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Biomedical subjects

T J Powell

Publications and source records attributed to T J Powell.

At least 19 recordsLinked to original sources
PubMed2006

Vaccination with recombinant fusion proteins incorporating Toll-like receptor ligands induces rapid cellular and humoral immunity.

Recognition of specific pathogen associated molecular patterns (PAMPs) is mediated primarily by members of the Toll-like receptor (TLR) family. Stimulation through these receptors results in quantitative and qualitative changes in antigen presentation and cellular activation, thereby linking innate and adaptive immunity. Consequently, the incorporation of TLR-ligands into vaccines could result in more potent and efficacious vaccines. To test this hypothesis, we employed a recombinant fusion protein strategy using the TLR5 ligand flagellin fused to specific antigens to promote protective immunity. These purified recombinant fusion proteins demonstrated potent TLR5-specific NF-kappaB dependent activity in vitro. Immunization of mice with the recombinant-flagellin-OVA fusion protein STF2.OVA resulted in potent antigen-specific T and B cell responses that were equal to or better than responses induced by OVA emulsified in Complete Freund's adjuvant. These included rapid and consistent antigen-specific IgG(1) and IgG(2a) antibody responses that were detectable within 7 days of immunization, and the development of protective CD8 T cell responses. Moreover, the enhanced immunogenicity to OVA is dependant on the direct fusion to flagellin, as co-delivery of OVA with flagellin unlinked failed to augment antigen-specific responses in vivo. Similar results were obtained using a recombinant fusion protein comprised of flagellin and a novel polypetide sequence containing two immuno-protective epitopes derived from the Listeria monocytogenes antigens p60 and listeriolysin O. Animals immunized with this recombinant protein demonstrated significant antigen-specific CD8 T cell responses and protection upon challenge with virulent L. monocytogenes. We conclude that immunization with PAMP:antigen fusion proteins induce rapid and potent antigen-specific responses in the absence of supplemental adjuvants. Collectively our data demonstrate that PAMP:antigen fusion proteins offer significant promise for developing recombinant protein vaccines.

Animals↗
PubMed2001

Predictors of psychosocial outcomes for patients with mood disorders: the effects of self-help group participation.

This study examined the predictors of psychosocial outcomes (daily functioning and management of illness) for people with mood disorders. After controlling for demographic, severity of illness, and social support predictor variables, the study evaluated whether participation in self-help groups would predict improved psychosocial outcomes. Post-hospitalization data were examined for 144 mood disorder patients using hierarchic multiple regression. More education predicted improved daily functioning; self-help involvement and education predicted management of illness. The implications of these findings for providing recovery-oriented rehabilitation services are discussed.

Adolescent↗
PubMed2000

A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes.

This study identifies a dendritic cell (DC) subset that constitutively transports apoptotic intestinal epithelial cell remnants to T cell areas of mesenteric lymph nodes in vivo. Rat intestinal lymph contains two DC populations. Both populations have typical DC morphology, are major histocompatibility complex class II(hi), and express OX62, CD11c, and B7. CD4(+)/OX41(+) DCs are strong antigen-presenting cells (APCs). CD4(-)/OX41(-) DCs are weak APCs and contain cytoplasmic apoptotic DNA, epithelial cell-restricted cytokeratins, and nonspecific esterase (NSE)(+) inclusions, not seen in OX41(+) DCs. Identical patterns of NSE electrophoretic variants exist in CD4(-)/OX41(-) DCs, intestinal epithelial cells, and mesenteric node DCs but not in other DC populations, macrophages, or tissues. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL)-positive DCs and strongly NSE(+) DCs are present in intestinal lamina propria. Peyer's patches and mesenteric but not other lymph nodes contain many strongly NSE(+) DCs in interfollicular and T cell areas. Similar DCs are seen in the ileum and in T cell areas of mesenteric nodes in gnotobiotic rats. These results show that a distinct DC subset constitutively endocytoses and transports apoptotic cells to T cell areas and suggest a role for these DCs in inducing and maintaining peripheral self-tolerance.

Animals↗
PubMed2000

Chronic neurobehavioural effects of mercury poisoning on a group of Zulu chemical workers.

