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Biomedical subjects

P C Doherty

Publications and source records attributed to P C Doherty.

At least 145 records · Page 8Linked to original sources
PubMed1991

Size and frequency characteristics of alpha beta and gamma delta T cells in the spleens of normal and cyclophosphamide-suppressed virus-infected chickens.

The characteristics of avian lymphocytes expressing surface CD8 (CT8) and T cell receptor (TCR) glycoproteins have been monitored by two-color flow microfluorimetry. Exposure of 1-month-old birds to a lethal influenza A virus, which is known to be lympholytic, significantly decreased the frequency of both the alpha beta TCR2+CT8+ and gamma delta TCR1+CT8- subsets in spleen. However, all categories of T cells showed evidence of greater mean cell size, indicating that they are responding. Inoculation of baby chicks with fowl pox virus induced a response more typical of specific immunity in the TCR2+CT8+ set, in that the lymphocytes increased in both frequency and mean cell size. Greater numbers of lymphoblasts were also found for the TCR2+CT8-, TCR1+CT8+, and TCR1+CT8- subsets, but the total cell counts for the minority TCR1+CT8- cells in spleen were consistently decreased. Immunosuppression with cyclophosphamide prior to infection eliminated 90% of the white blood cells from spleen, with the greatest effect being on the TCR1+ populations. The CT8+ alpha beta T cell response in chick spleen following exposure to a poxvirus is thus comparable to the situation observed for this subset of lymphocytes in mice infected with other viruses. However, although the gamma delta T cells increase in size, their frequency in spleen either does not change (CT8+) or is significantly decreased (CT8-).

Animals↗
PubMed1991

Lack of an inhibitory effect of hyperprolactinemia on androgen-dependent marking.

An experiment was performed to determine if hyperprolactinemia (chronically elevated serum prolactin levels), which inhibits testosterone-activated male sexual activity, also affects other androgen-dependent behaviors. Thus defecation and urine marking in response to a novel environment were examined in sham-operated and pituitary-grafted (hyperprolactinemic) male rats that had been castrated or castrated and given subcutaneous testosterone implants. Both castration and pituitary grafting significantly inhibited defecation, with the inhibitory effects of hyperprolactinemia being most pronounced in the castrated non-testosterone-treated animals. In contrast, castration significantly reduced the amount of urine marking observed, but pituitary grafting was without effect on this behavior. Thus, although hyperprolactinemia may inhibit sexual activity through an antagonism of the activational effects of testosterone, these results suggest that this effect is specific to sexual behavior and does not involve a more generalized inhibition of the effects of testosterone on androgen-dependent behaviors.

Animals↗
PubMed1991

Influenza virus RNA in the lung and lymphoid tissue of immunologically intact and CD4-depleted mice.

The distribution and clearance of viral RNA (vRNA) and mRNA has been analysed for the acute and recovery stages of the pneumonia induced by intranasal infection of C57BL/6J mice with H3N2 influenza A viruses. Amplification of viral genomic material by the polymerase chain reaction showed that the influenza haemagglutinin (HA) gene was eliminated from the lungs of immunologically intact mice by day 14 post-infection, whereas in vitro depletion of the CD4+ T cells delayed clearance by at most 4 days. Viral RNA encoding the HA gene was first demonstrated in the regional mediastinal lymph nodes at 48 h, and continued to be present until day 6 or day 10 after infection of the intact and CD4-depleted mice, respectively. Evidence for the presence of vRNA in the thymus, but not in the mesenteric lymph nodes or the spleen, was found in some situations. Otherwise, the distribution and clearance of vRNA was as would be predicted from earlier studies using virus isolation procedures to monitor localization patterns, and shows a lack of long-term persistence of the influenza virus genome.

Acute Disease↗
PubMed1991

Preferential increase in pituitary prolactin versus vasoactive intestinal peptide as a function of estradiol benzoate dose in the ovariectomized rat.

