Biomedical subjects
Publications and source records attributed to H Koprowski.
A combination of different types of data suggests that some multiple sclerosis patients respond immunologically to, and have cerebrospinal T cells containing, a retrovirus that is related to, but distinct from, the three types of human T-cell lymphotropic viruses. The role of this virus in multiple sclerosis is uncertain.
Rabies virus-specific monoclonal antibodies (MAbs) have served to describe operationally the topography of the antigenic structure of the glycoprotein and nucleocapsid proteins of rabies virus. With the use of nucleocapsid protein-specific MAbs and cleavage fragments of the nucleoprotein and phosphoprotein, it has been possible to identify the chemical structure of two antigenic sites of the nucleoprotein and one antigenic site of the phosphoprotein. Antisera produced to synthetic peptides that make up the structure of these antigenic sites exhibited reactivities similar to those of MAbs. Analysis of a large number of isolates of rabies virus from different animal species and from different geographic locations revealed that rabies viruses differ considerably in their antigenic structure and can be identified according to their characteristic reactivity patterns with MAbs. Analysis of field virus isolates has also revealed that strains of rabies virus generally are associated with only one or a few major mammalian hosts within any given geographic area. Protection experiments in mice have not demonstrated correlations between protective activity and degree of antigenic difference between the vaccine strain and the challenge virus. Therefore, changes in antigenic structure, as determined by analysis with rabies virus-specific MAbs, cannot predict whether a given rabies vaccine will protect against a particular field virus.
Raccoon rabies exists in epizootic proportions in the southeastern and mid-Atlantic regions of the United States, but efficacious oral vaccines for control of rabies in this important vector have not been previously demonstrated. Alternatively, a vaccinia recombinant virus vaccine (V-RG) expressing the ERA (Evelyn-Rokitnicki-Abelseth) rabies virus glycoprotein was highly immunogenic for laboratory animals and raccoons by the intradermal, intramuscular, and oral routes. Raccoons that ate a synthetic sponge bait containing 1.0 mL (10(8) pfu/mL) of V-RG were completely (eight of eight) or 80% (eight of 10) protected from challenge with street rabies virus at 30 and 205 days after ingestion, respectively. In laboratory contact trials limited V-RG transmission occurred between animals that were rabies seronegative and those that were orally immunized and seropositive. After ingestion of bait, V-RG virus was recovered from buccal mucosa, tonsil, and parotid or submandibular lymph nodes of raccoons within 24-48 hours of oral immunization but not thereafter. Adult and immature raccoons showed no adverse clinical signs or gross or microscopic lesions attributable to V-RG vaccination at any time.
Much is now known about the chemical composition of the rabies virus but little is known of its pathogenesis. Techniques used commonly in molecular biology research can and should be applied to questions about the behavior of the rabies virus and the responses of the challenged host so that new generations of vaccines may be produced. The vaccinia-rabies glycoprotein recombinant vaccine acts by inducing neutralizing antibody to rabies virus and completely protects various species of vaccinated animals against challenge with rabies virus. The vaccinia-rabies glycoprotein recombinant vaccine is the most promising of the new generation of rabies serums.
A parainfluenza type 1 virus (6/94) recovered from brain cell cultures of two patients with multiple sclerosis (MS) was inoculated into newborn chimpanzees by the intranasal (IN) or intracerebral (IC) routes. Four of the five animals receiving the virus IN developed clinical signs ranging from mild fever, with or without rhinorrhea, to severe respiratory disease. Two of the chimpanzees died as a result of pneumonia. Virus could be recovered from respiratory tracts for as long as 9 days after exposure and was followed by development of specific neutralizing antibody to the 6/94 virus but not to the HA2 strain of parainfluenza type 1. Brain examination showed astrocytosis, especially of posterior fossa structures, activation of microgliacytes and, in one animal, round cell infiltration of leptomeninges. Of thse three animals receiving virus IC, two developed recurrent seizures beginning 14 months after inoculation. One of these was sacrificed at 23 months of age after progressive neurologic disease, with electroencephalographic abnormalities, developed. The third animal died at 3 months of age of intercurrent pneumonia. No virus was recovered from these animals, although all showed antibody conversion to 6/94 but not HA2 virus. A variety of pathologic lesions were seen in the brains of both animals coming to necropsy particularly in the sacrificed chimpanzee. These included subacute encephalitis, extensive cortical and subcortical degeneration, vascular sclerosis, white matter gliosis and axonal dystrophy.