PRIMARY OBJECTIVE: To assess the nature and severity of reported neurobehavioural symptoms of mercury poisoning, in a group of Zulu chemical workers (n = 16), employed by a mercury processing plant, exposed to neurotoxic levels of mercury, 5 years after exposure. RESEARCH DESIGN: A group-control design was adopted, where the exposed group was matched for age, sex, race, occupational and educational background. METHOD/PROCEDURES: Both groups were administered a specially selected battery of psychometric tests to measure neuropsychological functioning. OUTCOME AND RESULTS: The exposed group had significantly impaired short term verbal and spatial memory, impaired sustained and divided attention, and impaired motor speed. They also suffered from elevated clinical levels of psychiatric symptomatology, including anxiety, depression and phobic avoidance, and neurological symptoms of tremor, weakness in the limbs, and excessive sweating. CONCLUSIONS: The exposed group suffered from varying degrees of permanent neuropsychological disability, which adversely affects their ability to work and be financially independent. Psychometric measures for monitoring cognitive symptoms are discussed.

Adult↗
PubMed2000

Psychiatrists' referrals to self-help groups for people with mood disorders.

The study examined psychiatrists' referrals to and support for participation in self-help groups by people with mood disorders. Massachusetts and Michigan psychiatrists with a special interest in patients with mood disorders were surveyed; the 278 respondents represented a 78 percent response rate. About three-fourths of the psychiatrists reported that they made referrals to and felt knowledgeable about self-help groups. However, less than half had self-help literature available or discussed self-help groups with their patients. Beliefs that a patient would gain a better understanding of the illness and would receive support after an episode of illness were positively related to support for self-help. Beliefs that the program was inappropriate and that it lacked professional oversight were negatively related.

Adult↗
PubMed1999

SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types.

SU5416, a novel synthetic compound, is a potent and selective inhibitor of the Flk-1/KDR receptor tyrosine kinase that is presently under evaluation in Phase I clinical studies for the treatment of human cancers. SU5416 was shown to inhibit vascular endothelial growth factor-dependent mitogenesis of human endothelial cells without inhibiting the growth of a variety of tumor cells in vitro. In contrast, systemic administration of SU5416 at nontoxic doses in mice resulted in inhibition of subcutaneous tumor growth of cells derived from various tissue origins. The antitumor effect of SU5416 was accompanied by the appearance of pale white tumors that were resected from drug-treated animals, supporting the antiangiogenic property of this agent. These findings support that pharmacological inhibition of the enzymatic activity of the vascular endothelial growth factor receptor represents a novel strategy for limiting the growth of a wide variety of tumor types.

3T3 Cells↗
PubMed1999

Growth inhibition of psoriatic keratinocytes by quinazoline tyrosine kinase inhibitors.

Psoriasis is characterized by hyperproliferation of keratinocytes associated with an inflammatory infiltrate in the epidermis. Among factors which may be related to hyperplasia of psoriatic keratinocytes is the persistent autocrine stimulation of the epidermal growth factor receptor (EGFR) by transforming growth factor-alpha. Owing to the pivotal role of the EGFR in driving the growth of human psoriatic keratinocytes, we examined two selective inhibitors of EGFR kinase activity: 4-(3-bromophenylamino)-6, 7-dimethoxyquinazoline (AG1517/SU5271) and 4-(3-chlorophenylamino)-6, 7-dimethoxyquinazoline (AG1478) on psoriatic keratinocytes. SU5271 potently inhibits ligand-induced autophosphorylation of EGFR, and downstream signal transduction events, including DNA replication and cell cycle progression. SU5271, at micromolar concentrations, inhibited the proliferation of keratinocytes isolated from psoriatic lesions in excellent correlation with its EGFR kinase inhibitory activity in these cells. Biologically active concentrations of SU5271 penetrated human cadaver skin, suggesting that this compound is a strong candidate as an antipsoriatic agent.

Animals↗
PubMed1999

Recommended default methodology for analysis of airborne exposures to mixtures of chemicals in emergencies.

