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Biomedical subjects

J Hilfenhaus

Publications and source records attributed to J Hilfenhaus.

At least 55 records · Page 3Linked to original sources
PubMed1983

Toxicity studies with human fibroblast interferon.

Acute toxicity studies of interferon derived from human fibroblasts (FHIF) were performed in mice and rats with doses between 6 X 10(4) and 480 X 10(4) IU/kg i.v. and an observation period of 14 days. No severe toxic effects, such as loss of weight or other pathological clinical signs were observed. In local innocuity studies (i.v., i.a., paravenous) in rabbits FHIF proved to have no adverse effects. 180,000 IU/kg were pyrogen free in rabbits, in the limulus test the content of lipopolysaccharides (LPS) was 208 pg/ml as compared to the FDA standard EC-2. Studies were performed to assess the pharmacological safety of FHIF in 10 monkeys (Macaca fascicularis). The i.v. injection of 60,000 IU/kg had no pathological effects on circulation, respiration, number of blood cells, or body temperature. In six monkeys a short decrease of arterial blood pressure was noted a few minutes after injection of 120,000 IU/kg i.v. Both doses caused an increase of thrombelastographic time (TEG). The proposed single human dose of approximately 60,000 IU/kg has been proved safe in the acute toxicity studies and the pharmacological safety assessment in mice, rats, rabbits, and monkeys. The LPS content is low.

Animals↗
PubMed1983

Comparison of effects of adjuvants on efficacy of virion envelope herpes simplex virus vaccine against labial infection of BALB/c mice.

A subunit virion envelope vaccine of herpes simplex virus type 1 was evaluated for its ability to protect labially infected mice from development of the primary herpetic lesion, encephalitic death, and latent virus infection in the trigeminal ganglion. Several adjuvants, including aluminum hydroxide and polyriboinosinic acid-polyribocytidylic acid complexed with poly-L-lysine and carboxymethyl cellulose were investigated for their ability to enhance protection of the subunit vaccine and were compared in effectiveness with complete Freund adjuvant. The subunit vaccine was demonstrated to be immunogenic, as shown by development of antibody detectable by an enzyme-linked immunosorbent assay. The humoral immune response was correlated with protection from herpetic encephalitis and, at a lower degree, with prevention of the appearance of primary herpetic lesions and acceleration of lesion resolution. The efficacy of the vaccine was most apparent in protecting mice from encephalitic death. To reduce or prevent the development of latent infection was most difficult, but was achieved with some vaccine regimens. Repeated administrations of vaccine with adjuvant were required for this protection. The most effective adjuvant was complete Freund adjuvant, but several synthetic adjuvants were effective, particularly aluminum hydroxide and the polyriboinosinic-polyribocytidylic acid-poly-L-lysine-carboxymethyl cellulose immunoadjuvant.

Adjuvants, Immunologic↗
PubMed1982

Herpes simplex virus subunit vaccine: characterization of the virus strain used and testing of the vaccine.

Herpes simplex virus type 1 (HSV-1) used for vaccine production was isolated from a nasal recurrent infection and propagated over a limited number of passages in human diploid cells only. It was designated as HSV-1 BW3 and has been characterized by neutralizing antibodies as a typical HSV type 1 strain. In vitro transformation studies performed with this isolate in mouse or hamster cells revealed only very low, if any, transforming capacity. A preparation of HSV-1 BW3 which can be used as seed lot for vaccine production has been proven to be free of any adventitious agents such as bacteria, fungi mycoplasma or viruses other than HSV-1 BW3. An envelope antigen (EAG) preparation was obtained from purified HSV-1 particles. It was free of detectable viral DNA and could be proven to be efficacious in mouse models against challenge infections with either HSV-1 or HSV-2. The potency of the vaccine was greatly enhanced by the addition of poly-inosinic-poly-cytidylic acid complexed with poly L-lysine and carboxymethylcellulose (PICLC) as adjuvant. A single vaccine dose was sufficient to protect mice from morbidity and the fatal outcome of HSV infection, but not from the establishment of latency. Persistent ganglionic infections could be, however, significantly reduced by repeated administration of the vaccine before primary infection.