880 individuals, 120 of which were exposed to rabid animals, were immunized pre- or post-exposure with 2 different BPL-inactivated and concentrated rabies vaccines prepared in HDC strains WI-38 and MRC-5. The vaccines were well tolerated and no major side effects were observed after primary immunization with 3-10 doses or 1 booster vaccination. The dynamics of neutralizing, antibody formation and persistence of antibodies in 4 different groups of vaccinees are described. The groups were vaccinated pre-exposure (I) on days 0, 28 and 56; (II) on days 0, 7 and 14; (III) on days 0, 3, 7 and 21; and (IV) post-exposure on days 0, 3, 7, 14, 30 and 90. High antibody levels--persisting for at least 30 months--were obtained in all patients. The CFT, using a concentrated and purified virion antigen, was highly specific for rabies virus antibody demonstration. Since in some 50 patients under severe risk, after having been bitten and/or scratched by proven rabid animals, not a single breakthough of immunity was observed during an observation time between 1/2 and 3 years, the protective effect of the HDCS-rabies vaccines seems to be excellent. With regard to their high immunogenicity and extremely low reactogenicity, the new HDCS-vaccines can be recommended for prophylactic and post-exposure immunization of man without any reserve. Data on simultaneous application of homologous anti-rabies gammaglobulin from man (20 I.E./kg body-weight) and HDCS-vaccines are also presented and discussed.
OBJECTIVES: Rabies virus variants associated with silver-haired bats (SHBRV) are responsible for most recent human rabies cases in the United States, which are not associated with a history of exposure. We compared their genotype and phenotype with those of dog rabies virus (DRV) variants, the classic cause of rabies in humans, to determine whether differences in these strains might have ramifications for therapeutic intervention, particularly vaccination. METHODS: Eleven silver-haired bat and 8 dog rabies virus isolates were characterized by sequencing the glycoprotein gene, by assessing their ability to replicate in neuronal versus nonneuronal cultures at optimal and suboptimal temperatures, by assessing their pathogenicity in mice, and by determining the resistance of these viruses to therapeutic immunization with commercial vaccines. RESULTS: SHBRV isolates were less genetically diverse, less neuronal cell specific, more temperature sensitive, but as pathogenic, on average, as DRV isolates. Immune protection was equivalent for SHBRV and DRV strains of similar pathogenicity. CONCLUSIONS: SHBRV strains have unique characteristics that may explain their exceptional association with human rabies but have little bearing on their lethality in mice. The pathogenicity of a particular virus, rather than its antigenic makeup, determines the outcome of immunization.
IgG3 murine MAb BR55-2 is directed against adenocarcinoma associated Y oligosaccharide. Isotype IgG1, IgG2b and IgG2a switch variants of the BR55-2 antibody were compared in antibody dependent-cell mediated cytotoxicity (ADCC) and complement mediated cytotoxicity (CDC) assays in the murine system. IgG3, IgG2a and IgG2b isotypes mediated ADCC with murine macrophages. Murine splenocytes mediated low levels of ADCC, with IgG3 and IgG2a being always more effective than IgG1 and IgG2b isotypes. All four isotypes were ineffective in CDC with murine serum as a source of complement. In the in vivo experiments, growth of human tumors xenotransplanted into nude mice was best inhibited by both IgG3 and IgG2a isotypes while IgG1 protein was the least effective. Thus, IgG3 and IgG2a isotypes are the most efficient proteins for cancer immunotherapy since they mediate the highest tumoricidal activities in vitro and in vivo.
