to produce HIV-Immunosomes. HIV-Immunosomes induced high titres of HIV-specific antibodies when tested by ELISA, IFA and neutralization, whereas equal amounts of purified glycoprotein alone produced lower antibody response. Similarly, HIV-Immunosomes induced antigen-specific Interleukin-2 production and blastogenic response upon restimulation with the same antigen, in animals vaccinated with HIV-Immunosomes, whereas no secondary response was observed in animals vaccinated with equal amounts of purified gp 160/120. Taken together, these results underline the importance of antigen presentation in the establishment of an adequate immune status and show the potential of HIV-Immunosomes as vaccine against AIDS.
Animals↗
Enhancement of antigen-specific interleukin 2 production by adding liposomes to rabies antigens for priming.
Antigen-specific IL-2 production was assessed, using splenocytes from rabies immune mice incubated for 24 h with rabies virus antigen. The antigenic material used for in vivo priming was either purified glycoprotein from rabies virus, or the inactivated virus. The time between priming, harvesting and restimulation of the splenocytes was 7 days. It was found that when antigenically inert liposomes were injected, together with antigenic material, to the prospective splenocyte donor mice, IL-2 production was enhanced. This augmentation was observed particularly when priming was performed with the inactivated rabies virus.
Animals↗
Interleukin-2 production in vitro: a new approach to the study of rabies vaccine immunogenicity as appraised by testing different glycoprotein presentations.
When injected as an immunosome presentation (molecules anchored to preformed liposome), rabies glycoprotein (GP) is capable of protecting animals against rabies either before or after viral infection. The presentation of the GP molecules in the correct form seems to be essential for the induction of antirabies protection. This condition must be taken in account in the making-up of a rabies subunit vaccine. In order to study the relationship between the immune responses induced by the rabies GP and its protective activity, different presentations of the GP were prepared. Purified glycoprotein molecules were associated under different physical forms: liposome-anchored, self-aggregated (rosettes) and associated with the viral lipids (virosomes). These presentations appeared different on electron microscopy. They also exhibited differences in the expression of an immunodominant epitope and in their protective activity. The non-specific immune response, as appraised by interferon production and natural cytotoxicity, was induced at a high level only by the purified viral particles. Specific immune responses (namely virus neutralizing antibody and interleukin-2 production) was induced at high levels only by the viral particle and by the liposome-anchored glycoprotein. A parallelism has previously been established between protection by glycoprotein preparations and interleukin-2 production in primed mice splenocytes. This suggests that the measure of interleukin-2 production in vitro could be used to evaluate the capability of a rabies antigen to induce a T-cell response and to confer protection.
Animals↗
Interleukin 2 increases protection against experimental rabies.
Vaccination with either whole inactivated rabies virus or immunosome (rabies glycoprotein anchored on liposomes) induces a high level of interleukin 2 (IL 2) production after in vitro specific stimulation of splenocytes from primed mice (9). On the contrary, infection with a live rabies virus does not specifically induce the production of IL 2: splenocytes from ill mice previously infected with wild rabies virus cannot be specifically stimulated by rabies antigens, whereas they can be non-specifically stimulated by a mitogen (Concanavalin A (Con A]. When injected in mice, exogenous IL 2 (purified rat IL 2 or human recombinant IL 2) exhibits an adjuvant effect on rabies virus vaccine or subunit vaccine tested in a pre-exposure potency test (NIH test). When injected in hamsters, according to a post-exposure potency test (infection with a wild rabies virus followed by vaccination), IL 2 has no adjuvant effect on the rabies vaccine. Nevertheless, when injected alone, IL 2 protects thirty to fifty percent of the infected animals treated (1 hour, 3 and 7 days post-infection) with 10 international units of human recombinant IL 2.
Animals↗
Biomechanics of healing of posterior cervical spinal injuries in a canine model.
The authors performed an in vivo experiment in a canine model to study the natural history of spinal stability as a function of healing time post-injury. Three injuries, in addition to sham, were investigated: 1) transection of supra- and interspinous ligaments at C4-C5; 2) laminectomy at C4; and 3) bilateral facetectomy at C4-C5. Standardized functional flexion/extension stereo-radiographs of the cervical spine were obtained before injury and at 1, 3, 6, 9, 12, and 24 weeks postinjury. The authors found decreased ranges of motion (ROM) at the C4-C5 level for all injuries, including the sham. The decreases, in general, seemed to be in direct proportion to the severity of the injury. When the ROM were normalized to that of the sham at each time point, the relative ROM at C4-C5 increased for Injury 1, remained the same for Injury 2, and decreased for Injury 3. The relative ROM remained the same or increased at C3-C4, and increased at C5-6 for all injuries. It should be emphasized that care should be taken in extrapolating any data from this animal study to the human cervical spine.
Animals↗
The natural history of motoneuron loss in amyotrophic lateral sclerosis.
Using a quantitative, reliable, sensitive and valid measurement technique, we analyzed the rate and pattern of motor deterioration in 50 strictly defined ALS patients for up to 67 months. We observed that the rate of motoneuron loss was linear and symmetric. Bulbar function deteriorated more slowly than respiratory, arm, and leg function. The loss of leg strength was slower than in the arm. No correlation was observed between age at onset and rate of deterioration, or with different regions of onset. Arm strength changed more slowly in women, but other functions showed no male-female differences. These data should prove useful in the design of clinical trials and in generating testable hypotheses of the etiology of this disease.