Adult↗
PubMed1981

Efficacy of a virion envelope herpes simplex virus vaccine against experimental skin infections in hairless mice.

Hairless mice were immunized with herpes simplex virus type 1 (HSV-1) envelope antigen (EAG), EAG in association with polyriboinosinic . polyribocytidylic acid-poly-L-lysine complexed with carboxymethylcellulose (PICLC), and inactivated purified HSV-1 (VAG). After 2 weeks the mice were challenged by a percutaneous HSV-1 infection in the orofacial (OF) or lumbosacral (LS) skin area. Following immunization a consistent cell-mediated immune response was observed in all immunized mice, although the humoral immune response was very low, or not detectable. After challenge, a marked secondary humoral and cell-mediated immune response developed in all immunized mice, and the animals were protected against the development of skin lesions and the fatal outcome of infection. However, the establishment of latent infections in the sensory ganglia was not prevented by the immunization procedure.

Animals↗
PubMed1981

Protectivity of herpes simplex virus antigens: studies in mice on the adjuvant effect of PICLC and on the dependence of protection on T cell competence.

The efficacy of a herpes simplex virus type 1 (HSV-1) envelope antigen (EAG) preparation against HSV infection was studied in T cell competent and T cell deficient mice. Immuno-competent mice were successfully protected against herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) infection when immunized 2 weeks prior to this infection with a heat-inactivated whole virus preparation or a HSV-1 envelope antigen (HSV-1 EAG) preparation. Since HSV-1 EAG was considerably less effective than the whole virus preparation, a poly.riboinosinic-poly.ribocytidylic acid complex with poly-L-lysine and carboxymethylcellulose (PICLC) was used as adjuvant. Immunization with HSV-1 EAG plus PICLC resulted in a pronounced increase of this protection rate as compared with that obtained after immunization solely with HSV-1 EAG. PICLC alone, however, offered no protection when given 2 weeks before challenge. In T cell deficient nu/nu mice no protection was achieved with HSV-1 EAG while their T cell competent, heterozygous littermates were protected. From these results it may be concluded that T cell competence is a prerequisite for establishing a protective immunity against HSV infection after immunization with HSV-1 EAG.

Adjuvants, Immunologic↗
PubMed1981

The influence of different modes of immunization on the experimental genital herpes simplex virus infection of mice.

Previous investigations, which simulated the usual sequence of the human Herpes simplex virus (HSV) infections, had shown that the oral infection of mice with HSV-1 caused only weak protection from genital infection with HSV-2, although the course of infection was attenuated and lethality diminished. This heterologous, heterotopic model was compared with a homologous, heterotopic and a heterologous, homotopic model. The results did not differ very much, although the homologous immunization protected best from lethal outcome, the homotopic immunization best from local infection. Three different preparations of a killed vaccine from purified HSV-1 virion had little effect on the course of the local infection, although protection from lethal outcome was as good as with live virus. In contrast, a crude UV-inactivated vaccine protected nearly completely from local infection. Latent infection in the lumbosacral ganglia was significantly inhibited by immunization with live virus, but only slightly prevented by killed vaccine. The prevalence of latent infection correlated with the extent of vaginal infection. The results show that neither the viral type nor the inoculation site used for immunization with live virus are very critical. Moreover, they allow the conclusion that generalized type-dependent immune factors seem to be engaged in protection against lethal disease; these may be circulating humoral antibodies. On the other hand, locally induced immune factors (probably cellular) are apparently of prime importance for the protection from acute local and latent ganglionic infection.

Animals↗
PubMed1981

Pharmacokinetics of human interferon-beta in monkeys.

