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J W Murphy

Publications and source records attributed to J W Murphy.

At least 73 records · Page 4Linked to original sources
PubMed1990

Characterization of a cell population which amplifies the anticryptococcal delayed-type hypersensitivity response.

Cell-mediated immunity to Cryptococcus neoformans can be detected by delayed-type hypersensitivity (DTH) to a culture filtrate antigen of C. neoformans. Recently, we have identified a population of cells in spleens of mice immunized with cryptococcal antigen that, when transferred to recipient mice at the time of immunization, amplifies the anticryptococcal DTH response. If the cell donor mice are treated with cyclosporin A during induction of the anticryptococcal DTH response, the amplifier cells are not induced, whereas the cells which transfer DTH (TDH cells) are induced. The purpose of this study was to characterize the amplifier cells with respect to their surface and functional properties and, in so doing, determine whether or not the amplifier cells are analogous to long-lived memory cells. We demonstrated that the amplifier cells were nylon-wool-nonadherent, antigen-specific, CD4 (L3T4+ Lyt-2-) T lymphocytes which appear in the spleens of mice 5 days postimmunization with cryptococcal culture filtrate antigen in complete Freund adjuvant. The amplifier T (Tamp) cells are not considered to be memory cells because they are relatively short-lived, being present 14 but not 18 days after the stimulating immunization. Moreover, the amplified anticryptococcal DTH response does not fulfill the criteria of the typical secondary immune (anamnestic) response in that the amplified response does not appear early relative to the appearance of the primary anticryptococcal DTH response, and it does not persist longer than the primary DTH response. We speculate that Tamp cells are not long-lived memory cells but rather act in a T-helper cell capacity to amplify the anticryptococcal DTH response.

Animals↗
PubMed1989

Effects of cyclosporin A on the cells responsible for the anticryptococcal cell-mediated immune response and its regulation.

Cyclosporin A (CsA), a potent immunosuppressive drug, was used to explore further the induction, expression, and regulation of lymphoid cells involved in the delayed-type hypersensitivity (DTH) response to cryptococcal antigen(s). We found that the induction of the cells responsible for DTH (TDH cells) was not affected by CsA, but their expression was inhibited in CsA-treated mice. The inhibition of expression of the TDH cells could not be attributed to the Cryptococcus neoformans-specific suppressor T (Ts) cells, even though the Ts cells were induced in CsA-treated mice. Instead, the suppressed expression of the TDH cells in CsA-treated mice was a direct effect of CsA or its products. Our studies with CsA also resulted in the first identification of a population of cells that significantly amplify the anticryptococcal DTH response. The amplifier cells were induced in mice that were given a primary immunizing dose of cryptococcal antigen in complete Freund adjuvant, and they amplified the anticryptococcal DTH response in recipient mice when they were transferred at the time of immunization of the recipient. The amplifier cell population was distinct from the TDH cells in that CsA inhibited the production of the amplifying cells but did not affect the induction of TDH cells. Amplification of the DTH response was a cell-mediated event, since cells but not serum from immunized mice mediated the amplified response in recipient mice. Thus, CsA enabled us to characterize anticryptococcal TDH and Ts cells further and to add to the immune cell circuit of the cryptococcal system a distinct population of cells that amplifies the anticryptococcal DTH response.

Animals↗
PubMed1989

Clearance of Cryptococcus neoformans from immunologically suppressed mice.

To assess the effects of cryptococcal antigen-induced immunosuppression on a Cryptococcus neoformans infection, CBA/J mice were injected intravenously with saline or suppressive doses of cryptococcal antigen (CneF) at weekly intervals and were then infected with viable C. neoformans cells. By the second week after infection, the cryptococcal antigen-injected mice had suppressed anticryptococcal delayed-type hypersensitivity (DTH) responses compared with the responses of the saline-treated, infected control mice. In addition, the immunosuppressed mice had higher numbers of cryptococcal CFU cultured from their lungs, livers, spleens, lymph nodes, and brains than did the control animals. A direct correlation of suppression of the anticryptococcal DTH response and reduced clearance of cryptococci from tissues was also observed after mice were given a single intravenous injection of CneF and infected. To determine whether or not the cryptococcal antigen was specifically reducing the clearance of C. neoformans or had a more generalized effect, mice were injected with saline or suppressive doses of CneF, infected with Listeria monocytogenes, and then followed daily for 7 days for the clearance of L. monocytogenes from spleens and on day 7 for DTH reactivity to Listeria antigen. There were no differences between the saline- and CneF-treated mice with respect to anti-Listeria DTH responses or clearance of L. monocytogenes from spleens, indicating that CneF was not altering natural resistance mechanisms responsible for early clearance of L. monocytogenes, nor was the CneF influencing the induction of the acquired immune response which was responsible for the late clearance of the bacteria. Together, these data indicate that the specific suppression of this cell-mediated immune response induced by cryptococcal antigen reduces the ability of the animals to eliminate the homologous organism (C. neoformans) but not a heterologous infectious agent, such as L. monocytogenes.

