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B Sherry

Publications and source records attributed to B Sherry.

At least 37 records · Page 2Linked to original sources
PubMed1998

Induction of the chemokine beta peptides, MIP-1 alpha and MIP-1 beta, by lipopolysaccharide is differentially regulated by immunomodulatory cytokines gamma-IFN, IL-10, IL-4, and TGF-beta.

The macrophage occupies a central role in the host response to invasion, exerting its control over the developing inflammatory response largely through the elaboration of an assortment of endogenous mediators including many cytokines. The beta chemokine peptides, macrophage inflammatory protein [MIP]-1 alpha and MIP-1 beta, are two such effectors markedly up-regulated in macrophages following exposure to bacterial lipopolysaccharide (LPS). These highly homologous peptides, like the other members of the beta chemokine family, exhibit diverse but partially overlapping biological activity profiles, suggesting that the cellular participants and intensity of an inflammatory response may in part be regulated by selective expression of these chemokines. Studies reported here demonstrate that, in contrast to the "balanced" MIP-1 alpha/MIP-1 beta chemokine responses of LPS-stimulated macrophage cultures in vitro, circulating levels of MIP-1 beta are significantly higher than those of MIP-1 alpha following LPS administration in vivo. Further studies have revealed that several immunomodulatory cytokines known to be up-regulated in vivo as a consequence of exposure to an invasive stimulus (gamma-IFN, IL-10, IL-4, and transforming growth factor [TGF]-beta) down-regulated the LPS-induced release of MIP-1 alpha by macrophages in vitro, but spared the MIP-1 beta response. This altered pattern of secretion may explain, at least in part, the high circulating levels of MIP-1 beta relative to MIP-1 alpha observed in vivo in response to LPS challenge.

Animals↗
PubMed1997

A mechanism for selective recruitment of CD8 T cells into B7-1-transfected plasmacytoma: role of macrophage-inflammatory protein 1alpha.

An important aspect of immunity is the recruitment and accumulation of lymphocytes into target tissues where Ags are localized. Because the TCR recognizes antigenic peptides presented by MHC molecules, the subset of T cells that exert effector function is determined by the class of MHC molecules expressed on a given tissue. We and others have demonstrated that CD8 T cells are preferentially recruited into B7-1-transfected class II-negative plasmacytoma J558, and the virus-infected central nervous system. However, the mechanism for such specificity has not been addressed. Here we analyzed the mechanism for selective recruitment of CD8 T cells into B7-1-transfected plasmacytoma J558. We show that sustained accumulation of CD8 T cells in vivo requires local expression of B7-1. In addition, we have observed a striking correlation between expression of macrophage-inflammatory protein 1alpha (MIP1alpha) and selective accumulation of CD8 T cells in the tumors. The selective recruitment of CD8 T cells is blocked by in vivo administration of neutralizing anti-MIP1alpha antisera. Moreover, gene-transfer studies reveal that locally produced MIP1alpha is sufficient to induce selective recruitment of CD8 T cells. Taken together, our study reveals that costimulation by B7 leads to sustained local production of MIP1alpha, which selectively recruits CD8 T cells into tumors. These results have important implications for T cell recruitment in vivo and for tumor immunotherapy.

Animals↗
PubMed1997

Construction and characterization of a reovirus double temperature-sensitive mutant.

The infectious reovirus RNA system was used to construct a mutant with two temperature-sensitive (ts) lesions in genome segments M2 and S2, respectively. The double mutant is about 300 times more ts than either of its parents, which are about 1,500 and 170 times more ts than their wild-type parent reovirus ST3 strain Dearing. At 39 degrees C the double mutant is essentially unable to multiply. In spite of its striking temperature sensitivity, the double mutant elicits the formation of significant amounts of neutralizing antibodies in newborn mice. Possible mechanisms responsible for this are discussed, as is the significance of this double ts mutant in relation to current searches for safe and efficient vaccine strains.

Animals↗
PubMed1997

Spermine inhibits proinflammatory cytokine synthesis in human mononuclear cells: a counterregulatory mechanism that restrains the immune response.