In 1986, a pilot Phase I/II project was initiated using Iodine-125 labeled anti-epidermal growth factor receptor-425 in the treatment of patients with recurrent glioblastoma multiforme of the brain. The monoclonal antibody was administered intra-arterially by the internal carotid arterial system or the vertebral arterial system depending upon the blood supply to the tumor. The treatment program was repeated at intervals for two or three times. Demonstrated was the intense localization of the monoclonal antibody in the brain tumor prior to therapy using Indium-111 labeled anti-epidermal growth factor receptor-425. This localization was demonstrated prior to any therapy as well as after failure from primary radiation therapy with or without concomitant chemotherapy. To date, 15 patients have been treated following recurrence of their glioma (1/15 metastatic adenocarcinoma) with the monoclonal antibody labeled with Iodine-125. Of the 15 patients, there has been one surgically documented complete response, two partial responders, and five patients with stable disease. The results indicate the potential activity of this radiolabeled monoclonal antibody and have prompted continued accession of patients into a Phase II study as a part of the primary treatment regimen (surgery, radiation therapy with or without chemotherapy) followed by administration of the Iodine-125 labeled anti-epidermal growth factor receptor-425.
Peptides composed of variants of a B-cell epitope followed by a T-cell determinant of rabies virus ribonucleoprotein (RNP) have been synthesized to elicit antibody production in mice. Conformation of the peptides was characterized by secondary structural prediction and circular dichroism measurements. It was found that only synthetic peptides with disrupted helical structure in the antigenic region were active on immunoblot assay, performed against a natural anti-protein monoclonal antibody (MAb) and provoked virus-neutralizing antibody production.
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Nuclear chromatin properties in control, SV40-infected and polyoma-infected cultures of mouse embryo fibroblasts were studied using quantitative image analysis. Distribution of Feulgen-DNA-content per nucleus was found to be similar in all three groups of cultures. No differences in nuclear area, mean optical density of chromatin and area of chromatin at different optical density thresholds were measurable between control and SV40-infected fibroblasts. Polyoma-infected fibroblasts were found to have smaller nuclei, more dense and less homogeneous chromatin than non-infected cells. The changes of chromatin in polyoma-infected cells occur in G1, middle S and G2 nuclei. The results are interpreted as an early manifestation of the cytopathic effect of polyoma virus.
We studied effects of varied cytokine combinations on allogeneic cytotoxic T lymphocyte (CTL) generation in a mixed lymphocyte-tumor cell culture. Sensitized with allogeneic melanoma cell line (MM-8.1 or MM-28), peripheral blood mononuclear cells (PBMC) were cultured in medium containing various combinations of cytokines that included human recombinant interleukin-2 (rIL-2) alone (MB-2), rIL-2 and rIL-4 (MB-2,4) and rIL-1, rIL-2, rIL-4 and rIL-6 (MB-1,2,4,6). Lymphocytes proliferated for more than 50 days and manifested stimulating cell-specific cytotoxicities in 1 of 5 cultures with MB-2, in 4 of 5 with MB-2,4 and in 5 of 5 with MB-1,2,4,6. Lymphocytes grew up to 10(6) fold in culture with MB-2,4 or MB-1,2,4,6 at day 90-100. Stimulating cell MM-8.1 (HLAABC+,DR-) induced CD3+, CD8+, CD56- CTLs and MM-28 (HLA-ABC+, DR+) mainly generated CD3+, CD4+, CD56- CTLs. Monoclonal antibodies against HLA-ABC and HLA-DR molecules suppressed the stimulating cell-specific cytolytic activity of CD8+ and CD4+ CTLs, respectively. These data indicate that combination of rIL-1, rIL-2, rIL-4 and rIL-6 offer an efficient system to generate allogeneic, tumor-specific CTLs from PBMCs and that HLA molecules expressed on stimulating cells play an important role in CTL generation.