Animals↗
PubMed1989

Murine natural killer cell interactions with a fungal target, Cryptococcus neoformans.

Earlier investigations have shown that murine natural killer (NK) cells bind to and inhibit the growth of the fungal pathogen Cryptococcus neoformans in vitro and in vivo. To define the stages of NK cell-mediated inhibition of C. neoformans growth and the requirements for the completion of these stages, the events which lead to cryptococcal growth inhibition were compared with those previously elucidated for NK cell-mediated tumor cell lysis. Our data indicate that NK cell-cryptococci binding is a distinct event that precedes inhibition; is temperature independent, although it is slowed at 4 degrees C; and is Mg2+ dependent. In contrast to binding, NK cell-mediated cryptococcal growth inhibition is temperature, Mg2+, and Ca2+ dependent. The removal of Ca2+ by EDTA addition within 3 h after maximal NK cell-cryptococci binding significantly reduced cryptococcal growth inhibition, indicating that Ca2+ is required either late in the NK cell trigger stage or early in the inhibitory stage. These stages and requirements are similar to those previously demonstrated for the model of NK cell-mediated tumor cell lysis; however, the NK cell-cryptococci interactions are somewhat slower than the interactions which culminate in the lysis of the YAC-1 tumor cell targets. These results suggest that C. neoformans cells, although structurally distinct from the standard tumor cell targets, are capable of similar cell-to-cell interactions with NK effector cells as the tumor cell targets.

Animals↗
PubMed1989

Therapeutic versus traditional foster care: theoretical and practical distinctions.

This article explores the conceptual and practical differences between traditional and therapeutic foster care. Most important is that therapeutic foster care is linked to an emerging philosophy referred to as postmodernism. If this philosophical basis is not understood, the thrust of therapeutic foster care may be seriously misconstrued, and a community-based style of treatment may be destroyed.

Community Mental Health Services↗
PubMed1988

Impact of unusual gastrointestinal problems on the treatment of tricyclic antidepressant overdose.

We report the cases of two patients with tricyclic antidepressant overdose in which the use of charcoal was hampered by gastrointestinal abnormalities. In the first patient, a previous gastric bypass procedure impeded the placement of an orogastric tube and subsequent charcoal administration, while potentially facilitating rapid absorption of the drug--factors that may have contributed to her death. In the second patient, severe esophageal spasm delayed therapy until IV nitroglycerin relieved the functional obstruction. Both circumstances are previously unreported complications associated with tricyclic antidepressant overdose. Potentially corrective measures are proposed.

Adult↗
PubMed1988

Induction and expression of cell-mediated immune responses in inbred mice infected with Coccidioides immitis.

Comparisons of the course of coccidioidomycosis in two strains of inbred mice established that BALB/c mice are significantly more susceptible to pulmonary infection with Coccidioides immitis than are DBA/2 mice. The susceptibility of BALB/c mice does not reside in their inability to mount a delayed-type hypersensitivity response to C. immitis antigen. That is, BALB/c mice manifested footpad hypersensitivity to coccidioidin early during the course of disease, to a level comparable to that of DBA/2 mice. In contrast to the more resistant DBA/2 mouse strain, however, BALB/c mice developed anergy by day 15 postinfection. Suppression of the delayed-type hypersensitivity response was not specific for C. immitis antigen, as evidenced by the finding that BALB/c mice immunized with mycobacterial purified protein derivative prior to infection with C. immitis were suppressed in their footpad response to mycobacterial antigen at day 15 postinfection. Taken together, these results establish that genetically determined susceptibility to this fungus is associated with an acquired suppression of cell-mediated immune reactivity.

Animals↗
PubMed1988

Serological, electrophoretic, and biological properties of Cryptococcus neoformans antigens.