The local production of proinflammatory cytokines mediates the host response to inflammation, infection, and injury, whereas an overexpression of these mediators can injure or kill the host. Recently, we identified a class of multivalent guanylhydrazone compounds that are effective inhibitors of proinflammatory cytokine synthesis in monocytes/macrophages. The structure of one such cationic molecule suggested a molecular mimicry with spermine, a ubiquitous endogenous biogenic amine that increases significantly at sites of inflammation and infection. Here, we addressed the hypothesis that spermine might counterregulate the innate immune response by downregulating the synthesis of potentially injurious cytokines. When spermine was added to cultures of human peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS), it effectively inhibited the synthesis of the proinflammatory cytokines tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, MIP-1alpha, and MIP-1beta. The inhibition of cytokine synthesis was specific and reversible, with significant inhibition of TNF synthesis occurring even when spermine was added after LPS. The mechanism of spermine-mediated cytokine suppression was posttranscriptional and independent of polyamine oxidase activity. Local administration of spermine in vivo protected mice against the development of acute footpad inflammation induced by carrageenan. These results identify a distinct molecular counterregulatory role for spermine in downregulating the monocyte proinflammatory cytokine response.

Animals↗
PubMed1997

Chemokines are expressed in a myeloid cell-dependent fashion and mediate distinct functions in immune complex glomerulonephritis in rat.

Using anti-glomerular basement membrane nephritis in rats, we investigated the mechanisms underlying in situ chemokine expression and the in vivo function of these cytokines during the acute phase of this model. We observed that CXC chemokine expression was monophasic and paralleled neutrophil (PMN) influx, whereas CC chemokine expression was biphasic with peaks coinciding with the influx of PMNs and macrophages (Mphi). The initial peak of chemokine expression was attenuated by decomplementation, neutropenia, and leukopenia, while the latter peak was attenuated only by leukopenia and augmented in the accelerated form of this disease model, corresponding to an increase in Mphi influx. Differential expression of chemokines by PMNs and Mphi was not an intrinsic property of these cells, as these leukocytes expressed similar profiles of chemokines in vitro. Immunostaining for Mphi inflammatory protein-1alpha, a CC chemokine, in acute nephritis validated that expression during acute nephritis was accompanied by local protein production. Moreover, neutralizing Ab to Mphi inflammatory protein-1alpha attenuated the acute phase proteinuria, but not the accompanying influx of PMNs. Neutralizing Ab to cytokine-induced neutrophil chemoattractant (a CXC chemokine), in comparison, inhibited both PMN influx and proteinuria. A combination of both Abs was not significantly more effective than either alone. In sum, the influx of myeloid cells is necessary for local chemokine expression in anti-glomerular basement membrane nephritis, although the differential expression of CXC and CC chemokines must involve additional factors. CXC and CC chemokines also mediate distinct, but overlapping, pathophysiologic roles in the acute phase of this model.

Acute-Phase Reaction↗
PubMed1997

High sensitivity polymerase chain reaction assay for active and latent feline herpesvirus-1 infections in domestic cats.

A polymerase chain reaction (PCR) assay was developed and used to detect feline herpesvirus-1 (FHV-1) in conjunctival and oropharyngeal swabs, and in latently infected tissues (trigeminal ganglia, optic nerves, optic chiasma, olfactory bulbs and corneas) collected from 10 experimentally infected cats. There was good agreement between parallel tests of the swab specimens by PCR and virus isolation assay during the phase of acute, latent and recurrent disease episodes (kappa = 0.63, P < 0.001). The PCR reliably detected < or = 240 copies of FHV-1 template DNA, significantly improving upon previously published PCR assays for the agent.

Animals↗
PubMed1997

Continuation of decline in prevalence of anemia in low-income children: the Vermont experience.

