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Biomedical subjects

P C Doherty

Publications and source records attributed to P C Doherty.

At least 199 records · Page 11Linked to original sources
PubMed1985

Consequences of cyclophosphamide treatment in murine lymphocytic choriomeningitis: evidence for cytotoxic T cell replication in vivo.

Administration of a large dose (400 mg/kg) of cyclophosphamide (Cy) prior to infection with lymphocytic choriomeningitis virus (LCMV) suppresses the virus-immune cytotoxic T lymphocyte (CTL) response. Treatment with 150 mg/kg of Cy before, at the time of, or on the day after LCMV infection has little effect on CTL function. In contrast, when given on 2-7 days after LCMV, this dose profoundly depresses the day-8 CTL response and delays the onset of neurological disease. Administration of as little as 50 mg/kg of Cy has a marked effect on CTL activity when given 5 days after virus. Therefore it seems likely that CTL are replicating for 5 or 6 days during this primary response. Multiplication of these T cells is apparently completed by day 8, since inoculation of 150 mg/kg of Cy at this time has little effect on the level of CTL activity measured on day 9. The CTL activity is not reconstituted by in vitro culture with added helper factors. The interpretation that CTL are replicating in vivo following inoculation of LCMV is in accord with other analyses of virus-specific precursor frequency in primed and naïve mice.

Animals↗
PubMed1985

Treatment of mice with polyinosinic-polycytidilic polyribonucleotide reduces T-cell involvement in a localized inflammatory response to vaccinia virus challenge.

Mice inoculated intracerebrally with 10(3) PFU of vaccinia virus developed a nonfatal meningitis which was maximal 7 days after challenge. Intravenous administration of an interferon (IFN) inducer, polyinosinic-polycytidilic polyribonucleotide [poly(I)-poly(C)], on days 4 and 6 postinjection was associated with a three- to fourfold decrease in the number of T lymphocytes present in cerebrospinal fluid, reflected primarily by a decreased number of vaccinia virus-specific cytotoxic T-lymphocyte precursors. The lack of a concomitant reduction in the overall cytotoxic activity of cerebrospinal fluid cells directed against virus-infected target cells seemed to be largely due to an increase in natural killer cell activity. IFN was implicated as mediating the effect of poly(I)-poly(C) because high systemic levels of IFN were evident after injection, and neither the magnitude of the inflammatory response nor the T-cell levels were affected when poly(I)-poly(C)-treated mice were also given anti-IFN antiserum. However, the poly(I)-poly(C)-induced IFN did not seem to reduce the localized inflammatory response by affecting viral replication in brain tissue because the vaccinia virus titers present on days 6 through 8 of infection were similar to the titers in phosphate-buffered saline controls. These findings are consistent with either an effect of IFN on T-cell recruitment to the central nervous system or an inhibition of proliferation of cells participating in the response. These findings suggest that there is a potential source of complications for clinical protocols that use IFN or inducers to enhance T-cell function in various disease situations, and this effect of IFN may be a contributing factor to the immunosuppression often associated with many viral infections.

Animals↗
PubMed1984

Inhibition of autoimmune neuropathological process by treatment with an iron-chelating agent.

Lewis rats that are primed with guinea pig spinal cord homogenized in complete Freund's adjuvant (GPSCH-CFA) develop overt symptoms of experimental allergic encephalomyelitis (EAE). Treatment with the iron-chelating agent, desferrioxamine B mesylate (DFOM), at various times before the onset of EAE, dramatically suppressed both the severity and duration of disease. When DFOM was administered to rats soon after the development of neurological signs, a rapid recovery occurred, though mild, transient symptoms could be seen approximately 1 wk after withdrawal of the drug. Treatment with DFOM was always accompanied by a diminution of T cell responsiveness on the part of the delayed-type hypersensitivity/helper subset and, on histological examination, an absence of inflammatory cells from lesions. Iron is believed to influence both the migration and function of immune effector cells. It can also act as a catalyst in the formation of free radicals, which are highly toxic agents causing tissue damage in sites of inflammation. The mechanisms underlying the effect of DFOM on the severity of EAE, and the possible implications for treatment of multiple sclerosis are discussed.

