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Biomedical subjects

M Bigby

Publications and source records attributed to M Bigby.

At least 37 records · Page 2Linked to original sources
PubMed2000

Preliminary functional analysis of human epidermal T cells.

The function of human epidermal T cells (ETC) is unknown. In the present study, dermal T cells (DTC), ETC and keratinocytes were cultured from normal human skin. DTC and ETC lines were expanded in medium containing interleukin 2. The autologous keratinocytes were transfected with a human papillomavirus 16 E6 and E7 plasmid to produce an immortal keratinocyte line "HEK001". Lymphocyte migration and adhesion to HEK001 was assessed in calcein fluorimetric assays. ETC migrated towards HEK001 three to four times more than DTC. ETC adhered to HEK001 two to four times more than DTC. The proportion of ETC expressing the cutaneous lymphocyte-associated antigen was greater than that of DTC (26% and 1%, respectively). The keratinocyte line HEK001 expressed ICAM-1 following stimulation with TNF-alpha or IFN-gamma and following coculture with autologous cutaneous T cells. A blocking anti-ICAM-1 antibody reduced DTC and ETC adhesion to HEK001 by 30% and 50%, respectively. Therefore, cutaneous T cells may upregulate keratinocyte ICAM-1 expression which mediates adhesion to autologous keratinocytes. These results are consistent with the hypothesis that the ETC and DTC populations are distinct. Both directed migration (epidermotropism) and selective retention may be involved in the development and maintenance of the ETC population in normal human skin.

Antigens, CD↗
PubMed2000

Evidence-based medicine in dermatology.

EBM is the use of the best current evidence in making decisions about the care of individual patients. Practicing EBM requires five steps: (1) formulating well-built clinical questions, (2) finding the best evidence to answer the questions, (3) critically appraising the evidence, (4) applying the evidence to specific patients, and (5) saving the critically appraised evidence. The Cochrane Library is the best source for finding the best evidence about treatment. The second best method for finding evidence about treatment and the best source for finding most other types of best evidence in dermatology is by searching the MEDLINE database using the PubMed Clinical search engine of the National Library of Medicine (http://++www.ncbi.nlm.nih.gov/PubMed/clin ica l.html). MEDLINE searches have inherent software and operator limitations that make their reliability quite variable. The quality (strength) of evidence is based on a hierarchy of evidence: results of systematic reviews of well-designed clinical studies, results of one or more well-designed clinical studies, results of large case series, and expert opinion. Once the best evidence has been found, the EBM approach involves critically appraising the quality of the evidence, determining its magnitude and precision, and applying it to the specific patient. Guidelines to appraise critically and apply evidence are available. The clinical question, best evidence, and its critical appraisal should be saved in a format that can be easily retrieved for future use.

Dermatology↗
PubMed2000

Autocytotoxic T-cell clones in lichen planus.

We examined the in vitro cytotoxic activity of cutaneous T-cell lines and clones from lichen planus (LP) patients against autologous epidermal keratinocytes. T cells were cultured from LP lesions and adjacent clinically normal skin and cloned by limiting dilution. Keratinocytes were cultured from LP lesions and adjacent clinically normal skin and immortalized by transfection with the E6 and E7 genes from human papillomavirus 16 (HPV16). The lesional T-cell line from one LP patient contained 27% gammadelta+ T cells and was significantly more cytotoxic against autologous lesional keratinocytes than the T-cell line from clinically normal skin. Clones isolated from the lesional T-cell line were significantly more cytotoxic against autologous lesional keratinocytes than clones isolated from the non-lesional T-cell line. Most cytotoxic clones from LP lesions were CD8+ and most non-cytotoxic clones from LP lesions were CD4+. One cytotoxic clone was CD4- and CD8- and expressed the gammadelta T-cell receptor. Two CD8+ LP lesional T-cell clones showed dose-dependent killing of HPV16 E6/E7-immortalized autologous lesional and normal keratinocytes, but no cytotoxic activity against Epstein-Barr virus-transformed autologous B-cell blasts. The cytotoxic activity of CD8+ lesional T-cell clones against autologous lesional keratinocytes was partially blocked with anti-major histocompatibility complex (MHC) class I monoclonal antibodies. These data support the hypothesis that CD8+ lesional T cells recognize an antigen associated with MHC class I on lesional keratinocytes and that CD8+ cytotoxic T cells lyse keratinocytes in LP lesions.

