Search PubMed⌕ Search

Biomedical subjects

P C Doherty

Publications and source records attributed to P C Doherty.

At least 217 records · Page 12Linked to original sources
PubMed1982

Central nervous system infection and immune response in mice inoculated into the lip with herpes simplex virus type 1.

Virus may be recovered from various areas of the central nervous system (CNS) of mice for as long as 11 days after inoculation of herpes simplex virus type 1 (HSV-1) into the lip. The probability of isolation from any particular region of the CNS seems to be a function of the distance of that area from the root-entry zone of the trigeminal nerve. It is also mouse strain-dependent, with much more extensive evidence of brain infection being found in BALB/c and C3H rather than C57BL/6 mice, in which it is limited to the pons. The virus could not be isolated from the CNS of BALB/c mice after 10 days, though HSV-1 is readily recovered from the trigeminal ganglia at least through day 38. Significant concentrations of HSV-1-specific immunoglobulin (Ig) were demonstrated consistently in cerebrospinal fluid (CSF) from day 12 after exposure to virus. The persistence of relatively high concentrations of IgM in the CSF indicates that much of this antibody may be synthesized locally in the brain.

Animals↗
PubMed1982

Modification of cytotoxic T-cell response patterns by administration of hemagglutinin-specific monoclonal antibodies to mice infected with influenza A viruses.

Mice injected with any influenza A virus develop a range of virus-immune cytotoxic T lymphocytes, some of which tend to be more lytic for cells expressing the virus used for priming (subtype-specific) while others are cross-reactive for targets infected with all influenza A viruses. Treatment with large doses of either of two monoclonal antibodies (which bind to the influenza virus hemagglutinin molecule) at 3-48 h after exposure to virus tends to selectively block the generation of the more subtype-specific cytotoxic T lymphocyte subset, although the magnitude of cross-reactive effector function may also be diminished. Inhibition that is less obviously selective is also seen for a third monoclonal antibody. A reasonable explanation for these findings is that there is afferent blockage at the level of T-cell recognition of the influenza virus hemagglutinin molecule expressed on stimulator cells. The inhibitory effect of the monoclonal antibody is apparently steric. Priming with parental strain virus followed by exposure to monoclonal antibody induces a population of cytotoxic T lymphocytes which manifest decreased cytotoxic activity for target cells infected with either the parental strain virus or with a variant virus to which the monoclonal antibody does not bind. A more practical consideration is that the administration of large doses of specific immunoglobulin may interfere with the development of cell-mediated immune mechanisms. This should be considered when developing possible therapeutic protocols using monoclonal antibodies.

Animals↗
PubMed1982

Capacity of influenza virus-monoclonal antibody mixtures to stimulate memory and cytotoxic T lymphocyte populations.

The magnitude of the cytotoxic T lymphocyte response in both immunologically naive mice and in mice primed with a serologically non-cross-reactive influenza A virus was greatly diminished if the virus used for challenge was first incubated with excess hemagglutinin-specific monoclonal antibody. However, the level of T cell stimulation was, when compared with virus stocks that are simply diluted, greater than would be expected from the infectivity titer remaining after exposure to the monoclonal antibody. Also, mice given mixtures of virus and monoclonal antibody were primed for a secondary cytotoxic T lymphocyte response, the frequency of memory T cells being approximately fourfold lower than that found for animals injected with virus alone. The possibility that such virus-antibody mixtures might be of value for immunization is worth further investigation.

Animals↗
PubMed1982

Limit-dilution analysis of weak influenza-immune T cell responses associated with H-2Kb and H-2Db.

A limiting-dilution analysis has been made of influenza-immune cytotoxic T lymphocyte (CTL) response patterns associated with H-2Kb and H-2Dd in the B10.A(5R), and H-2Kk and H-2Db in the B10.A(2R) and B10.A(4R) recombinant mouse strains. In previous in vivo experiments the H-2Kb allele has been shown to be associated with low responsiveness or nonresponsiveness, whereas Db-restricted influenza-specific responses were found to be weak in recombinant strains that possessed the Kk allele. Influenza-immune CTL restricted to the more "dominant" H-2Dd and H-2Kk alleles were found consistently when primed T cells were restimulated in vitro under limiting-dilution conditions. Precursors were present at frequencies of at least twice background levels (lysis of normal targets) in the great majority of experiments, performed with or without added helper factors. The H-2Kb- and H-2Db-restricted responses were much more variable and, for H-2Kb but not for H-2Db, were completely absent when the culture medium did not contain added interleukin preparations. Even so, experiments in which individual microcultures were tested on more than one target demonstrated conclusively both that H-2Kb-restricted CTL can be generated under limiting-dilution conditions and that most, if not all, of these T cells do not cross-react with influenza virus presented in the context of H-2Dd. The characteristics of these "weak" responses are thus that they are more help dependent and show evidence of greater variability between individual mice than the "dominant" CTL clones do.

Animals↗
PubMed1982

Sequential analysis of the virus-immune responder characteristics of thymocytes from F1 leads to parent radiation chimeras.