Vasoactive intestinal peptide (VIP) is synthesized in various tissues, including the anterior pituitary gland, where it may stimulate the release of PRL. Because estrogen plays a central role in the regulation of PRL, it becomes important to determine the effects of this steroid on both pituitary VIP and PRL. To study this, pituitary VIP and PRL and plasma PRL were assayed in ovariectomized rats after treatment with estradiol benzoate (EB; 0.007, 0.07, 0.7, 7 or 70 microgram/rat). Pituitary and plasma TSH were also determined as well as VIP content in the medial basal hypothalamus, suprachiasmatic region, cerebral cortex, and jejunum. Oil-treated rats served as controls. Injection of 0.7 or 7 microgram EB resulted in a significant increase in pituitary PRL without changing plasma PRL levels or pituitary VIP content compared to values in the control group. Only treatment with 70 microgram EB produced a significant increase in both pituitary VIP and PRL as well as in plasma PRL compared to control values. EB treatment at any of the doses used had no significant effect on pituitary and plasma TSH or VIP content in any of the other tissues examined. These data show that pituitary PRL and VIP are differentially regulated in response to estrogen. The increases in pituitary VIP and basal plasma PRL after treatment with the highest dose of EB suggest that pituitary VIP may be involved in the development of estrogen-induced hyperprolactinemia. These data also show that the regulations of pituitary VIP and TSH are independent of each other in the estrogen-treated rat.

Animals↗
PubMed1990

Late dominance of the inflammatory process in murine influenza by gamma/delta + T cells.

The inflammatory response in the lungs of mice infected with an influenza A virus consists largely of macrophages and CD3+ T cells. Most T lymphocytes recovered before day 7 after infection express mRNA for the T cell receptor alpha/beta (TCR-alpha/beta), while TCR-gamma/delta mRNA+ cells are found at much higher frequency over the next 7 d. The predominant surface phenotype for the TCR-gamma/delta mRNA+ population is CD3+4-8-TCR-alpha/beta-. Some lymphocytes expressing all the known V gamma genes are found in the inflammatory exudate, but V gamma 2+/V gamma 1+ and V gamma 4+ T cells are present at highest frequency. The response is staged, with maximal numbers of V gamma 4+ cells occurring on day 10 after infection, while the predominant phenotype on day 13 is V gamma 2/V gamma 1+. The emerging peak in numbers of V gamma 4+ lymphocytes is paralleled by increasing numbers of macrophages expressing hsp mRNA. The later maxima found for the V gamma 2+/V gamma 1+ T cells is consistent with the possibility that at least some of these lymphocytes are responding to the hsp+ cells and are functioning to resolve the inflammatory process.

Animals↗
PubMed1990

Cellular events in the lymph node and lung of mice with influenza. Consequences of depleting CD4+ T cells.

The cellularity of the mediastinal lymph nodes of mice infected intranasally with a high dose of an H3N2 influenza A virus increases massively within 5 days. All classes of lymphocytes are involved. A similar, but much smaller, expansion in cell numbers occurs after exposure to a comparable dilution of normal chick allantoic fluid. In the control group, this increase in lymph node size is totally prevented by the in vivo depletion of CD4+ T cells whereas there is only a 50% reduction in the virus-infected mice. The lymphocyte component of the cellular exudate in the lungs of infected mice is dominated by activated, CD8+ T cells, which are also prevalent in the mediastinal lymph nodes. Elimination of the CD4+ subset does not greatly diminish the severity of this inflammatory process. The CD4-depleted mice clear the virus from the lung, and there is little effect on the frequency of virus-specific, cytotoxic T lymphocyte precursors in either the lymph node or the lung. Substantial involvement of CD4+ T cells is not essential for the development of effective cell-mediated immunity in mice with influenza.

Animals↗
PubMed1990

Hyperprolactinemia preferentially inhibits erectile function in adrenalectomized male rats.

To determine if the inhibitory effects of hyperprolactinemia on sexual arousal and serum LH levels could be dissociated from those on erectile function, copulatory behavior was examined in pituitary-grafted, adrenalectomized male rats that had been castrated and given 20mm subcutaneous testosterone implants. Whereas transplantation of three pituitaries under the kidney capsules inhibited mounting rates in intact animals, pituitary grafting did not significantly reduce mounting rates in the adrenalectomized group beyond the effect of adrenalectomy alone. In contrast, the effects of pituitary grafting on erectile function were enhanced in the adrenalectomized animals. Hyperprolactinemia also caused a significant reduction in serum LH, but only in the intact animals. These results suggest that: 1. the effects of hyperprolactinemia on erectile function occur independently from those on sexual arousal, and 2. the inhibitory effects of hyperprolactinemia on sexual arousal are linked to the effects of hyperprolactinemia on LH release.

Adrenalectomy↗
PubMed1990

Dissection of an inflammatory process induced by CD8+ T cells.

A massive delayed type hypersensitivity (DTH) reaction occurs in the cerebrospinal fluid (CSF) of mice with lymphocytic choriomeningitis (LCM). In this article, Peter Doherty and colleagues analyze this reaction together with the population dynamics of the regional lymph node to give a comprehensive picture of the events underlying this CD8+ T-cell-mediated immunopathological disease. Their findings are of general relevance to the understanding of inflammation.