Emergency planning and hazard assessment of Department of Energy (DOE) facilities require consideration of potential exposures to mixtures of chemicals released to the atmosphere. Exposure to chemical mixtures may lead to additive, synergistic, or antagonistic health effects. In the past, the consequences of exposures to each chemical have been analyzed separately. This approach may not adequately protect the health of persons exposed to mixtures. This article presents default recommendations for use in emergency management and safety analysis within the DOE complex where potential exists for releases of mixtures of chemicals. These recommendations were developed by the DOE Subcommittee on Consequence Assessment and Protective Actions (SCAPA). It is recommended that hazard indices (e.g., HIi = Ci/Limiti, where Ci is the concentration of chemical "i") be calculated for each chemical, and unless sufficient toxicological knowledge is available to indicate otherwise, that they be summed, that is, sigma i(n) = 1HIi = HI1 + HI2 + ... + HIn. A sum of 1.0 or less means the limits have not been exceeded. To facilitate application of these recommendations for analysis of exposures to specific mixtures, chemicals are classified according to their toxic consequences. This is done using health code numbers describing toxic effects by target organ for each chemical. This methodology has been applied to several potential releases of chemicals to compare the resulting hazard indices of a chemical mixture with those obtained when each chemical is treated independently. The methodology used and results obtained from analysis of one mixture are presented in this article. This article also demonstrates how health code numbers can be used to sum hazard indices only for those chemicals that have the same toxic consequence.

Air Pollutants↗
PubMed1999

Attitudes of AA contact persons toward group participation by persons with a mental illness.

Alcoholics Anonymous groups are underused by persons with the dual diagnoses of mental illness and substance use disorder, and mental health professionals are cautious about referring them to AA because of fears that the AA group will discourage them from taking prescribed medication. The study assessed the attitudes of 125 AA contact persons about the participation of persons with mental illness. The majority had positive attitudes toward such persons, and 93 percent indicated that they should continue taking their medication. Fifty-four percent felt that participation in a group especially for persons with a dual diagnosis would be more desirable than in a traditional AA group. However, such groups are often not available.

Alcoholics Anonymous↗
PubMed1997

Inhibition of platelet-derived growth factor-mediated signal transduction and tumor growth by N-[4-(trifluoromethyl)-phenyl]5-methylisoxazole-4-carboxamide.

Many reports have cited coexpression of platelet-derived growth factor (PDGF) and its receptors by tumor cells or cells supporting tumor growth, suggesting both autocrine and paracrine mechanisms for PDGF-mediated tumor growth. We found that a small organic molecule, N-[4-(trifluoromethyl)phenyl] 5-methylisoxazole-4-carboxamide (SU101, leflunomide), inhibited PDGF-mediated signaling events, including receptor tyrosine phosphorylation, DNA synthesis, cell cycle progression, and cell proliferation. SU101 inhibited PDGF-stimulated tyrosine phosphorylation of PDGF receptor (PDGFR) beta in C6 (rat glioma) and NIH3T3 cells engineered to overexpress human PDGFRbeta (3T3-PDGFRbeta). SU101 blocked both PDGF- and epidermal growth factor (EGF)-stimulated DNA synthesis. Previously, this compound was shown to inhibit pyrimidine biosynthesis by interfering with the enzymatic activity of dihydroorotate dehydrogenase. In the current study, EGF-stimulated DNA synthesis was restored by the addition of saturating quantities of uridine, whereas PDGF-induced DNA synthesis was not, suggesting that the compound demonstrated some selectivity for the PDGFR pathway that was independent of pyrimidine biosynthesis. Selectivity was further demonstrated by the ability of the compound to block the entry of PDGF-stimulated cells into the S phase of the cell cycle, without affecting cell cycle progression of EGF-stimulated cells. In cell growth assays, SU101 selectively inhibited the growth of PDGFRbeta-expressing cell lines more efficiently than it inhibited the growth of PDGFRbeta-negative cell lines. SU101 inhibited the s.c., i.p., and intracerebral growth of a panel of cell lines including cells from glioma, ovarian, and prostate origin. In contrast, SU101 failed to inhibit the in vitro or s.c. growth of A431 and KB tumor cells, both of which express EGF receptor but not PDGFRbeta. SU101 also inhibited the growth of D1B and L1210 (murine leukemia) cells in syngeneic immunocompetent mice, without causing adverse effects on the immune response of the animals. In an i.p. model of tumor growth in syngeneic immunocompetent mice, SU101 prevented tumor growth and induced long-term survivors in animals implanted with 7TD1 (murine B-cell hybridoma) tumor cells. Because PDGFRbeta was detected on most of the tumor cell lines in which in vivo growth was inhibited by SU101, these data suggest that SU101 is an effective inhibitor of PDGF-driven tumor growth in vivo.

3T3 Cells↗
PubMed1996

A follow-up study of patients hospitalized after minor head injury.