Human fibroblast-derived interferon (HuIFN-beta) was administered to cynomolgus monkeys i.m. (2 x 10(5) iu/kg), i.v. (2 x 10(5) iu/kg) or intrathecally (3 x 10(5) iu/monkey) or given by a 3 hr i.v. infusion (2 x 10(5) iu/kg). One hr after intrathecal administration, interferon titers in the CSF were 1000-2000 iu/ml, and declined to less than 10 iu/ml during the first 24 hr. At the same time only minute amounts of HuIFN-beta were found in the sera of these animals. After i.m. administration, 5 iu/ml were found on average in the serum during the first 8 hr, with no interferon titer ever exceeding 10 iu/ml. No antiviral activity was found 24 hr after HuIFN-beta injection. HuIFN-beta injected i.v. resulted in serum interferon titers of approx. 300 iu/ml 30 min after administration, which then decreased to about 5 iu/ml during the first 8 hr 24 hr after injection no antiviral activity was detectable. Daily HuIFN-beta i.v. administrations over a period of four days did not affect the interferon clearance from the circulation. During HuIFN-beta infusion, constant HuIFN-beta titers of about 80 iu/ml were observed which then decreased during the following 5 hr to 2 iu/ml. The choice between a single i.v. injection, resulting in high serum titers for a few minutes, and a 3 hr infusion, resulting in an about fourfold lower but constant interferon level for over two hr, will depend on the mechanism of interferon action in vivo and on the question as to whether side effects can be diminished by infusion.

Animals↗
PubMed1981

Experimental infection of inbred mice with herpes simplex virus type 1. I. Investigation of humoral and cellular immunity and of interferon induction.

Considerable differences exist in the lethality of herpes simplex virus type 1 (HSV-1) after intraperitoneal (i.p.) infection in different inbred strains of mice. In this study humoral and cellular immunity and interferon production were compared in resistant and susceptible mice. The serum IgG response, as determined by an enzyme-linked immunosorbent assay (ELISA), was the same in different strains of mice. There was also no difference in neutralizing antibodies between resistant C57BL/6 and susceptible DBA/2 mice. The production of macrophage migration inhibitory factor, obtained from spleen cells of mice 7 days after infection with different doses of HSV-1, was the same in resistant and susceptible mice. Serum interferon could be detected 8 h after i.p. injection of 10(7) p.f.u. of HSV-1, but not at lower virus doses. At 8 h, high interferon titres [less than 1000 reference research units (iu)/ml] were observed in the serum of C57BL/6 mice but low titres (about 100 iu/ml) were found in the serum of DBA/2 mice. At 24 h, the titres were low in both strains of mice. Interferon production was also measured in vitro in spleen cell cultures exposed to inactivated HSV-1. These studies also showed high interferon production in spleen cell cultures of resistant mice, whereas low titres were produced by spleen cells of susceptible mice. Thus, our study has failed to reveal any differences in humoral or cellular immunity in mice resistant or susceptible to HSV but a difference in HSV-induced interferon production.

Animals↗
PubMed1981

Correlation of herpes simplex virus antibody titers and specific lymphocyte stimulation in adult blood donors.

Antibody titers to herpes simplex virus type 1 in sera from healthy adult donors were assayed by complement fixation, microneutralization, and an enzyme immunoassay (ELISA). This last test proved to be the most sensitive method for antibody detection. It was estimated that ELISA antibody titers were up to 40-fold higher than neutralizing antibody titers and up to 100-fold higher than complement fixation antibody titers. Due to the higher sensitivity of ELISA, only 3 of 36 blood donors tested in this assay were shown to be seronegative, whereas 6 additional persons of the same group were termed seronegative by the microneutralization assay. Furthermore, four of the latter also did not respond in the complement fixation test. In vitro stimulation of peripheral lymphocytes by using a partially purified herpes simplex virus type 1 particle antigen was achieved for all seropositive blood donors. Only those three donors who were ELISA negative reacted negatively in this stimulation assay. From these results it may be concluded that ELISA is an appropriate method not only for rapid and sensitive antibody determination but also for selecting herpes simplex virus-negative patients.

Adult↗
PubMed1980

Studies of the producer cell of herpes simplex virus-induced interferon in mouse spleen cell cultures.