Animals↗
PubMed1990

Binding of monoclonal antibodies and T cell effector function in vivo.

The capacity of adoptively transferred CD8+ effector T cells to induce meningitis in immunosuppressed, or unsuppressed, recipients infected with lymphocytic choriomeningitis virus (LCMV) may be diminished by prior incubation of the lymphocytes with IgM monoclonal antibodies (MAbs) specific for CD8 or Thy1.2. The same is true, though to a lesser extent, for the further proliferation of donor T cells in the spleens of the immunosuppressed mice. This inhibition of cell mediated immunity can be overcome, at least for the unsuppressed recipients, by increasing the numbers of cells that are transferred, even though exposure to Mab+ complement abrogates all cytotoxic T cell activity in vitro. The LCM model thus provides a quantitative system for assessing the consequences of MAb binding for T cell trafficking and effector function in vivo.

Animals↗
PubMed1989

Tumor necrosis factor inhibits the development of viral meningitis or induces rapid death depending on the severity of inflammation at time of administration.

Administration of human rTNF to both male and female mice with severe, but clinically inapparent, lymphocytic choriomeningitis caused death within 2 to 3 h. The development of fatal symptoms was accompanied by a two- to threefold reduction in the number of cells present in the cerebrospinal fluid, with this effect being more apparent in female mice. Giving the same dose of rTNF earlier in the course of the disease was not fatal and reduced the level of subsequent meningitis. In addition, prior exposure to rTNF protected against the acute development of lethal disease when a second dose of the cytokine was given later. The extent of this "tolerance" to rTNF was directly related to the degree of reduction of the inflammatory process resulting from the primary exposure to the cytokine.

Animals↗
PubMed1989

Phenotypic and functional analysis of the cellular response in regional lymphoid tissue during an acute virus infection.

A phenotypic and functional analysis has been made of the cellular response in regional lymphoid tissue of C57BL/6J mice infected with lymphocytic choriomeningitis virus. Massive recruitment of nondividing cells occurred from 3 days after infection, with total numbers of CD8+ T lymphocytes, B220+ B cells, and Thy-1- B220- null cells being high from day 4 to day 6. In contrast, the peak counts for CD4+ T cells were recorded on day 4 and declined dramatically thereafter. Enhanced expression of IL-2R and Ly-24, both of which can be regarded as T cell activation markers, was found for both the CD4+ and the CD8+ subsets, being most prominent for the CD8+ T cells on day 6. Evidence of T cell proliferation was not recognized until days 5 and 6, coincident with enhanced responsiveness of the lymphocytes to rIL-2 and the development of virus-specific cytotoxic activity. Elimination of the CD4+ T cells by treatment of mice with mAb did not modify either the pathogenesis of lymphocytic choriomeningitis, or the expression of activation markers on the CD8+ T cells which are known to be the key effectors in this disease. Thus, the pattern of responsiveness for the CD8+ population is of recruitment to the lymph node, progressive increase in the expression of activation markers and enhanced sensitivity to rIL-2, with late proliferation and generation of cytotoxic activity. This model provides a system for the rigorous in vivo analysis of parameters influencing lymphocyte differentiation and activation in a virus infection.

Animals↗
PubMed1989

Persistence of the irradiated host component in thymocyte populations from bone marrow radiation chimeras infected with lymphocytic choriomeningitis virus.

The thymus of chimeras made using T cell-depleted donor bone marrow from Thy1.1+ mice and 950 rad Thy 1.2+ recipients is dominated initially by cells expressing the Thy 1.2+ phenotype of the irradiated host. The thymocyte population recovered at 2 weeks after reconstitution comprises 80% Thy 1.2+ cells (host), the remainder being Thy 1.1+ (donor). This situation is normally reversed within a further week, with the host Ty 1.2+ (donor). This situation is normally reversed within a further week, with the host Thy 1.2+ thymocytes being present at a frequency of less than 5% from Week 4. Infection with lymphocytic choriomeningitis virus (LCMV) at 1 week after reconstitution with bone marrow causes a profound and persistent drop in the total number of thymocytes. The decline is equivalent for all categories of donor-derived thymocytes defined by two-color flow microfluorometric analysis for CD4 and CD8. However, there is a partial compensation by the retention of cells originating from the Thy 1.2+ host, which constitute 30-40% of the total thymocyte pool as late as 8 weeks after administration of bone marrow in the LCMV-infected chimeras. These radiation-resistant precursors give rise to CD4-8-, CD4-8+, CD4+8-, and CD4+8+ thymocytes, with the latter category being present at increased frequency. The potential skewing of the mature T cell repertoire as a consequence of persistent virus infection is discussed.