Minor head injury accounts for 95% of all head injury. In this study 62 patients, hospitalized after minor head injury, were assessed within 48 h, and invited to attend for review and retesting 3 months later. Thirty-five patients were followed up in this way and 11 more were interviewed over the telephone. There was significant improvement on all psychometric tests between initial evaluation and follow-up. Between 51% and 86% reported troublesome late post-concussional symptoms, of which headaches and tiredness were the most frequently reported symptoms. Length of post-traumatic amnesia (PTA) was related to severity of symptoms. Clinical levels of anxiety and stress were noted in approximately one-third of the whole group; 95% of the group had returned to work by 3 months with a mean absence rate of 9.4 days. The therapeutic implications of these results are discussed.

Adolescent↗
PubMed1995

Moloney leukemia virus-induced cell surface antigen mimicry by monoclonal antibodies.

We have investigated antigen-independent modulation of immune responses by monoclonal antibodies directed against both viral and nonviral antigens. BALB/c mice were immunized with monoclonal IgM (i.e. Ab1) specific for either Moloney murine leukemia virus-induced cell surface antigen (MCSA) or the hapten 2,4-dinitrophenyl (DNP). Injection with either Ab1 activated a functional idiotypic (Id) network as evidenced by production of both anti-Id (Ab2) antibodies and anti-anti-Id (Ab3) antibodies. A subset of induced Ab3 (designated Ab1'), exhibited specificity for antigen (virus or DNP). In mice immunized with anti-Id antibodies (Ab2), production of Ab3 and Ab1' was also observed. In the MCSA system, antibody-induced Ab1' responses were effective in protecting mice from tumor development upon subsequent challenge with live virus. Furthermore, antigen-independent modulation of immunity to both viral and nonviral antigens was found to be thymus-dependent. Similar findings in other viral systems suggest that antibody-induced activation of Id networks may prove a viable alternative vaccine strategy that can elicit antigen-specific responses, and in some cases protection, in the apparent absence of exposure to antigen.

Animals↗
PubMed1995

A tumor-derived protein which provides T-cell costimulation through accessory cell activation.

A recently described tumor-derived glycoprotein, designated 90K, has been shown to have positive effects on the generation of cytotoxic effector cells (NK/LAK) from human PBMC. To determine the mechanism of these effects, we have examined the effects of 90K on cytokine production by human PBMC. A culture of normal PBMC with 90K alone did not result in IL-2 secretion; however, in coculture with suboptimal doses of ConA, 90K increased IL-2 secretion by PBMC. Coculture of PBMC with 90K and ConA also resulted in increased production of the cytokines IL-1, IL-6, GM-CSF, and TNF alpha. T cells depleted of accessory cells failed to respond to ConA alone, 90K alone, or the combination of ConA and 90K, suggesting that this protein does not have a direct effect on T cells. However, 90K alone was sufficient to induce cytokine production by unfractionated PBMC (IL-1, IL-6, GM-CSF, and TNF alpha) or by CD14-enriched PBMC (IL-1 and IL-6). In addition, expression of ICAM-1 was increased on a human monocytic cell line cultured with purified 90K in the absence of any other stimulus. This 90K-induced upregulation of ICAM-1 expression was accompanied by an increased accessory function of the monocytes, demonstrated by their ability to support ConA-induced activation of peripheral blood T cells. Based on the current data, we propose a model in which 90K activates accessory cells, resulting in the secretion of cytokines and the expression of adhesion molecules, which in turn act as costimulatory signals for T-cell activation. Activated T cells then produce cytokines such as IL-2, which lead to a more vigorous cell-mediated immune response to tumor cells and virus-infected cells. Thus, 90K shows promise as an immunotherapeutic reagent for diseases such as cancer and viral infection.

Antigen-Presenting Cells↗
PubMed1994

The secreted tumor-associated antigen 90K is a potent immune stimulator.

Immunization of mice with conditioned media from human breast cancer cells yielded the monoclonal antibody SP-2, which recognized an antigen of approximately 90-95 kDa. This protein, designated 90K, was found to be present in the serum of healthy individuals and at elevated levels in the serum of subpopulations of patients with various types of cancer and AIDS. Here we report the primary structure of the SP-2 antigen and demonstrate its relationship to a family of proteins which carry a scavenger receptor cysteine-rich domain. Northern blot analysis of normal tissues, primary tumors, and tumor-derived cell lines indicates a broad expression spectrum of the 90K gene at widely varying levels. Functional characterization reveals stimulatory effects of 90K on host defense systems, such as natural killer cell and lymphokine-activated killer cell activity, and indicates that its immunostimulatory effects may be mediated through the induction of interleukin-2 and possibly other cytokines.