We compared a cryptococcal culture filtrate antigen referred to as CneF with chemically defined cryptococcal antigen fractions isolated by Cherniak and co-workers by using double immunodiffusion gels, polyacrylamide gel electrophoresis, immunoblots, and footpad reactivity of immunized mice. The three previously described components of cryptococcal culture filtrates are a high-molecular-weight glucuronoxylo-mannan (GXM), which is the major constituent, a galactoxylomannan (GaIXM), and a mannoprotein (MP). In this study we demonstrated that CneF contained components which were serologically and electrophoretically similar to the three previously described cryptococcal culture filtrate fractions. The MP fraction elicited significantly stronger delayed-type hypersensitivity responses than did the GXM or GaIXM fraction when used in mice immunized either with the CneF in complete Freund adjuvant or whole heat-killed Cryptococcus neoformans yeast cells. These findings were confirmed when the footpads of immunized mice were challenged with GaIXM and MP preparations from a culture filtrate of a C. neoformans acapsular mutant that does not produce GXM. Thus, we concluded that the MP was the primary component recognized by the anticryptococcal cell-mediated immune response in mice.

Antibodies, Fungal↗
PubMed1988

Induction of antigen-specific T suppressor cells by soluble Paracoccidioides brasiliensis antigen.

In naturally acquired paracoccidioidomycosis, patients have depressed in vivo and in vitro cell-mediated immune (CMI) responses to Paracoccidioides brasiliensis antigen. In addition, it has been reported that these patients have significant levels of circulating paracoccidioidal antigen in their sera. The primary purpose of this investigation was to assess the effects of P. brasiliensis antigen on the CMI responses in a mouse model. On the basis of findings with other fungal agents, we predicted that circulating paracoccidioidal antigen may be inducing suppressor cells which modulate the CMI response. In this study, we show (i) that a soluble P. brasiliensis culture filtrate antigen (Pb.Ag) emulsified in complete Freund adjuvant and injected subcutaneously into mice induces reasonably high levels of delayed-type hypersensitivity (DTH) in CBA/J mice; (ii) that Pb.Ag elicits DTH reactions specific for P. brasiliensis when injected into footpads of immunized mice; and (iii) that an intravenous injection of Pb.Ag induces a population of lymph node and spleen cells which, upon adoptive transfer, suppress the afferent limb of the DTH response to paracoccidioidal antigen. The afferent suppressor cells can be detected in spleens as early as 5 days after Pb.Ag treatment, are present in significant numbers by 7 days in both spleens and lymph nodes, and are virtually absent by 14 days. In contrast, at 14 days after antigen injection, efferent suppressor cells were detected in spleens and lymph nodes. The Pb.Ag-induced afferent suppressor cells specifically inhibit the antiparacoccidioidal DTH response. They are nylon wool-nonadherent cells, and their activity is abrogated by anti-Thy-1 and complement treatment, indicating that they are T lymphocytes. The phenotype of these afferent suppressor T cells is L3T4+ Lyt-1+2- I-J+. The Pb.Ag-specific suppressor cells described in this paper are similar to the Ts1 cells in the azobenzenearsonate, 4-hydroxy-3-nitrophenyl acetyl, and cryptococcal models of suppression of the DTH response and to the afferent suppressor cells in the dinitrofluorobenzene contact sensitivity system.

Animals↗
PubMed1988

Characterization of efferent T suppressor cells induced by Paracoccidioides brasiliensis-specific afferent T suppressor cells.

Previously, we reported that Paracoccidioides brasiliensis culture filtrate antigen (Pb.Ag) when injected i.v. into mice induces antigen-specific suppressor cells which down-regulate the anti-P. brasiliensis delayed-type hypersensitivity (DTH) response. The suppressor cells are present in both spleens and lymph nodes of Pb.Ag-treated animals and suppress the afferent limb but not the efferent limb of the DTH response to P. brasiliensis. The suppressor cells induced by Pb.Ag are L3T4+ Lyt-1+2- I-J+ T cells and are considered to be equivalent to the Ts1 cells described for other antigen-specific suppressor cell pathways. This report provides data which show that Ts1 cells induced by Pb.Ag or a soluble factor derived from Ts1 cells (TsF1) stimulates the production of second-order or efferent suppressor cells. The second-order suppressor cells are detectable in spleens and lymph nodes of mice 7 days after injection of Ts1 cells or TsF1 and are specific in suppressing the paracoccidioidal DTH response. In addition, the second-order suppressor cells are T cells with an L3T4- Lyt-2+ I-J+ phenotype and are effective in suppressing only the efferent limb of the P. brasiliensis DTH response. On the basis of the characteristics defined in this study, the paracoccidioidal second-order suppressor cells are equivalent to the Ts2 cells described for other antigen-specific suppressor-cell pathways. Thus, the suppressive circuit induced by Pb.Ag is similar to the suppressor-cell pathways that regulate the DTH responses to azobenzenearsonate, 4-hydroxy-3-nitrophenyl acetyl, lysozyme, and Cryptococcus neoformans antigen. We propose that such a suppressor-cell circuit as defined here with the murine model could be responsible for the depressed cell-mediated immune responses observed in paracoccidioidomycosis patients who have antigen circulating in their sera.