Animals↗
PubMed1984

Frequency of influenza-responsive cytolytic T-lymphocyte precursors in the thymus and spleen of unprimed mice.

Limiting dilution culture conditions were established which allowed the differentiation and quantitation of influenza-specific cytotoxic T-cell precursors (CTL.Ps) from naive mouse spleen and thymus. One in 49,000 nucleated spleen cells and 1 in 40,000 thymocytes responded to stimulation with influenza-infected, anti-Thy 1.2 and complement-treated spleen cells, in the presence of ConA-stimulated cell supernatant, with the production of cytotoxic effector cells. These frequencies are 4- to 15-fold higher than those for influenza-responsive B cells in the relevant lymphoid compartments, and it is argued that major quantitative discrepancies may exist in the sizes of the B- and CTL-receptor repertoires.

Animals↗
PubMed1984

Immunological surveillance of tumors in the context of major histocompatibility complex restriction of T cell function.

The immunological surveillance hypothesis was formulated prior to the realization of the fact that an individual's effector T cells generally only see neoantigen if it is appropriately presented in the context of self MHC glycoproteins. The biological consequence of this mechanism is that T lymphocytes are focused onto modified cell-surface rather than onto free antigen. The discovery of MHC-restricted T cell recognition, and the realization that T cell-mediated immunity is of prime importance in promoting recovery from infectious processes, has thus changed the whole emphasis of the surveillance argument. Though the immunological surveillance hypothesis generated considerable discussion and many good experiments, there is no point in continuing the debate in the intellectual context that seemed reasonable in 1970. It is now much more sensible to think of "natural surveillance" and "T cell surveillance," without excluding the probability that these two systems have elements in common. We can now see that T cell surveillance probably operates well in some situations, but is quite ineffective in many others. Part of the reason for this may be that the host response selects tumor clones that are modified so as to be no longer recognized by cytotoxic T cells. The possibility that this reflects changes in MHC phenotype has been investigated, and found to be the case, for some experimental tumors. In this regard, it is worth remembering that many "mutations" in MHC genes that completely change the spectrum of T cell recognition are serologically silent. The availability of molecular probes for investigating the status of MHC genes in tumor cells, together with the capacity to develop cloned T cell lines, monoclonal antibodies to putative tumor antigens, and cell lines transfected with genes coding for these molecules, indicates how T cell surveillance may profitably be explored further in both experimental and human situations.

Animals↗
PubMed1984

Effect of an iron-chelating agent on lymphocyte proliferation.

The effect of the iron-chelating agent desferrioxamine on lymphocyte proliferation has been studied. Desferrioxamine at concentrations of 15 microM totally inhibited the proliferation of Concanavalin A-stimulated lymphocytes, whereas iron-saturated desferrioxamine was ineffective. Other metal salts, however, had little or no effect on the inhibition induced by this drug. Desferrioxamine was more effective at suppressing proliferation of T lymphocytes than B lymphocytes and additionally suppressed mixed lymphocyte cultures and the generation of cytotoxic T cells.

Animals↗
PubMed1984

The localized primary cytotoxic T-cell response to cells expressing minor histocompatibility differences.

Cytotoxic T lymphocytes (CTL) are able to eliminate P815 (DBA/2) mastocytoma cells growing in cerebrospinal fluid of BALB/c H-2-compatible but minor histocompatibility (H) antigen-different mice and in H-2-incompatible C3H/He mice. We examined the magnitude of the primary CTL response to multiple, minor H antigens and to determinants of the major histocompatibility complex (MHC) by using a direct cytolytic assay and limiting-dilution analysis to estimate CTL frequency. By these criteria, no obvious differences emerged, and the responses appeared comparable at the site of inflammatory process, despite differences in the number of clonal progenitors. Experiments with radiation chimeras showed evidence of a strong cytotoxic T-cell response against P815 cells in [(ddd X bbb)F1----ddd] and (F1----bbd), but not in (F1----bbb) radiation chimeras. Therefore, this cytotoxic T-cell response against minor H antigens obeys the postulated rules for thymic restriction of precursors. Compatibility at the H-2 D-end of the MHC is apparently sufficient to ensure a strong response.