3T3 Cells↗
PubMed1993

Ontogeny of tolerogen-responsive lymphocytes following neonatal inoculation of class II disparate semiallogeneic cells.

Spleens of adult mice of the A strain background that were rendered tolerant as neonates of class II alloantigens only (A.TH tolerant of A.TL, A.TL tolerant of A.TH) contain large numbers of tolerogen-responsive T cells, many of which secrete IL-4, but not IL-2. Since these spleens also contain suppressor cells that can adoptively transfer skin allograft acceptance in vivo and can prevent generation of class II-specific cytotoxic T cells in vitro, it is important to determine the origins during postnatal development of these cells. Class II disparate, semiallogeneic haematopoietic cells were injected into newborn A.TH and A.TL mice. Periodically thereafter (1 to 60 days post-injection, but prior to challenge with a tolerogen-bearing skin graft), thymocytes and splenocytes from these mice were examined in vitro for tolerogen-specific reactivity in mixed lymphocyte reactions during which proliferation and IL-2 and IL-4 production were assayed. Within 24 hours of neonatal injection, the thymus and spleens of injected mice were profoundly depleted of tolerogen-responsive T cells. However, there was no commensurate loss of I-E-related V beta 5+ cells in the thymus of A.TH mice that received neonatal inoculations of I-E-bearing A.TL cells. During the ensuing weeks, tolerogen-responsive proliferative and IL-4-secreting T cells were detected in thymus and spleen. However, not until after the mice were more than 60 days of age were tolerogen-responsive cells able to secrete IL-2. Since physical clonal deletion of tolerogen-related V beta 5+ cells is a characteristic of neither neonatal nor adult A.TH and A.TL mice that received injections of semiallogeneic cells at birth, and since tolerogen-responsive IL-4 producing cells exist in adult mice that have permanently accepted (A.TH x A.TL)F1 skin grafts, our results imply that the tolerogen-responsive T cells detected in adult tolerant mice are descendants of the novel IL-4-producing T cells that arise in the thymus almost immediately after the tolerance conferring inoculum of semiallogeneic cells. The possible mechanisms responsible for generation of IL-4-producing, tolerogen-responsive T cells and the role of these cells in maintenance of tolerance of class II alloantigens are discussed.

Animals↗
PubMed1991

Influence of I-E expression on induction of neonatal transplantation tolerance.

Neonatal transplantation tolerance was one of the first experimental systems to reveal that tolerance could be achieved to non-self antigens in living animals. Functional and direct evidence (obtained by the use of monoclonal antibodies directed at T cell receptors specifically reactive with I-E molecules) confirm that tolerance is achieved, at least in part, via clonal elimination of developing thymocytes. In this report, we show that induction of tolerance of class I alloantigens in neonatal mice is governed by expression of I-E molecules. Neonatal I-E non-expressor mice proved to be highly resistant to the acquisition of class I tolerance if the donor inoculum expressed disparate class I antigens as well as I-E molecules. The spleens of the few class I-tolerant, I-E non-expressor mice that were generated were found to be depleted of I-E-reactive (RR315+) T cells, whereas no such depletion was observed in their neonatally injected, but non-tolerant littermates. By contrast we found no resistance to tolerance of I-A alloantigens when neonatal I-E non-expressor mice received injections of I-A-disparate, I-E-bearing donor cells. In these tolerant mice, splenic I-E-reactive T cells were readily detected in apparently normal amounts. These results indicate that lack of I-E expression in newborn mice confers resistance to tolerance induction to class I alloantigens, especially when the latter are expressed on donor cells that also display I-E molecules. The possible mechanisms operating to produce resistance to tolerance induction in neonatal mice are discussed, including the possibilities that (a) I-E may act as a restricting element during tolerance induction (an ontogenic process), and (b) the expression of I-E on H-2-disparate, I-E-expressing test skin allografts may provide a source of "help" for CD8+ cytotoxic T cell precursors, leading to graft rejection.

Animals↗
PubMed1991

Self-help research and the public mental health system.

Discusses views of self-help leaders, researchers, and policy makers from the public mental health system about collaborative research with self-help groups. Topics include assumptions underlying collaborative research, barriers to collaborative research, and the potential benefits of collaborative research. Special attention is given to the rationale and methods for including minorities in self-help research. Initial discussions were held at a meeting convened by the NIMH-funded Center for Self-Help Research and Knowledge Dissemination at the University of Michigan.

Community Mental Health Services↗