Animals↗
PubMed1988

Characterization of an in vitro-stimulated, Cryptococcus neoformans-specific second-order suppressor T cell and its precursor.

Using a cryptococcal culture filtrate antigen (CneF) in a murine model, we have demonstrated previously that a cascade of Cryptococcus neoformans-specific suppressor T cells and soluble factors function in suppressing the cryptococcal delayed-type hypersensitivity (DTH) response. In addition, we have successfully hybridized the C. neoformans-specific, first-order T-suppressor (Ts1) cell and have established that the culture supernatant (hTsF1) from this hybridoma induces second-order T-suppressor (Ts2) cells in vivo. Here we report the in vitro induction of expression-phase suppressor cells. The suppressor cells were induced by culturing nylon wool-nonadherent splenic cells from naive mice with hTsF1 in the absence of CneF. Nylon wool-nonadherent splenic cells similarly cultured with supernatants from the BW5147 thymoma cells, the fusion partners of the hybridoma, did not significantly suppress the cryptococcal DTH response. The suppressor cells were designated Ts2 cells based on their similarities in function, specificity, and phenotype, i.e. L3T4-, Lyt-2+, and I-J+, to the in vivo-induced Ts2 cells. By employing the in vitro culture technique, we demonstrated that the precursors of the functional Ts2 cells were L3T4- Lyt-1-2+ I-J- cells. The induction of Ts2 cells was not associated with [3H]thymidine incorporation; therefore, we concluded that hTsF1 induces the Lyt-2+ I-J- cells to differentiate into Lyt-2+ I-J+ functional Ts2 cells without a significant amount of proliferation. From the results of this study, a better understanding of the processes involved in the regulation of the DTH response to CneF was achieved. The in vitro culture technique will allow for further detailed studies of the interactions between the various cell populations and the Ts1 cell-derived soluble factor during the induction of Ts2 cells.

Animals↗
PubMed1988

Induction of antigen-specific suppression by circulating Cryptococcus neoformans antigen.

Immunoaffinity chromatography of sera from mice infected with Cryptococcus neoformans (Inf-MS) on a column with rabbit anti-cryptococcal antibody as the ligand resulted in the adsorption of the component(s) that induce suppression of the cryptococcal delayed-type hypersensitivity (DTH) response. In contrast, immunoaffinity chromatography of Inf-MS on columns coupled with cryptococcal antigen or goat anti-mouse IgM, IgG, and IgA did not adsorb the suppressive component(s). Quantification of cryptococcal antigen and anti-cryptococcal antibody in Inf-MS and column fractions established a direct correlation between cryptococcal antigen levels and suppressive activity; no correlation was observed between anti-cryptococcal antibody levels and suppressive activity. The suppression induced by Inf-MS was shown to be specific in that suppressive sera did not affect the induction of DTH responses to Listeria monocytogenes or dinitrofluorobenzene. These collective results provide evidence that cryptococcal antigen is the component in Inf-MS that induces antigen-specific suppression of the cell-mediated immune response to C. neoformans.

Animals↗
PubMed1987

Research note: Identifying "at risk" persons in community based research.

Since the passage of the U.S. 1963 Community Mental Health Act, all social planning is supposed to be community based. This means that policy research should be guided by the principle of community sensitivity, and not merely technical or logistical concerns. In this article the general tenets of community based research are outlined and applied to analyzing the currently controversial issue of what it means for a person or community to be clinically 'at risk'. Normally this topic is addressed in a purely technical manner, yet this approach must be altered if need identification is to be consistent with a community's own self-perception, thereby producing valid data.

Community Mental Health Services↗
PubMed1987

Characterization of a third-order suppressor T cell (Ts3) induced by cryptococcal antigen(s).