OBJECTIVE: To examine whether the prevalence of childhood anemia in white low-income children has continued to decline into the 1990s. DESIGN: An examination of 14 years of hematocrit data from the Centers for Disease Control and Prevention's Pediatric Nutrition Surveillance System in Vermont from 1981 through 1994. SETTING: Public health clinics for the Special Supplemental Nutrition Program for Women, Infants, and Children in Vermont. The same screening method and criteria for identifying and defining anemia and the same quality-assurance procedures were used during the 14 years. The program eligibility criteria were also consistent except for part of 1991 and 1992. MAIN OUTCOME MEASURE: The annual prevalence of anemia. RESULTS: Between 1981 and 1994, the prevalence of anemia halved (from 7.9% to 3.6%, P<.001). For children aged 6 to 24 months, this decline was from 7.8% to 4.6% (P<.001); for children aged 2 to 5 years, the decline was from 7.9% to 3.1% (P<.001). CONCLUSION: The decline in the prevalence of anemia among low-income children observed by the Centers for Disease Control and Prevention's Pediatric Nutrition Surveillance System up to the mid-1980s has continued into the 1990s in Vermont. This finding indicates that iron nutrition in infancy and early childhood is still improving.

Anemia↗
PubMed1997

Effect of a live attenuated intranasal vaccine on latency and shedding of feline herpesvirus 1 in domestic cats.

A prospective study was conducted that evaluated duration of virus shedding through acute and experimentally-induced recurrent disease episodes in 12 cats, and tissue distribution of latent infections, following intranasal vaccination with a temperature sensitive (ts) mutant strain of feline herpesvirus 1 (FHV1). Six of these cats were challenged with a virulent field strain of the agent to assess the extent to which vaccination affected subsequent shedding of virus and the establishment of latent infections. Virus isolation (VI) tests were done in parallel with a polymerase chain reaction (PCR) assay to compare the performance of each diagnostic method. The PCR confirmed that all 12 cats shed virus throughout the periods of vaccination, challenge or mock-challenge, and a cyclophosphamide-dexamethasone stress protocol to reactivate latent infections. Shedding to the tsFHV1 was documented by VI for up to 25 days following vaccination and for up to 15 days following challenge, but not after experimental stress. Overall, FHV1 was present in 144 of 300 (48%) cat-days of testing by PCR compared to 32 of 300 (11%) by VI. The frequency and distribution of latent FHV1 detected in neurologic, ophthalmic, and other tissues by PCR were identical for vaccine-only and vaccine-challenge groups, thereby disproving previous hypotheses that tsFHV1 mutants administered by this route protect against latency.

Administration, Intranasal↗
PubMed1997

The critical role of p38 MAP kinase in T cell HIV-1 replication.

BACKGROUND: Replication of HIV-1 in human T lymphocytes requires the activation of host cellular proteins. This study identifies p38 mitogen-activated protein kinase (MAPK) as one such kinase necessary for HIV-1 replication in T cells. MATERIALS AND METHODS: Primary human T lymphocytes were infected with the LAI strain of HIV-1 and Jurkat cells were infected with the RF strain of HIV-1. HIV replication was measured by reverse transcriptase activity. Cellular expression of endogenous p38 MAPK protein was analyzed using immunoprecipitation. Blockade of p38 MAPK expression was achieved using antisense oligonucleotides to p38 MAPK and the guanylhydrazone compound CNI-1493, an inhibitor of p38 MAPK activation. RESULTS: HIV-1 infection of both primary human T lymphocytes and a T cell line rapidly activated the cellular p38 MAPK pathway, which remained activated for the duration of the culture. Addition of phosphothioated antisense oligonucleotides to p38 MAPK specifically inhibited viral replication. Blockade of p38 MAPK activation by addition of CNI-1493 also inhibited HIV-1 viral replication of primary T lymphocytes in a dose- and time-dependent manner. Stimulation of p38 MAPK activation did not occur with the addition of heat-inactivated virus, suggesting that viral internalization, and not just membrane binding, is necessary for p38 MAPK activation. CONCLUSIONS: These results indicate that activation of the p38 MAPK cascade is critical for HIV-1 replication in primary T lymphocytes, and that blockade of this signal transduction pathway may be a novel therapeutic approach to the treatment of HIV-1 infection.

Blotting, Western↗
PubMed1996

Mechanism of suppression of cell-mediated immunity by measles virus.

