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Biomedical subjects

T J Hill

Publications and source records attributed to T J Hill.

At least 19 recordsLinked to original sources
PubMed1995

Immune cell infiltration and persistence in the mouse trigeminal ganglion after infection of the cornea with herpes simplex virus type 1.

Following inoculation of the mouse cornea with herpes simplex virus type 1 (HSV-1), the spread of virus was investigated and the types of immune cell infiltrating the trigeminal ganglion (TG) were identified in low temperature paraffin wax sections. Virus antigen was first found on day 3 and was absent after day 14. Early presentation of antigen to T cells may occur since increased expression of major histocompatibility complex (MHC) class II antigens, including de novo expression on satellite and Schwann cells, was detected in foci of such antigen on day 3. A second large peak of such expression was detected on day 10 together with increasing numbers of B and T cells. Large numbers of these lymphocytes and extensive expression of MHC class II were seen in the TG well into the phase of virus latency; the significance of this is discussed.

Animals↗
PubMed1995

Immunohistochemical detection of T-cell subsets and other leukocytes in paraffin-embedded rat and mouse tissues with monoclonal antibodies.

We describe a method for immunohistochemical localization of T-cells, CD4+ T-cells, CD8+ T-cells, B-cells, activated lymphocytes, major histocompatibility complex (MHC) class II antigens, macrophages, dendritic cells, and granulocytes in rat and mouse tissue fixed in periodate-lysine-paraformaldehyde (PLP) and embedded in paraffin. Rat and mouse spleen and eyes were fixed in PLP for 18-24 hr, rapidly dehydrated, infiltrated under vacuum with paraffin at 54 degrees C, sectioned, and stained with appropriate monoclonal antibodies (MAbs). Sections of PLP-fixed, paraffin-embedded spleen were compared with acetone-fixed frozen spleen sections with respect to morphology and staining quality. Nine of 10 MAbs to rat antigens and eight of nine MAbs to mouse antigens stained paraffin sections equally or more intensely than frozen sections. The two MAbs that showed weaker staining still gave good staining on paraffin sections. Paraffin-embedded rat and mouse eyes were easier to section serially than frozen eyes, showed superior morphology, and individually stained cells were readily identified. Therefore, a combination of PLP fixation and low-temperature paraffin embedding permits detection of the major types of immune cell in rat and mouse tissues while maintaining good morphology, particularly in diseased, damaged, or delicate tissues.

Animals↗
PubMed1994

Ocular infection with herpes simplex virus in several strains of rat.

PURPOSE: To assess the suitability of the rat for studies of ocular infection with herpes simplex virus (HSV). METHODS: LEW, AO, DA, PVG, and (DAxLEW)F1 x LEW backcross generation rats, 7 to 9 weeks of age, were inoculated with HSV-1 McKrae. The course of primary disease was assessed by clinical observation using a slit lamp. Infectious virus was assayed in ocular and nervous tissue, and the incidence of latent infection was determined. RESULTS: LEW and AO strains were the most susceptible. All LEW rats died after an inoculum of 4 x 10(2) plaque-forming units (pfu) and developed severe corneal disease and uveitis. In contrast, all PVG rats survived 10(4) pfu, 60% survived 4 x 10(4) pfu, and eye disease was restricted to epithelial lesions, sometimes accompanied by mild stromal haze. This resolved, even in animals that developed central nervous system disease. The DA strain showed intermediate susceptibility. Resistance was dominant because disease in backcross generation (DA x LEW)F1 x LEW rats resembled that of the DA rather than the LEW strain. Resistance appeared to be linked to coat color (P < 0.001) rather than to major histocompatibility complex (MHC) type. Chronic stromal disease did not occur in survivors (DA, PVG, and hybrid strains only). CONCLUSIONS: The susceptibility of rat strains to infection of the cornea with HSV varies, and, as with mice, resistance seems to be controlled by non-MHC genes. Rats may prove useful for immunologic studies. Virus reactivation will be the subject of a future report.

Animals↗
PubMed1993

Latent infection with the MS strain of herpes simplex virus type 2 in the mouse following intracerebral inoculation.