Adolescent↗
The association of the rabies glycoprotein with liposome (immunosome) induces an in vitro specific release of interleukin 2.
BALB/c mice were primed by receiving a unique intraperitoneal injection of rabies virus antigens presented as complete inactivated virus (P.V. strain) or as purified glycoproteins either in the aggregated form or in physical combination with liposomes (i.e., in the form of "immunosomes"). The splenocytes of these mice were restimulated, 6-15 days after priming, in culture with rabies virus antigens, and antigen-specific IL-2 production was measured. It was found that rabies antigens presented as immunosomes were as active as the inactivated virus, whereas equivalent amounts of purified glycoproteins were inactive. The optimal amounts of rabies immunosomes used for priming was found to be 0.5 to 0.05 micrograms per mouse.
Animals↗
Specific adherence of thymocytes to a thymic medullary epithelial cell line.
TMF, a glycoprotein found preferentially at the contact points between thymocytes and thymic medullary epithelial cells, was investigated for its participation in adherence between these two cell types. It was found that thymocytes adhere specifically to a TMF+ cell line, that anti-TMF antibody can inhibit the adherence and that extraneous TMF can effectively compete with the adherence reaction. It is concluded that TMF is indeed involved in the temporary contact which occurs between thymocytes and medullary epithelial cells.
Animals↗
Mouse response to influenza immunosomes.
Immunosome preparations consisting of surface glycoproteins, extracted from five influenza virus strains and anchored onto performed liposomes, were tested in mice. Serum antibody responses were essentially similar to those elicited by whole virus vaccines and higher than responses induced by subunit preparations. Antibody titres were assessed by haemagglutination-inhibition technique. Survival of mice immunized with 6 micrograms haemagglutinin of attenuated, inactivated, subunit or immunosome A/Aichi/2/68 vaccines and later challenged with variants of the same subtype was also assessed. All vaccine preparations induced similar percentage survival when mice were challenged with variants prevalent from 1968 to 1977. However, the attenuated vaccine induced a significant higher protection level against the 1979 variant.
Animals↗
Rabies immunosome (subunit vaccine) structure and immunogenicity. Pre- and post-exposure protection studies.
Rabies immunosomes (glycoprotein anchored on pre-formed liposomes) have been prepared in order to study their structural, biological and immunological properties. The glycoprotein molecules appear to have the same orientation on the immunosome as on the viral particle: (1) electron microscopy analysis shows particles of 40 to 70 nm with spikes protruding outward, (2) one particular epitope shows the same accessibility to a neutralizing monoclonal antibody as on the viral particle. When injected into animals, rabies immunosomes are cleared from the organism by a process different from that for the liposomes used to anchor the glycoprotein: a higher rate of transition through the spleen is observed with immunosomes than with purified glycoprotein or liposomes. Immunosomes induce high levels of neutralizing antibodies and protect animals against challenge with virulent strains. This protective activity is not altered after several months of storage at 4 degrees C. Furthermore, rabies immunosomes were shown to be efficient in post-exposure treatment of laboratory animals that had been experimentally infected with a lethal dose of a rabies wild strain.
Animals↗
Structural and immunogenic characteristics of rabies immunosomes.
Rabies immunosomes are prepared by the anchorage of glycoprotein molecules to preformed liposomes. Virosomes are associations of glycoprotein molecules with viral or non viral lipids. Virosomes can be obtained spontaneously after removal of the detergent used for lipids solubilization. Under the electron microscope immunosomes look like homogenous spherical vesicles (50-60 nm) evenly covered with spikes, although glycoprotein molecule orientation in virosomes is not yet clearly established. In addition, the size of virosomes is very heterogeneous. When glycoprotein molecules are in immunosome form, their accessibility to a lectin (WGA) is identical to that of the purified virus. Under the same conditions with virosomes accessibility is weaker. Protection induced in mice is ten to twenty fold higher with rabies immunosomes than with purified glycoprotein or virosomes. The results presented here and previous reports (10) show that immunosomes have structural and immunogen characteristics closer to those of purified and inactivated virus than does any other form of glycoprotein lipids association.
Animals↗
Purification and properties of a plant endonuclease specific for apurinic sites.
An endonuclease which hydrolyzes depurinated DNA has been isolated from Phaseolus multiflorus enbryos; it has a molecular weight around 40,000. The enzyme is specific for apurinic sites; it has no action on normal DNA strands or on alkylated sites, and is without exonulcease activity. The rate of phosphoester bond hydrolysis near apurinic sites is far greater in native than in denatured DNA. The endonuclease is not inactivated by 10 mM EDTA, but is activity is however stimulated by Mg2+ or Mn2+. Its optimum pH is 7.5 to 8.0, and its optimum temperature 40degrees although, at this temperature, it is rapidly denatured; even low NaCl concentrations inhibit the enzyme activity. The endonuclease for apurinic sites of P. multiflorus is a non-histone protein of chromatin; the properties (like thermosensitivity of susceptibility to ionic strength) of the enzyme in situ, working on chromatin DNA, might be different from those described for the isolated endonuclease in homogenous aqueous solution.
Alkylation↗