Antibodies, Monoclonal↗
PubMed1998

Snake oil for the 21st century.

Dermatology has been associated with quackery for at least a century. The dictionary defines a quack as "a pretender to medical knowledge or skill; ignorantly or falsely pretending to cure." The term quack is derived from quacksalver, or one who quacks like a duck in promoting his salves. Quacksalvers hacked many potions, including snake oil, with claims that it cured everything from dermatitis to rheumatism. With the current promulgation of skin "products" and their promotion and even sale by dermatologists, and the use of treatments of no proven efficacy, this association between dermatology and quackery is set to continue well into the 21st century. The list of offending treatments includes silicone gel sheets and onion extract cream (Mederma) for keloids, alpha-hydroxy acid creams and peels, topical ascorbic acid and phytonadione, "laser resurfacing," and cimetidine for warts, to name only a few.

Clinical Trials as Topic↗
PubMed1998

Evidence-based medicine in a nutshell. A guide to finding and using the best evidence in caring for patients.

Evidence-based medicine is the use of the best current evidence in making decisions about the care of individual patients. Practicing EBM requires recognition that in most encounters with patients, questions arise that should be answered to provide the patient with the best available medical care. Asking well-built clinical questions that contain 4 elements--a patient or problem, an intervention, a comparison intervention (if necessary), and an outcome--is an important step in practicing EMB. Once appropriate questions have been formulated, the best source for finding most types of best evidence is by searching the MEDLINE database by computer. MEDLINE searches have inherent software and operator limitations that make their reliability quite variable. One should be aware of these limitations and improve one's skills in searching. The Cochrane Collaboration Controlled Clinical Trials Registry contains more than 190,000 controlled clinical trials and is the best source of evidence about treatment. The quality (strength) of evidence is based on a hierarchy of evidence: results of systematic reviews of well-designed clinical studies, results of 1 or more well-designed clinical studies, results of large case series, expert opinion, and personal experience. Once the best evidence has been found, the EBM approach involves critically appraising the quality of the evidence, determining its magnitude and precision, and applying it to the specific patient. Guidelines to critically appraise and apply evidence are available. The clinical question, best evidence, and its critical appraisal should be saved in a format that can be easily retrieved for future use.

Dermatology↗
PubMed1996

Understanding and evaluating clinical trials.

In this review, we attempt to provide the basic knowledge necessary to understand and evaluate clinical trials because properly conducted, randomized clinical trials are the best sources for determining the best available treatment. Other commonly used sources rarely provide sufficient detail necessary to determine the efficacy and safety of any treatment, and they often contain biases or pitfalls that make them unacceptable or unreliable. Our method for reviewing clinical trials allows a busy clinician to use his or her time most efficiently by deciding not to read the majority of poorly conceived, designed, executed, or reported trials and those trials with insignificant results. It provides a means to determine the quality of the trials that one does decide to read and to retain and retrieve the information when it is needed. The method involves recognizing and evaluating the features that strengthen clinical trials and help validate their conclusions. These features include proper selection and allocation of patients, inclusion of an appropriate control group, randomization, prior selection of clinically and biologically important outcome variables, blinding of assessment, consideration of patient compliance and drop out, and proper presentation and statistical analysis of results.

Bias↗
PubMed1996

Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation.

Mice homozygous for an Ikaros null mutation display distinct defects in the development of fetal and adult lymphocytes. Fetal T lymphocytes, and fetal and adult B lymphocytes and their earliest progenitors are absent. Postnatally, hematopoietic stem cells give rise to thymocyte precursors that undergo aberrant differentiation into the CD4 lineage and clonal expansion. The lack of NK cells and some gamma delta T cell subsets and a large reduction in thymic dendritic APCs suggest that Ikaros is essential for establishing early branch points in the postnatal T cell pathway. The lymphoid defects detected in Ikaros null mice reveal critical molecular differences between fetal and postnatal hematopoietic progenitors that dictate their ability to give rise to T cells. These studies also establish Ikaros as a tumor suppressor gene acting during thymocyte differentiation. Phenotypic comparison of this null mutation with a severe dominant-negative Ikaros mutation identifies molecular redundancy in the postnatal hemolymphoid system.