Intracerebral inoculation of the MS strain of herpes simplex virus type 2 (HSV-2) into mice causes an acute encephalitis associated with multifocal demyelination and necrotizing retinitis. We have studied the distribution of latent virus in mice that had recovered from the acute encephalitis. Four weeks or longer after inoculation, HSV-2 could be recovered from the trigeminal ganglia of all mice examined by co-culture of explants in roller tubes. The virus could not be recovered from explants of retina or brain stem. HSV-2 latency associated transcript (LAT) was readily detected in the trigeminal ganglia by reverse transcriptase-PCR more than 4 months after inoculation. LAT was also demonstrated in the brain but this required nested PCR for consistent detection. Both LAT and ICP0 mRNA were detected in brain tissue during the acute encephalitis but, unlike LAT, ICP0 mRNA could not be amplified from the trigeminal ganglia or brain beyond 4 weeks after inoculation of the virus. In situ hybridisation with a double-stranded DNA probe to the ICP0/LAT overlap region of HSV-2 revealed signal in trigeminal ganglion neurons and occasional cells in the brain stem. These findings indicate that HSV-2 introduced by intracerebral inoculation becomes latent in the trigeminal ganglia and that transcription of LAT also persists within the brain.

Animals↗
PubMed1993

MS strain of type 2 herpes simplex virus produces necrotizing retinitis in mice.

Intracerebral inoculation of mice with the MS strain of type 2 herpes simplex virus (HSV-2) causes a brief encephalitis associated with multifocal central nervous system demyelination. Many of the mice develop unilateral or bilateral impairment of the pupillary light reflex. We have examined the development of ocular disease in inbred NIH mice inoculated intracerebrally with a low dose (10 pfu) of HSV-2 (MS). The resulting acute encephalitis was fatal in 30-50% of the mice. By 1 month after inoculation, the pupillary response to light was absent or impaired in approximately 80% of the surviving mice. Infectious virus could be isolated from the trigeminal ganglia and optic nerves from day 2 and from the eyes by day 4. Viral antigen was first immunohistochemically detectable in the optic nerves on day 5 and in the retinae on day 6. During the second week after inoculation up to half of the mice developed unilateral or bilateral necrotising retinitis associated with high titres of virus in the eyes and abundant viral antigen in the retinae. Electron microscopy confirmed the presence of viral particles in the retinae, in glia and degenerating neurons. No viral antigen was detected in the corneas and only rarely was antigen found in the ciliary body or iris. Infectious virus persisted longer in the eyes than in the trigeminal ganglia or optic nerves and could still be isolated from a few of the animals 2 weeks after inoculation. By 1 month the titres of virus within the eyes had fallen to undetectable levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Acute and latent infection of mice immunised with HSV-1 ISCOM vaccine.

The effect of immunisation with an HSV-1 antigen preparation (containing at least 6 viral glycoproteins) on primary infection with HSV and the establishment of latency, was assessed in two mouse models (involving either skin or corneal challenge with virus). The vaccine preparation, given either with Freund's complete adjuvant or aluminium hydroxide gel or in the form of immunostimulating complexes (ISCOMS), induced high ELISA antibody responses (highest with HSV as the ISCOM preparation) and low levels of neutralising antibody. In both models, immunisation with the HSV ISCOM preparation significantly reduced the incidence of zosteriform spread of virus and the severity of disease and, in some cases, the incidence of latent infection in sensory ganglia. In the eye model it was possible to show that immunisation with the HSV ISCOMS restricted the establishment of latency almost entirely to the ophthalmic part of the trigeminal ganglion. Protection from establishment of latency correlated with prechallenge antibody levels.

Acute Disease↗
PubMed1992

Experimental in vivo generation of intertypic recombinant strains of HSV in the mouse.

The primary replication of one strain of HSV was generally unaffected by the simultaneous inoculation of another strain either at the same site or at a different site within the same dermatome. Exceptions to this were the result of the generation of intertypic recombinants which were readily isolated only from sensory ganglia 5 and 6 days after inoculation with a mixture of HSV-1 and HSV-2 and from explant culture of the resultant latently infected ganglia. By restriction enzyme analysis the majority of the recombinant strains from primary infection were characterized as HSV 1; all those from latently infected ganglia were characterized as type 2.

Animals↗
PubMed1992

beta-Carboline and pentylenetetrazol effects on conflict behavior in the rat.

The beta-carbolines and the convulsant agent pentylenetetrazol (PTZ) have been reported as "anxiogenic" in several animal models for anxiety. The present study examined the effects of the beta-carboline noreleagnine (NOR) and PTZ, administered alone and in combination with the benzodiazepine antagonist, Ro 15-1788, on behavior in the conditioned suppression of drinking (CSD) conflict procedure. In daily 10-min sessions, water-deprived female SD rats were trained to drink from a tube that was electrified (0.25 mA). Electrification was signaled by a tone. Acute (20-min) treatment with NOR or PTZ resulted in a dose-dependent decrease in both punished responding (shocks received) and unpunished responding (water intake). Both NOR and PTZ decreased punished responding only at doses that also depressed unpunished responding. Coadministration of Ro 15-1788 (2 mg/kg) reduced the effects of NOR on punished, but not unpunished, responding; this Ro 15-1788 cotreatment reduced the effects of PTZ on both punished and unpunished responding. These data suggest that both PTZ and NOR produce benzodiazepine receptor-mediated anxiogenic-like effects on conflict behavior.