Animals↗
PubMed1984

Effects of experimentally induced chronic hyperprolactinemia on the ultrastructure of pinealocytes in male rats.

The influence on the ultrastructure of pinealocytes of long-term hyperprolactinemia caused by ectopic pituitary transplants and of suppression of prolactin release by bromocriptine was examined morphometrically in male rats. Hyperprolactinemia resulted in an increase in the relative volumes of granular endoplasmic reticulum, vacuoles containing a flocculent material, mitochondria, and lipid droplets. Treatment of grafted rats with bromocriptine reversed the effects of hyperprolactinemia. However, bromocriptine had no apparent influence on the pinealocytes of intact rats. The effects of hyperprolactinemia on the ependymallike secretory process in the pinealocyte were especially pronounced.

Animals↗
PubMed1984

Priming of virus-immune memory T cells in newborn mice.

Neonatal BALB/c mice can be primed at birth by intravenous inoculation of a small dose of A/Puerto Rico/8/34 (H1N1) (PR8) influenza virus. UV-inactivated PR8 virus, or PR8 virus complexed with monoclonal antibody to give a secondary cytotoxic T lymphocyte response when restimulated in vitro as adults. The frequency of responding T cells after secondary stimulation in vitro is approximately 40% of that found for adult mice primed intraperitoneally with a large dose of PR8 virus. The majority of the T cells generated from mice primed at birth or as adults are cross-reactive for H-2-compatible targets infected with the PR8 (H1N1) or A/Hong Kong/X31 (H3N2) viruses. Splenocytes from neonates receiving UV-inactivated vaccinia virus at birth give an augmented secondary cytotoxic T lymphocyte response when restimulated 8 days later in adoptive irradiated adult hosts. We found no indications of specific immunological unresponsiveness in mice exposed to either virus.

Animals↗
PubMed1984

Effects of estrogen-induced hyperprolactinemia on endocrine and sexual functions in adult male rats.

Chronic estrogen treatment can lead to development of prolactin (PRL) secreting pituitary tumors. We have tested the ability of diethylstilbestrol (DES) to produce persistent hyperprolactinemia (hyperPRL) in adult male rats and examined the effects of this treatment on hypothalamic-pituitary-testicular function, adenohypophyseal structure, copulatory behavior and fertility. Silastic capsules containing approximately 5 mg DES were subcutaneously implanted into adult male CDF (F-344)/CrlBR rats and removed 15 or 20 weeks later. Extreme hyperPRL, as well as suppression of plasma LH and FSH levels, persisted after DES capsules were removed. In contrast, plasma testosterone levels increased rapidly after removal of DES capsules and reached normal levels within 4-6 weeks. Copulatory behavior was assessed on two occasions between 7 and 14 weeks after removal of the DES capsules and was found to be suppressed in DES-treated rats, as evidenced by significant increases in latencies to mount, to intromit and to ejaculate. Moreover, when the animals were placed with normal females, the interval until conception was significantly greater in DES-treated than in control males. In spite of these differences in copulatory behavior, 10 of 11 DES-treated males were fertile. At autopsy, 44 weeks after capsule implantation (i.e. 24 or 29 weeks after capsule removal), DES-treated rats had marked enlargement of the anterior pituitary, increased weights of the lateral prostate and the adrenals, increased levels of testicular hCG-binding sites, reduced concentration of dopamine and norepinephrine in the median eminence and increased concentration of LHRH in the preoptic area.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1984

Induction of early alloantigen tolerance in thymus and spleen.