The virus-immune responder characteristics of thymocytes, spleen and lymph node (LN) cells from (P1 X P2)F1 leads to P1 radiation chimeras have been examined sequentially at weekly intervals. Adoptively-transferred thymocytes generate strong cytotoxic thymus-derived lymphocyte (CTL) responses from 28 to 100 days after reconstitution with bone marrow, which are almost invariably restricted to recognition of virus presented in the context of P1. This pattern of H-2 restriction is also maintained for spleen and LN cells from the [(H-2kXd)F1 leads to H-2k] and [(H-2kXb)F1 leads to H-2k] combinations but there is random emergence of reactivity to H-2k+virus for peripheral lymphoid cells from [(H-2KkXb)F1 leads to H-2b] chimeras. Treatment of established [(P1 X P2)F1 leads to P1] chimeras with a low dose of cyclophosphamide (Cy) did not lead to the emergence of significant CTL effector function for P2 + virus. Also, administration of a large dose of Cy prior to irradiation of the chimera recipients did not modify the H-2 restriction profile of the chimera, though the level of CTL responsiveness associated with the appropriate H-2 type was apparently enhanced.

Animals↗
PubMed1981

Uptake and retention of androgen in neurons of the brain of the golden hamster.

The distribution of cells capable of concentrating androgen was studied in the male hamster after injection of 5 alpha-dihydro-[1,2,4,5,6,7,(n)-3H]testosterone([3H]DHT) using the technique of thaw-mount autoradiography. Castrated adult male hamsters were injected with 0.2 microgram/100 g body weight of [3H]DHT (107 Ci/mmol) and killed 1.5 h later. Brains were rapidly removed and processed for autoradiography. Localization of radioactivity in high concentrations occurred chiefly in limbic forebrain structures and hypothalamic nuclei associated with the control of reproductive function including the following areas: the septal-preoptic region, the amygdala, and the anterior, ventromedial and arcuate nuclei of the hypothalamus. In addition, labeled cells in lesser concentrations were found in the lateral preoptic area, lateral hypothalamus, hippocampus, mesencephalon and various cortical regions. Treatment with 100-fold excess of testosterone, but not estradiol or diethylstilbestrol, inhibited nuclear localization. These studies provide information on the precise anatomical localization of androgen concentrating cells in the hamster brain and demonstrate the similarity of distribution of androgen binding in the rat, mouse and hamster.

Amygdala↗
PubMed1981

Thymocytes can be stimulated to give a strong vaccinia virus-immune cytotoxic T lymphocyte response.

The emergence of virus-specific cytotoxic T lymphocyte (CTL) precursors in thymus can be examined directly by stimulating thymocytes for 6 days in irradiated, virus-infected recipients. Responsiveness is a characteristic of the thymocytes themselves and does not reflect the presence of contaminating, blood-bourne T cells. Strong CTL activity may be generated earlier from thymus than from spleen or lymph node of lethally irradiated, bone marrow reconstituted mice. Also, the reconstitution of virus-immune CTL function in these peripheral lymphoid organs is thymus-dependent. Use of this simple experimental protocol offers considerable possibilities for the analysis of the role of the thymus in the ontogeny of the T cell repertoire.

Animals↗
PubMed1981

Rejection of allogeneic tumor cells growing in mouse cerebrospinal fluid. Functional analysis of the inflammatory process.

Mice injected intracerebrally (i.c.) with mastocytoma cells reject the tumor, which grows rapidly in cerebrospinal fluid (CSF), within 7 or 8 days. The characteristics of the inflammatory exudate have been examined by several different, functional criteria. Potent cytotoxic T-lymphocyte populations are readily demonstrated in CSF, and both phagocytic and non-phagocytic cells capable of mediating antibody-dependent cell-mediated cytotoxicity are also present. However, no tumor-specific antibody was detected in CSF of mice that had recently rejected the tumor, using sensitive complement-dependent and lymphocyte-dependent cytotoxic assay systems. The process of cell-mediated tumor rejection does not obviously compromise the blood-CSF barrier to immunoglobulins.

Animals↗
PubMed1981

Breakdown of the blood--cerebrospinal fluid barrier to immunoglobulin in mice injected intracerebrally with a neurotropic influenza A virus. Post-exposure treatment with monoclonal antibody promotes recovery.

Mice may be protected from the invariably fatal consequences of intracerebral (i.c.) inoculation of A/WSN influnza virus by intravenous injection with 0.5 mg of virus-specific monoclonal anti-hemagglutinin antibody given 2 days after i.c. challenge. The integrity of the blood-cerebrospinal fluid (CSF) barrier in such mice has been examined by comparing specific immunoglobulin (Ig) titers in serum and CSF. It seems that the process of virus growth results directly in substantial breakdown of the blood-CSF barrier at some time between 63 and 96 h after i.c. exposure to virus. The exogenously administered, virus-specific monoclonal antibody is not obviously involved either in abrogating the integrity of this physiological barrier system or in promoting inflammation. In fact, higher Ig titers are found in CSF for an antibody that does not bind to the virus. This presumably reflects the fact tht virus-infected cells in the central nervous system are adsorbing specific Ig from the CSF.

Animals↗