Animals↗
PubMed1994

In vivo treatment with anti-ICAM-1 and anti-LFA-1 antibodies inhibits contact sensitization-induced migration of epidermal Langerhans cells to regional lymph nodes.

Development of contact hypersensitivity in mice depends on the migration of Langerhans cells from the epidermis to regional lymph nodes. Since ICAM-1 and LFA-1 play important roles in leukocyte migration, we sought to determine whether in vivo administration of anti-ICAM-1 and anti-LFA-1 antibodies would inhibit contact sensitization-induced migration of epidermal Langerhans cells to regional lymph nodes. Twenty-four hours after contact sensitization of mice with FITC, a brightly FITC-stained Ia+ population of dendritic cells capable of stimulating a FITC-specific Ia-restricted T-cell hybridoma was readily detected in their draining lymph nodes. Animals treated with anti-Ia mAb, which depletes Ia+ cells in lymph nodes and spleen but not Ia+ Langerhans cells in the epidermis, had normal numbers of FITC-bearing Ia+ cells capable of stimulating the T-cell hybridoma. Dendritic lymph node cells from mice treated with anti-ICAM-1 and anti-LFA-1 mAb were devoid of brightly FITC-stained cells and cells capable of stimulating the FITC-specific T-cell hybridoma. The combination of anti-ICAM-1 and anti-LFA-1 mAb completely inhibited the induction of contact hypersensitivity to FITC. Animals treated with anti-ICAM-1 or anti-LFA-1 monoclonal antibodies alone had significantly reduced (by 79 and 36%, respectively) numbers of brightly stained cells capable of stimulating the hybridomas. These data suggest that the adhesion molecules, ICAM-1 and LFA-1, play a significant role in contact hypersensitivity-induced migration of Langerhans cells to regional lymph nodes. The immunomodulatory effects of anti-adhesion molecule antibodies in vivo may be in part due to their effects on antigen-presenting cell migration.

Animals↗
PubMed1994

The Ikaros gene is required for the development of all lymphoid lineages.

The Ikaros gene encodes a family of early hematopoietic- and lymphocyte-restricted transcription factors. Mice homozygous for a germline mutation in the Ikaros DNA-binding domain lack not only T and B lymphocytes and natural killer cells but also their earliest defined progenitors. In contrast, the erythroid and myeloid lineages were intact in these mutant mice. We propose that Ikaros promotes differentiation of pluripotential hematopoietic stem cell(s) into the lymphocyte pathways. In the absence of a functional Ikaros gene, these stem cells are exclusively diverted into the erythroid and myeloid lineages.

Animals↗
PubMed1994

Inhibition of human melanoma growth and metastasis in vivo by anti-CD44 monoclonal antibody.

CD44 is a M(r) 90,000 surface glycoprotein believed to be involved in cell adhesion and migration. We investigated the role of CD44 in tumor growth and metastasis using human melanoma cell lines SMMU-1 and SMMU-2. Both SMMU-1 and SMMU-2 form tumors in the s.c. tissues when injected s.c. in SCID mice but only SMMU-2 metastasizes. Approximately one-half of SCID mice receiving injections of SMMU-2 s.c. develop metastatic tumors. SMMU-2 but not SMMU-1 expresses high levels of the hematopoietic form of CD44 and binds fluorescence-conjugated hyaluronic acid in vitro. GKW.A2 is a monoclonal antibody specific for human CD44 that can completely inhibit the binding of hyaluronic acid to SMMU-2 tumor cells in vitro. Moreover, in vivo injection of GKW.A3 inhibited the growth and metastatic potential of SMMU-2 tumor cells. Administration of GKW.A3 i.v. 1 week after s.c. tumor injection did not inhibit local tumor development but inhibited the formation of metastatic tumors and prolonged animal survival. Therefore, interactions between CD44 on tumor cells and its ligands in vivo may be necessary for tumor growth and metastasis.

Animals↗
PubMed1994

Palmitoylation of CD44 interferes with CD3-mediated signaling in human T lymphocytes.