Both thymocytes and splenocytes from B6 (H-2b) mice injected as neonates with C3H(H-2k) or (B6 X C3H)F1 cells exhibited specific nonresponsiveness to the H-2KD alloantigens in question. Thus, tolerance could be induced in strain combinations which did not share H-2 antigens. Induction of specific allotolerance did not require the presence of Thy-1.2+, Ia+ or G10-Sepharose-adherent cells in the donor inoculum, however injection of irradiated (1200 rad) cells was ineffective. Evidence of specific unresponsiveness was found as early as 5 days after birth and was not abrogated by adding either irradiated normal spleen cells or exogenous interleukin-2 in vitro. In fact, in some experiments there was evidence for the presence of stimulated helper T cells within the population of 'tolerant' cytotoxic T cells exposed to alloantigen. However, this could reflect the operation of a syngeneic mixed lymphocyte reaction directed at, for instance, fetal calf serum components expressed in the context of the tolerated Ia determinants.

Age Factors↗
PubMed1983

Cross-reactivity patterns of vaccinia-specific cytotoxic T lymphocytes from H-2Kb mutants.

Limit-dilution cultures were used to select vaccinia-immune T-cell populations from bm1 and bm3 mutant mice that were not lytic for virus-infected targets expressing the Kb and Db MHC glycoprotein. Approximately 30% of virus-immune CTL were restricted in each case to Kbm1 and Kbm3, rather than to Db. Evidence of extensive cross-reactivity was found for these virus-immune CTL. Bm3 and bm11 mice sharing one amino acid mutation from wild-type but differing by a second mutation seen only in bm3 are the most cross-reactive pair in their presentation of vaccinia. The bm1 and bm10 pair with dissimilar mutations from wild-type affecting the same CNBr fragment are also largely cross-reactive. However, 30% cross-reactivity is also found for bm1 and bm3, which differ in separate CNBr fragments. That mutants expressing amino acid substitutions in the same region of the peptide tend to show more evidence of cross-reactivity does not necessarily mean the T cells see linear arrays of amino acids on the MHC glycoprotein. For instance, Kbm1 and Kbm10 differ for three amino acids, but bm1 T cells are highly lytic for bm10 virus-infected targets. However, there is no cross-reactivity for Kbm1 and Kb, which differ at only two amino acids. The key to further understanding may rest with defining the nature of the conformational differences among the Kbm1, Kbm10, and Kb glycoproteins.

Animals↗
PubMed1983

Specific and nonspecific T-cell recruitment in viral meningitis: possible implications for autoimmunity.

Specific and nonspecific T-cell invasion into cerebrospinal fluid has been investigated in the nonfatal viral meningoencephalitis induced by intracerebral inoculation of mice with vaccinia virus. At the peak of the inflammatory process on Day 7 approximately 5 to 10% of the Lyt 2+ T cells present are apparently specific for vaccinia virus. Concurrently, in mice primed previously with influenza virus, 0.5 to 1.0% of the appropriate T-cell set located in cerebrospinal fluid is reactive to influenza-infected target cells. This vaccinia virus-induced inflammatory exudate may thus contain as many as 500 influenza-immune memory T cells. These findings are discussed from the aspect that such nonspecific T-cell invasion into the central nervous system during aseptic viral meningitis could result in exposure of potentially brain-reactive T cells to central nervous system components.

Animals↗
PubMed1983

Hierarchies of T cell responsiveness are reflected in the distribution of effector T cells in viral meningitis.