The mechanisms underlying the profound suppression of cell-mediated immunity (CMI) accompanying measles are unclear. Interleukin-12 (IL-12), derived principally from monocytes and macrophages, is critical for the generation of CMI. Measles virus (MV) infection of primary human monocytes specifically down-regulated IL-12 production. Cross-linking of CD46, a complement regulatory protein that is the cellular receptor for MV, with antibody or with the complement activation product C3b similarly inhibited monocyte IL-12 production, providing a plausible mechanism for MV-induced immunosuppression. CD46 provides a regulatory link between the complement system and cellular immune responses.

Antibodies, Monoclonal↗
PubMed1996

Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone.

An overproduction of proinflammatory cytokines by activated macrophages/monocytes mediates the injurious sequelae of inflammation, septic shock, tissue injury, and cachexia. We recently synthesized a tetravalent guanylhydrazone compound (CNI-1493) that inhibits cytokine-inducible arginine transport and nitric oxide (NO) production in macrophages, and protects mice against lethal endotoxemia and carrageenan-induced inflammation. During these investigations we noticed that CNI-1493 effectively prevented lipopolysaccharide (LPS)-induced NO production, even when added in concentrations 10-fold less than required to competitively inhibit L-arginine uptake, suggesting that the suppressive effects of this guanylhydrazone compound might extend to other LPS-induced responses. Here, we report that CNI-1493 suppressed the LPS-stimulated production of proinflammatory cytokines (tumor necrosis factor [TNF], interleukins 1beta and 6, macrophage inflammatory proteins 1alpha and 1beta) from human peripheral blood mononuclear cells. Cytokine suppression was specific, in that CNI-1493 did not inhibit either the constitutive synthesis of transforming growth factor beta or the upregulation of major histocompatibility complex class II by interferon gamma (IFN-gamma). In contrast to the macrophage suppressive actions of dexamethasone, which are overridden in the presence of IFN-gamma, CNI-1493 retained its suppressive effects even in the presence of IFN-gamma. The mechanism of cytokine-suppressive action by CNI-1493 was independent of extracellular L-arginine content and NO production and is not restricted to induction by LPS. As a selective inhibitor of macrophage activation that prevents TNF production, this tetravalent guanylhydrazone could be useful in the development of cytokine-suppressive agents for the treatment of diseases mediated by overproduction of cytokines.

Animals↗
PubMed1996

Human immunodeficiency virus type 1 infection alters chemokine beta peptide expression in human monocytes: implications for recruitment of leukocytes into brain and lymph nodes.

Two chemokine (chemoattractant cytokines) beta peptides, macrophage inflammatory proteins 1 alpha and 1 beta (MIP-1 alpha and MIP-1 beta), were induced in human monocyte cultures following infection with the human immunodeficiency virus type 1 (HIV-1). Induction depended on productive viral infection: not only did the kinetics of MIP-1 peptide induction closely follow those of viral replication, but monocyte cultures inoculated with heat-inactivated virus or infected in the presence of AZT failed to produce these chemokine beta peptides. In addition, HIV infection markedly altered the pattern of beta chemokine expression elicited by tumor necrosis factor (TNF), itself a potent proinflammatory cytokine upregulated during the development of AIDS. Reverse transcription (RT)-PCR and RT-in situ PCR studies on brain tissue from patients with AIDS dementia demonstrated elevated MIP-1 alpha and MIP-1 beta mRNA expression relative to comparable samples from HIV-1-infected patients without dementia. Cells expressing chemokines in HIV-1-infected brains were identified morphologically as microglia and astrocytes. As MIP-1 alpha and MIP-1 beta are potent chemoattractants for both monocytes and specific subpopulations of lymphocytes, this dysregulation of beta chemokine expression may influence the trafficking of leukocytes during HIV infection. These data, taken together, suggest a mechanism by which HIV-1-infected monocytes might recruit uninfected T cells and monocytes to sites of active viral replication or inflammation, notably the brain and lymph nodes.

AIDS Dementia Complex↗
PubMed1996

Reovirus-induced acute myocarditis in mice correlates with viral RNA synthesis rather than generation of infectious virus in cardiac myocytes.