Animals↗
PubMed1992

Non-traumatic acquisition of herpes simplex virus infection through the eye.

Primary ocular herpes is usually seen as a follicular conjunctivitis and blepharitis, with or without involvement of the cornea. It is unknown, however, to what extent asymptomatic and/or subclinical primary disease occurs, and whether primary ocular herpes follows direct droplet spread to the eye. Previous models of murine ocular herpes have used trauma (scarification) to introduce virus into the cornea, producing disease which results in significant corneal scarring. To mimic a likely route of infection in humans, a droplet containing virus was placed on the mouse eye and clinical disease recorded. At least 1 month after inoculation, serum was assayed for neutralising antibodies and the cornea, iris, and trigeminal ganglion were investigated for evidence of herpes simplex virus type 1, by cocultivation and the polymerase chain reaction. Some animals showed a severe ulcerative blepharitis with little to no involvement of the cornea, while disease was undetectable in others. The development of disease depended on the dose and strain of virus and age of the animal, with older mice appearing more resistant. Virus was isolated from the trigeminal ganglion of younger animals inoculated with higher doses of virus, after 21 days in culture, suggesting that latency had been established. Neutralising antibodies were present in most mice irrespective of the presence of recognisable clinical disease. Using primers for the thymidine kinase and glycoprotein C regions of the viral genome, herpes simplex virus type 1 DNA was found in the cornea, iris, and trigeminal ganglion of most animals and showed a good correlation with the presence of neutralising antibodies. It would thus appear that herpes simplex virus type 1 is able to accede into the cornea, iris, and trigeminal ganglion following nontraumatic application of virus onto the mouse eye. This model mimics primary ocular disease in humans and may be useful for studies on recurrent disease and the spread of ocular herpes.

Animals↗
PubMed1991

Herpes simplex virus infection and damage in the central nervous system: immunomodulation with adjuvant, cyclophosphamide and cyclosporin A.

The role of the immune system in damage to the central nervous system (CNS) following infection with herpes simplex virus (HSV) was studied with the use of immune adjuvants and immunosuppressive drugs. The incidence of paralysis was found to be influenced significantly by the immune status of the animal. Thus, cyclosporin A (CsA) reduced the incidence of ear paralysis following inoculation of the pinna with virus, whilst cyclophosphamide (CY) increased the incidence of hind limb paralysis following i.v. inoculation with virus. Non-specific immunopotentiation with complete Freund's adjuvant (CFA) increased the incidence of hind limb paralysis. The inclusion of CNS antigen (mouse spinal cord homogenate) with the adjuvant enhanced the effect of adjuvant alone. The findings suggest that regulation of the immune response in the CNS may be of importance in the control of HSV-induced neuropathology.

Adjuvants, Immunologic↗
PubMed1991

Effects on murine epidermal Langerhans cells of drugs known to cause recrudescent herpes simplex virus infection in a mouse model.

A number of agents have been shown to alter the latent state of herpes simplex virus in murine sensory ganglia. However, it seems that effective triggers of recrudescent disease must act not only to reactivate latent HSV infection, but also to create a favorable environment in the skin for viral replication. The possibility that alteration of the local Langerhans cell population is one way in which effective triggers of recrudescence may act has been investigated. Of the agents tested, which affect latent HSV, only DMSO significantly altered the numbers of ATPase-bearing Langerhans cells in the epidermis, maximally reducing their density by 83% in 48 h. Xylene and retinoic acid had no discernible effect on numbers of ATPase-staining cells over the 4 d tested. However, the extent to which agents reduced ATPase-staining cell numbers did not correlate with their ability to affect the antigen-presenting capacity of the cells in HSV-specific T-cell proliferative assays in vitro. Xylene and retinoic acid markedly reduced the accessory cell function of epidermal cell suspensions, whereas DMSO had no effect.

Adenosine Triphosphatases↗
PubMed1991

Murine epidermal antigen-presenting cells in primary and secondary T-cell proliferative responses to herpes simplex virus in vitro.