Previous studies from our laboratory have shown that a high dose of cryptococcal culture filtrate antigen (CneF) administered intravenously induces a complex suppressor cell cascade which down-regulates the cell-mediated immune response to Cryptococcus neoformans antigens. The primary objective of this investigation was to determine whether a suppressor cell induced by immunization is required for efferent suppression of the cryptococcal delayed-type hypersensitivity (DTH) response. Our approach to this problem was to immunize CBA/J mice with CneF emulsified in complete Freund adjuvant and then 6 days later to collect spleen cells from the immunized mice and adoptively transfer these cells along with C. neoformans-specific second-order suppressor T cells (Ts2) to naive syngeneic recipients at the time of footpad challenge of the recipients with CneF. To establish which populations of cells in the spleens of immunized mice play a suppressive role, mass cytolysis with specific antibodies and complement was performed before the spleen cells were transferred to naive animals. Since the phenotype of the cells responsible for the transfer of the cryptococcal DTH response had not been completely determined, we first demonstrated that the cells responsible for DTH were L3T4+ Lyt-2- cells. Subsequently, we established that a Thy-1+ L3T4- Lyt-2+ I-J+ cell population induced by immunization was required along with C. neoformans-specific Ts2 cells for efferent suppression of the cryptococcal DTH response. In addition, we demonstrated that the suppressor cells in the immune cell population were derived from cyclophosphamide-sensitive precursors. These data indicate that a third suppressor cell population is required for efferent suppression of the cryptococcal DTH response. As in the azobenzenearsonate and 4-hydroxy-3-nitrophenyl acetyl hapten suppressor models, the Ts2 cells in the circuit mediate their effects through this third suppressor component. Since the mode of induction and the phenotype of the third C. neoformans-specific suppressor cells are similar to those reported for Ts3 cells in other antigen-specific suppression models, we referred to this third suppressor cell in the C. neoformans-specific suppressor cell cascade as a Ts3 cell.

Animals↗
PubMed1986

Natural cellular resistance of beige mice against Cryptococcus neoformans.

Previous reports have demonstrated that natural killer (NK) cells are capable of inhibiting the growth of Cryptococcus neoformans in vitro, and recent studies indicate that adoptively transferred NK cell-enriched spleen cell populations enhance clearance of cryptococci from the tissues of cyclophosphamide-pretreated recipients. The primary objective of these studies was to confirm that NK cells participate in early clearance of C. neoformans in vivo. Secondarily, the anti-cryptococcal activities of polymorphonuclear leukocytes and macrophages were examined. Seven-week-old C57BL/6 bg/+ mice, which have normal levels of NK cell activity, were compared with their bg/bg littermates, which have impaired NK cell function. One and 3 days after injecting both groups of mice i.v. with 2 X 10(4) cryptococci, we assessed the NK cell activities in spleens, lungs, and livers and clearance of the organism from corresponding tissues as determined by the mean log10 numbers of cryptococcal colony-forming units (CFU) per organ. Three days postinfection, the mean numbers of cryptococcal CFU in lungs and spleens of bg/+ mice were significantly lower than in the corresponding organs of bg/bg mice. NK cell activities in spleens and lungs of bg/+ mice were significantly higher than were the NK cell activities in similar cell populations from bg/bg mice. In contrast, the mean numbers of cryptococcal CFU in livers of the two groups of animals were nearly equivalent, a situation not unexpected, since liver NK cell activities were extremely low and similar in both groups of animals. Although these data indicated a correlation between early clearance of cryptococci from tissues and levels of NK cell activities in the corresponding tissues, it was also possible that differences in phagocytic cell function between the bg/+ and bg/bg animals could account for the observed differences in clearance of cryptococci from the tissues. Therefore, phagocytic cells from the two groups of animals were compared with respect to their abilities to phagocytize and inhibit the growth of cryptococci and to their abilities to respond to chemotactic stimuli in vivo. Peritoneal PMNL from bg/+ and bg/bg mice were similar in their abilities to phagocytize and inhibit the growth of cryptococci, as well as in their chemotactic responses to viable cryptococci or sodium caseinate. In addition, there were no differences in splenic macrophage functions between the two groups of mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Uncompensated care by hospitals or public insurance for the poor. Does it make a difference?

Results from two recent surveys of access to medical care, one nationwide and the other in Arizona, were analyzed to determine the consequences of reductions in Medicaid coverage for low-income Americans and the accompanying shift of responsibility for their health care to clinics and hospitals that provide uncompensated or subsidized care. The analysis indicated that in 1982, low-income persons received substantially less care from physicians if they resided in states without Medicaid programs or with only limited programs. In Arizona, the only state at the time without a Medicaid program, poor children saw physicians 40 percent less often, and poor rural residents saw physicians 22 percent less often, than poor residents of states with Medicaid programs; the proportion of poor Arizona residents refused care for financial reasons was almost double that in states with Medicaid programs. In addition, poor residents of states with the highest proportions of their low-income populations covered by Medicaid fared better than those in states with less extensive coverage. Moreover, poor elderly Americans were found to have comparable access to health care, regardless of where they lived, as a result of almost universal coverage under Medicare. Thus, this analysis suggests that the growing reliance on uncompensated care provided by hospitals and clinics may not be an effective substitute for public insurance and may adversely affect the health care received by the poor.

Adolescent↗