The capacity for different reovirus reassortant viruses to induce acute myocarditis in mice correlates with cytopathogenic effect in primary cultures of murine cardiac myocytes. Multiple viral genes encoding proteins involved in viral RNA synthesis are determinants of this disease. We therefore evaluated the role of viral RNA synthesis in induction of acute myocarditis by infecting primary cultures of cardiac myocytes with a panel of myocarditic and nonmyocarditic viruses and quantitating RNA synthesis. RNA synthesis correlated with induction of myocarditis and with the S1 and M1 reovirus genes. Since one consequence of viral RNA synthesis is generation of infectious virus, we looked next at viral yield from cardiac myocyte cultures. Yield of infectious virus at an early time postinfection or as a final yield from primary infections did not correlate with myocarditis, but instead both correlated with the S1 gene. The S1 gene also determined the fraction of cells infected during primary infections in the culture, which varied dramatically between viruses. Viral yields per infected cell were similar for most myocarditic and nonmyocarditic reoviruses and did not correlate with induction of myocarditis or any reovirus gene. Together, the data provide two insights into reovirus-induced acute myocarditis in mice. First, while the S1 gene. which encodes the viral attachment protein sigma1 (as well as a nonstructural protein, sigma1s, of unknown function) does not determine the myocarditic potential of these viruses, it does determine the efficiency with which they infect cardiac myocytes. Second, while viral RNA synthesis is a determinant of acute myocarditis, this is not due to generation of infectious virus. This finding suggests that some other consequence of viral RNA synthesis, for example, induction of interferon, may determine reovirus-induced acute myocarditis.

Acute Disease↗
PubMed1996

A critical role of nitric oxide in human immunodeficiency virus type 1-induced hyperresponsiveness of cultured monocytes.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) infection leads to a general exhaustion of the immune system. Prior to this widespread decline of immune functions, however, there is an evident hyperactivation of the monocyte/macrophage arm. Increased levels of cytokines and other biologically active molecules produced by activated monocytes may contribute to the pathogenesis of HIV disease both by activating expression of HIV-1 provirus and by direct effects on cytokine-sensitive tissues, such as lung or brain. In this article, we investigate mechanisms of hyperresponsiveness of HIV-infected monocytes. MATERIALS AND METHODS: The study was performed on monocyte cultures infected in vitro with a monocytetropic strain HIV-1ADA. Cytokine production was induced by stimulation of cultures with lipopolysaccharides (LPS) and measured by ELISA. To study involvement of nitric oxide (NO) in the regulation of cytokine expression, inhibitors of nitric oxide synthase (NOS) or chemical donors of NO were used. RESULTS: We demonstrate that infection with HIV-1 in vitro primes human monocytes for subsequent activation with LPS, resulting in increased production of pro-inflammatory cytokines tumor necrosis factor (TNF) and interleukin 6 (IL-6). This priming effect can be blocked by Ca(2+)-chelating agents and by the NOS inhibitor L-NMMA, but not by hemoglobin. It could be reproduced on uninfected monocyte cultures by using donors of NO, but not cGMP, together with LPS. CONCLUSIONS: NO, which is expressed in HIV-1-infected monocyte cultures, induces hyperresponsiveness of monocytes by synergizing with calcium signals activated in response to LPS stimulation. This activation is cGMP independent. Our findings demonstrate the critical role of NO in HIV-1-specific hyperactivation of monocytes.

Calcium↗
PubMed1995

Transferrin secretion by lens epithelial cells in culture.