The vaccinia-virus-immune cytotoxic T lymphocyte (CTL) response, associated with H-2Kk in B10,A(2R) [KkDb] mice, is much more potent than that occurring in the context of H-2Db. This differential reactivity is true for T-cells recovered either from cerebrospinal fluid (CSF) of mice injected intracerebrally (i.c.) with a low dose of virus or from spleen populations primed by intravenous (i.v.) inoculation of a large amount of virus. Further stimulation of CSF inflammatory cells in vitro for 7 days under limiting dilution conditions indicated that the hierarchy of cytotoxic T-cell activity was a function of the relative frequencies of H-2Kk- and H-2Db-restricted lymphocytes. We therefore conclude that the immune response gene effect described previously for cells found in lymphoid tissue is also expressed in a virus-induced inflammatory exudate in the central nervous system.

Animals↗
PubMed1983

Characteristics of poxvirus-induced meningitis: virus-specific and non-specific cytotoxic effectors in the inflammatory exudate.

Mice injected intracerebrally with a sublethal dose of vaccinia virus develop severe meningitis. The number of inflammatory cells in cerebrospinal fluid (CSF) increases approximately threefold each day for 3 to 7 days after intracerebral challenge, subsequent to which samples can no longer be obtained because the cisterna magna is obliterated owing to brain swelling. Examination of this inflammatory exudate during the later stages of this pathological process shows evidence of both cytotoxic T lymphocyte (CTL) function and the presence of Lyt1+ and Lyt2+ cells on days 6 and 7. In addition, potent non-T-cell (Lyt2-) cytotoxic activity is found in CSF taken from younger (12 weeks) mice as early as after day 3 and is still present on day 6. The level of non-T-cell-mediated cytotoxicity in CSF on day 5 or 6 (but not day 3) is considerably decreased in animals that were also given a large dose of virus intravenously to maximize T-cell stimulation in lymphoid tissue, and the extent of CTL activity is concomitantly increased. The diminution of non-specific cytotoxic function does not seem to reflect simple dilution in the presence of excess virus-immune T cells.

Animals↗
PubMed1983

Cross-reactivity patterns of influenza-specific cytotoxic T lymphocytes from H-2Kb mutant mice.

Limit dilution cultures were used to test for influenza immune T cell populations from bm1 and bm3 mutant mice that were not lytic for virus-infected targets expressing the Kb and Db major histocompatibility complex glycoproteins. Both Kbm3- and Kbm1-restricted cytotoxic T cells were detected. Such effectors showed minimal cross-recognition of influenza on other mutant targets, except for the case of bm1 and bm10 targets. This is dissimilar to previous findings concerning vaccinia presentation in which bm3+bm11, bm1+bm9, and bm3+bm9 pairs each showed high cross-reactivity. These differences illustrate the role of the H-2K glycoprotein in immune responsiveness. Not only are multiple determinants on each H-2K glycoprotein involved in antigen presentation, they appear to play differential roles in the presentation of different viral antigens.

Animals↗
PubMed1982

Induction of neonatal tolerance to H-2k in B6 mice does not allow the emergence of T cells specific for H-2k plus vaccinia virus.

Thymocytes and spleen cells from C57BL/6 mice (H-2b) neonatally tolerized to H-2k alloantigens do not generate an anti-vaccinia response restricted to H-2Kk when adoptively transferred to appropriate irradiated hosts. This is in sharp contrast to the case for negatively selected C57BL/6 spleen cells acutely depleted of alloreactivity. No evidence for suppression was found in cell mixture experiments. We have shown elsewhere that our neonatally tolerized animals have a centrally induced delection-type tolerance in the absence of obvious suppression.2 We now suggest that in the neonatally tolerized mouse, chronic, central delection of anti-H-2k clones during early T cell ontogeny eliminates the major source of cells able to give rise, via somatic mutation and expansion, to anti-H-2Kk + vaccinia specific cytotoxic T lymphocyte precursors (CTL-P) in the adult. A similar mechanism may operate in the (k + b) leads to b chimera; however, the presence of H-2kxb accessory and presenting cells may permit the eventual generation (via cross-stimulation) of an H-2k-restricted vaccinia-specific repertoire. This would account for our observation of such "aberrant recognition" CTL-P emerging in the spleens of older (k x b) leads to b chimeras.

Animals↗