The role of epidermal Langerhans' cells in infection with herpes simplex virus (HSV) was investigated using a culture system that supports antigen-specific primary and secondary T-cell proliferative responses. Epidermal cell suspensions were capable of restimulating the response of in vivo primed T cells to UV-inactivated HSV. This capability was also present in cell suspensions enriched for Langerhans' cells, but was abrogated by the depletion of I-A-bearing cells. The magnitude, kinetics and phenotype of the responding cells were similar to those elicited when HSV was presented to primed T cells by antigen-presenting cells from the spleen. In marked contrast, whereas splenic antigen-presenting cells induced strong antigen-specific proliferation of unprimed T cells (primarily of the helper phenotype), Langerhans' cells failed to invoke any detectable reaction of such cells.

Animals↗
PubMed1990

Heterotypic and homotypic re-inoculation of mice already latently infected with herpes simplex virus type 1.

Mice were infected at 4 weeks of age with a type 1 strain of herpes simplex virus (HSV) and re-infected 4 weeks later with either a type 1 or a type 2 strain of HSV. The virus used for first infection could be distinguished from that used later since it was resistant to phosphonoformic acid and formed syncytial plaques. Sites used for the second inoculation were as follows: at the site of primary infection, at a different site within the same dermatome or in the equivalent dermatome on the opposite side (also called "remote" site). Re-infection caused no detectable reactivation of the latent PFA resistant virus. After re-infection with a homotypic virus replication of the re-infecting virus was limited to the inoculation site. However after heterotypic re-infection the type 2 strain was occasionally isolated from the ganglia. Previous infection with the PFA resistant type 1 strain clearly reduced the ability of the homotypic or heterotypic strains to establish a latent infection. However, in a few animals ganglia were found to be latently infected with virus from both the first and second inoculations. Analysis of the results suggests that resistance to the establishment of a second latent infection in a ganglion is determined by the general immunity of the animal rather than "immunity" of the latently infected ganglion itself.

Animals↗
PubMed1990

Chronic antidepressant and clonidine treatment effects on conflict behavior in the rat.

The present studies examined the effects of chronic treatment with several antidepressants and clonidine on conflict behavior. In daily ten-minute sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.25 or 0.5 mA). Electrification was signalled by a tone. Chronic desipramine (5 mg/kg, IP, b.i.d.) or clonidine (40 micrograms/kg, b.i.d.) treatment resulted in time-dependent anticonflict effects, with a latency to onset of approximately 3-4 weeks. In contrast, chronic buproprion (up to 10 mg/kg, IP, b.i.d.), mianserin (up to 10 mg/kg, IP, b.i.d.) or trazodone (up to 40 mg/kg, IP, b.i.d.) treatment resulted in at best only a weak anticonflict effect. The efficacy of these antidepressants and clonidine to increase punished responding when administered chronically correlates well with their efficacy as antipanic agents in man.

Animals↗
PubMed1990

Possible latent infection with herpes simplex virus in the mouse eye.

Herpes simplex virus (HSV) was isolated from organ cultures of anterior segments of the eyes of mice inoculated with virus on the snout or directly onto the cornea at least 5 weeks previously. The frequency of isolation of the virus was not decreased by treatment of the animals with acyclovir, suggesting that the virus is latent by the criteria usually applied. Peroxidase-antiperoxidase staining of organ cultures that had shed virus showed that viral antigens were predominantly present in the anterior uvea. Inoculation of mouse eye anterior segments in vitro showed that this tissue was the most susceptible to productive infection. These results suggest the possibility that HSV can establish a latent infection in tissues of the anterior segment of the mouse eye.

Acyclovir↗
PubMed1990

Reactivation of latent infection and induction of recurrent herpetic eye disease in mice.

During primary ocular infection of mice with herpes simplex virus type 1 (HSV-1) strain McKrae, dendritic corneal ulcers developed and many eyes became permanently damaged. When primary infection had subsided, latent infection was detected in the three parts of the trigeminal ganglion and in the superior cervical ganglion. Such latently infected mice were treated with cyclophosphamide, dexamethasone and u.v. irradiation, or cyclophosphamide and dexamethasone alone. After treatment with immunosuppressive drugs and u.v. irradiation infectious virus was isolated from the ophthalmic part of the trigeminal ganglion, and in eyelids and eyewashings; recurrent herpetic eye disease was seen but only in eyes undamaged by primary infection. After treatment with cyclophosphamide and dexamethasone alone there was a lower incidence of virus isolated from eyewashings and no recurrent disease was seen. There was a good correlation between the pattern and distribution of recurrent lesions and the distribution of cells stained due to the presence of virus antigens.

Animals↗