Transferrin (Tf), the plasma iron transport protein which supports cell proliferation and differentiation and has bacteriostatic, antioxidant and anti-inflammatory activity, has been found in relatively high concentrations in the intraocular fluids. Intraocular synthesis of Tf has recently been demonstrated, although the intraocular tissue(s) responsible have not been identified. We designed this study to determine whether certain ocular tissues can make and secrete transferrin. Transferrin content of aqueous and vitreous humors and whole lenses was determined by ELISA. Transferrin secretion by cultured epithelia from lens and ciliary body was also measured. In addition, Northern blots of RNA from cultured lens epithelial cells, ciliary body pigmented and non-pigmented epithelial cells, and from whole iris, ciliary body and retina were probed with riboprobes for Tf mRNA and 18S rRNA. Transferrin made up 23% and 16% of total canine aqueous and vitreous protein. All ocular tissues and cultured cells tested contained mRNA for Tf, however Tf was secreted into the bathing medium from lens epithelial cell cultures, but not from either the pigmented or non-pigmented epithelial cells of the ciliary body cultures, but not from either the pigmented or non-pigmented epithelial cells of the ciliary body Cycloheximide inhibited secretion of Tf from the lens epithelial cells. Lenses from inflamed eyes contained higher levels of Tf than their contralateral controls. This is the first experimental demonstration that an intraocular tissue can make and secrete Tf. Transferrin secretion by the lens may contribute significantly to the IOF content of this important intraocular protein.

Animals↗
PubMed1995

An inhibitor of macrophage arginine transport and nitric oxide production (CNI-1493) prevents acute inflammation and endotoxin lethality.

BACKGROUND: Nitric oxide (NO), a small effector molecule produced enzymatically from L-arginine by nitric oxide synthase (NOS), is a mediator not only of important homeostatic mechanisms (e.g., blood vessel tone and tissue perfusion), but also of key aspects of local and systemic inflammatory responses. Previous efforts to develop inhibitors of NOS to protect against NO-mediated tissue damage in endotoxin shock have been unsuccessful, largely because such competitive NOS antagonists interfere with critical vasoregulatory NO production in blood vessels and decrease survival in endotoxemic animals. Accordingly, we sought to develop a pharmaceutical approach to selectively inhibit NO production in macrophages while sparing NO responses in blood vessels. MATERIALS AND METHODS: The process of cytokine-inducible L-arginine transport and NO production were studied in the murine macrophage-like cell line (RAW 264.7). A series of multivalent guanylhydrazones were synthesized to inhibit cytokine-inducible L-arginine transport. One such compound (CNI-1493) was studied further in animal models of endothelial-derived relaxing factor (EDRF) activity, carrageenan inflammation, and lethal lipopolysaccharide (LPS) challenge. RESULTS: Upon activation with cytokines, macrophages increase transport of L-arginine to support the production of NO by NOS. Since endothelial cells do not require this additional arginine transport to produce NO, we reasoned that a competitive inhibitor of cytokine-inducible L-arginine transport would not inhibit EDRF activity in blood vessels, and thus might be effectively employed against endotoxic shock. CNI-1493, a tetravalent guanylhydrazone, proved to be a selective inhibitor of cytokine-inducible arginine transport and NO production, but did not inhibit EDRF activity. In mice, CNI-1493 prevented the development of carrageenan-induced footpad inflammation, and conferred protection against lethal LPS challenge. CONCLUSIONS: A selective inhibitor of cytokine-inducible L-arginine transport that does not inhibit vascular EDRF responses is effective against endotoxin lethality and significantly reduces inflammatory responses.

Animals↗
PubMed1994

Risk factors for dropping out of a parenting education program.

This study compared those who completed a clinic-based parenting program to dropouts in an attempt to identify risk factors for parents not completing the program. The program, aimed at mothers at risk for child maltreatment, was offered at three Seattle, Washington health centers providing comprehensive pediatric care to low-income families. We obtained baseline information from an intake questionnaire, the Nursing Child Assessment Teaching Scale (NCATS), and the Home Observation for Measurement of the Environment (HOME). Of the 172 enrollees, 124 (72%) completed the program. Univariate analyses showed that dropouts were more likely to be located at Clinic Site Three (42% vs. 10%, p < .001), teenaged (44% vs. 23%, p = .010), and African-American (56% vs. 32%, p = .010), and to have HOME scores less than 32 (57% vs. 33%, p = .023). There were no statistically significant differences between those who dropped out and those who didn't in marital status, education, referral rate to Child Protective Services prior to the start of parenting classes, or NCATS scores. Multivariate analyses showed that age less than 20 was significantly associated with dropping out when race and HOME scores were taken into account. There was significant interaction between age less than 20 and Clinic Site Three. These data suggest that program planners need to develop appropriate strategies to retain teenage mothers in parenting programs.

Adult↗