Animals↗
PubMed1989

Extra-hypothalamic dopamine is not involved in the effects of hyperprolactinemia on male copulatory behavior.

Experiments were performed to determine if the inhibition of copulatory behavior observed in male rats with chronically elevated serum prolactin levels (hyperprolactinemia) is associated with changes in central dopaminergic function in the nigrostriatal and mesolimbic systems. Chronic hyperprolactinemia, induced by ectopic pituitary grafts, inhibited sexual activity but was not associated with changes in locomotor activity, serotyped behavior in response to various doses of apomorphine, or 3H-spiroperidol binding to striatal homogenates. However, open-field defecation was reduced in the pituitary grafted animals. The results of the present study show that changes in nigrostriatal dopamine receptor sensitivity do not contribute to the inhibition of sexual behavior in hyperprolactinemic male rats. In addition, these results also demonstrate that the effects of hyperprolactinemia are relatively specific to copulatory behavior and appear not to involve general behavioral suppression.

Animals↗
PubMed1989

Influence of non-major histocompatibility complex differences on the severity of lymphocytic choriomeningitis.

The role of the non-major histocompatibility complex (MHC) genetic background in the development of lymphocytic choriomeningitis (LCM) was examined for a range of mouse strains of the H-2k haplotype. The onset of meningitis relative to the time of injection of LCM virus was delayed and the maximal level of cellular extravasation into cerebrospinal fluid was lower in C3H/HeJ and CBA/H compared with AKR/J, B10.Br and BALB/c.H-2k mice. Adoptive transfer experiments indicated that the C3H mice are genuine low responders, but immune spleen cells from the CBA/H were as potent on a cell-for-cell basis as those from the AKR/J. Further analysis with CBA/H, AKR/J and (CBA/H x AKR/J)F1 mice showed that the pattern of high response for the AKR/J was dominant, with the differential kinetics of the development of meningitis correlating with the cellularity of the cervical lymph nodes. Thus, the generation of the LCM inflammatory process is not dictated solely by the MHC phenotype.

Animals↗
PubMed1989

Consequences of exposure to ionizing radiation for effector T cell function in vivo.

The adoptive transfer of actuely primed and memory virus-immune CD8+ T cells causes enhanced meningitis in both cyclophosphamide (Cy) suppressed, and unsuppressed, recipients infected with lymphocytic choriomeningitis virus (LCMV). The severity of meningitis is assessed by counting cells in cerebrospinal fluid (CSF) obtained from the cisterna magna, which allows measurement of significant inflammatory process ranging from 3 to more than 300 times the background number of cells found in mice injected with virus alone. Exposure of the donor immune population to ionizing radiation prior to transfer has shown that activated T cells from mice primed 7 or 8 days previously with virus may still promote a low level of meningitis in unsuppressed recipients following as much as 800 rads, while this effect is lost totally in Cy-suppressed mice at 600 rads. Memory T cells are more susceptible and show no evidence of in vivo effector function in either recipient population subsequent to 400 rads, a dose level which also greatly reduces the efficacy of acutely-primed T cells. The results are interpreted as indicating that heavily irradiated cells that are already fully functional show evidence of primary localization to the CNS and a limited capacity to cause pathology. Secondary localization, and events that require further proliferation of the T cells in vivo, are greatly inhibited by irradiation.

Animals↗
PubMed1989

In vivo treatment with an appropriate anti-Thy-1.2 monoclonal antibody abrogates hybrid resistance to Thy-1.1+ virus-immune effector T cells.

The hybrid resistance (Hr) effect operates to limit the induction of T-cell-mediated inflammatory processes following transfer into recipients injected with murine lymphocytic choriomeningitis virus (LCMV). Adoptively transferred Thy-1.1+ H-2b (KbDb) LCM virus-immune T cells are inhibited in cyclophosphamide (Cy)-suppressed, virus-infected mice that are heterozygous for H-2Db (e.g. H-2k x b F1). Injection of recipient animals with monoclonal antibody (mAb) to Thy-1.2 resulted in the elimination of Thy-1.2+ H-2b x d F1 effectors on transfer to H-2b x d F1 recipients. The Hr effect was removed by mAb treatment of Thy-1.2+ F1 recipients given H-2b Thy-1.1+-immune T cells. Apparently Hr is mediated by a cell which is Thy-1+.

Animals↗