We studied the interactions between CD44 and four different monoclonal anti-CD44 antibodies. All four monoclonal anti-CD44 antibodies studied (P3H9, Bu52, IM.7, and GKW.A3) act in synergy with human anti-CD2 antibodies in stimulating normal human peripheral blood lymphocytes to proliferate. GKW.A3 and IM.7 but not P3H9 or Bu52 inhibited the proliferation of normal human peripheral blood lymphocytes stimulated by anti-CD3. Interestingly, only GKW.A3 and IM.7 stimulated the incorporation of [3H]palmitic acid and palmitoylation of CD44 molecules by normal human peripheral blood lymphocytes. The two monoclonal anti-CD44 antibodies (P3H9 and Bu52) that failed to inhibit anti-CD3 induced proliferation also failed to induce the incorporation of [3H]palmitic acid. More importantly, the inhibitory effects of GKW.A3 were reversed in the presence of cerulenin, an inhibitor of protein palmitoylation. Therefore, palmitoylation of CD44 may interfere with anti-CD3 mediated signaling pathways. These data support the hypothesis that palmitoylation of cell surface receptors may play an active role in receptor and receptor interactions and signal transduction in normal human T lymphocytes.

Antibodies, Monoclonal↗
PubMed1994

Trinitrophenol reactive T-cell hybridomas recognize antigens that require antigen processing.

Protein antigens must be taken up, processed, and displayed on the surface of antigen-presenting cells in association with major histocompatibility complex molecules before they can be recognized by T cells. Whether recognition of the haptens used to study allergic contact hypersensitivity in murine models similarly requires processing has not been determined. We analyzed whether presentation of trinitrophenol to trinitrophenol reactive T-cell hybridomas requires antigen processing by studying the effects of inhibitors of antigen processing and presentation on the ability of a syngeneic B-cell tumor (A20) to present trinitrophenol to a series of interleukin-2 producing, trinitrophenol specific, major histocompatibility complex class II-restricted T-cell hybridomas. The ability of trinitrophenol modified A20 cells to stimulate the hybridomas was completely inhibited by monoclonal, anti-trinitrophenol, or anti-Ia antibodies and was significantly reduced by paraformaldehyde fixation immediately after trinitrophenol modification. Trinitrophenol-modified A20 cultured at 37 degrees C for 2 h prior to fixation was significantly more effective at stimulating the hybridomas than trinitrophenol-modified A20 fixed immediately. The ability of A20 to present trinitrophenol was inhibited by chloroquine. Paraformaldehyde fixation and chloroquine treatment had similar effects on the ability of trinitrophenol modified lymph node dendritic cells to stimulate the trinitrophenol specific hybridomas. Paraformaldehyde fixation and chloroquine treatment had similar effects on the ability of A20 cells to present ovalbumin to ovalbumin-specific hybridomas as they had on the ability of trinitrophenol modified A20 cells to present trinitrophenol to the trinitrophenol specific hybridomas. One of seven T-cell hybridomas responded to trinitrophenol modified ovalbumin but not other trinitrophenol modified proteins. These results suggest that, at least in part, T cells in the contact hypersensitivity response to trinitrophenol recognize antigens that require processing and that trinitrophenol modified proteins can be recognized.

Albumins↗
PubMed1994

T-cell lines derived from lesional skin of lichen planus patients contain a distinctive population of T-cell receptor gamma delta-bearing cells.

Lichen planus is characterized by a dense infiltrate of T lymphocytes at the dermoepidermal junction. To determine the phenotypic and functional characteristics of the infiltrating lymphocytes, T-cell lines from normal and lesional skin from the same patients with lichen planus were established by culture with interleukin 2 followed by stimulation every 14 d with phytohemagglutinin and irradiated allogeneic feeder cells. Resultant T-cell lines were immunophenotyped by staining with monoclonal antibodies and their reactivity tested by determining their cytolytic activity to selected targets. T-cell lines from 13 lesional and nine normal biopsy specimens were studied. T-cell lines from normal skin were 61% CD4+ and 32% CD8+, whereas lines from lesional skin had significantly fewer CD4+ cells (13%) and more CD8+ cells (62%). T-cell lines from lesional skin contained a distinctive population of gamma delta T cells that was rarely present in lines derived from normal skin. We were able to culture gamma delta T cells out of the lesional skin of 12 of 13 patients. In these 12 patients, lesional T-cell lines were 17% gamma delta+ (range 2% to 47%). Only one T-cell line from normal skin contained significant numbers of gamma delta T cells. The gamma delta population from lesional skin was commonly V delta 1J delta 1+. These results suggest that CD8+ and TCR gamma delta+ T lymphocytes may be involved in the development or the maintenance of lichen planus.

Cell Line↗