The producer cell of type I interferon was studied in spleen cell cultures of C57BL/6 mice stimulated by inactivated Herpes Simplex Virus (HSV). Interferon production was not abolished by pretreatment of the spleen cells by anti-theta serum plus complement. The producer cell of interferon was not removed by plastic adherence and was not destroyed by the addition of silica. It was present in spleens of 3 day old C57BL/6 mice and in spleens of nu/nu mice. It was not inactivated by treatment of nu/nu spleen cells by anti-theta serum plus complement. HSV-induced interferon production was abolished by passage of the spleen cells through nylon wool columns and by irradiation (1000 R) of the spleen cells. Collectively these data suggest that in murine spleen cell cultures type I interferon is produced by B cells. However, our data do not allow to rule out that the interferon producing cell may be an immature macrophage or an immature T cell.

Animals↗
PubMed1979

Intramuscular and/or intralumbar postexposure treatment of rabies virus-infected cynomolgus monkeys with human interferon.

From 9 to 10 of 10 cynomolgus monkeys infected with rabies street virus died of rabies about 20 days postinfection (pI). Symptoms of illness appeared 1 to 4 days before death. In an attempt to protect infected animals from the disease, human leukocyte interferon (HIF) was administered intramuscularly (i.m.) near the site of infection or into the cerebrospinal fluid between the first and second lumbar vertebrae (i.e., intralumbarly [i.l.]). Multiple HIF doses given over a period of several days proved more effective than a single HIF dose. In every experiment, i.m. HIF treatment was started 1 day pI. The best result obtained was a survival rate of 7 of 10 monkeys. The i.l. HIF administration schedules, consisting of multiple doses given over a period of at least 8 days, were started on day 3, 7, or 11 pI. Here the best result noted was the protection of 5 of 10 treated monkeys. The latest successful postexposure i.l. HIF treatment began on day 11 pI. The highest protection rate, 8 survivors of 10 treated monkeys, was achieved by a combined i.m. and i.l. HIF treatment. From these results we conclude that human patients severely bitten by rabid animals should in addition to an active immunization be i.m. and i.l. treated with HIF. Particularly, i.l. HIF administration could be effective, even when given several days pI. Whether an HIF administration starting after the appearance of clinical symptoms of rabies can help cannot be decided upon from the studies made in this monkey model. The most obvious difference between rabies in humans and cynomolgus monkeys is the duration of illness between the outbreak of the disease and death (1 to 4 days only in this animal model). It might have been due to this short period of illness that i.l. and i.m. HIF treatment at the appearance of clinical symptoms failed to help any of the monkeys treated.

Animals↗
PubMed1978

[A purified rabies vaccine from human diploid cell cultures (author's transl)].

In order to improve the tolerance of rabies vaccine from human diploid cell cultures, the rabies virus antigen is purified in the sucrose density gradient by means of a flow ultracentrifuge. The purified virus has a specific infectiosity of 10(9) LD50 and a speicific activity of 250 units "relative activity" per 1 mg protein. The purified vaccine has been shown to be well tolerated, effective and stable.

Animals↗
PubMed1978

[The importance of interferon for rabies prophylaxis (author's transl)].

The importance of interferon for the prophylaxis of rabies is not yet fully understood. About 50% of cynomolgus monkeys infected with rabies virus could be protected from the disease with human interferon which was administered at a total dose of 1--10 million units per animal either intramuscularly 24 hours after infection or by intralumbar injection up to 11 days after. The clinical relevance of the findings is discussed.

Animals↗
PubMed1978

A purified human diploid cell rabies vaccine.

Continuous-flow isopycnic banding of rabies virus in sucrose gradient was used to purify the antigen for the preparation of a human diploid cell rabies vaccine. Prior to the addition of the stabilizer, the average specific potency of several vaccine batches was 234 antigenic values per 1.0 mg of protein. Further data regarding potency and stability of this vaccine are presented.

Antigens, Viral↗