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D D Metcalfe

Publications and source records attributed to D D Metcalfe.

At least 145 records · Page 8Linked to original sources
PubMed1991

The treatment of mastocytosis: an overview.

The treatment of mastocytosis requires a recognition of specific disease patterns of involvement, with consequent institution of appropriate therapy based on the disease pattern manifested in a given patient. Treatment for most forms of mastocytosis is conservative and symptomatic. H1 and H2 antihistamines in combination or alone remain the primary drugs of choice. In specific cases, patients may require aspirin and/or steroids; some must be prepared to self-administer epinephrine for severe anaphylactic episodes. In patients with associated hematologic disorders, the treatment of the disorder will depend on the hematologic findings. In rare cases, and in aggressive forms of mastocytosis only, it may be necessary to consider limited forms of chemotherapy.

Histamine H1 Antagonists↗
PubMed1991

Effects of tixocortol pivalate on gastrointestinal disease in systemic mastocytosis: a preliminary study.

Tixocortol pivalate is a steroid reportedly without significant adrenal-pituitary axis suppression when administered via the gastrointestinal tract. To determine whether this steroid would suppress the gastrointestinal manifestations of systemic mastocytosis, we performed an open clinical trial for safety and efficacy with tixocortal pivalate in four patients for periods of 8-15 weeks. All patients showed a decrease in the symptoms of abdominal pain and frequency of stools. Laboratory parameters of malabsorption improved in parallel with symptom relief. Histopathologic abnormalities of the small bowel improved in one patient. There was no significant suppression of the pituitary-adrenal axis. Two patients developed fluid retention while on tixocortol pivalate, which was attributed to a mineralocorticoid effect. One patient had a fall in AM cortisol. In summary, this study strongly suggests that tixocortol pivalate, when administered orally, has gastrointestinal anti-inflammatory activity comparable to conventional steroids, but may not be entirely without adrenal-suppressive effect and may lead to fluid retention in some patients. Further studies are warranted to assess the value of tixocortol pivalate in the therapy of inflammatory diseases of the upper gastrointestinal tract.

Adult↗
PubMed1991

Early development of mast cells.

Mast cells originate from pluripotential cells in the bone marrow. Specifically, human mast cells originate from CD 34-positive progenitor cells. Mast cell proliferation requires IL-3. In the mouse, additional mast cell growth is achieved by the addition of IL-4, and GM-CSF prevents mast cell proliferation. Early bone-marrow-derived mast cells can be identified by their IgE receptors, although they may not yet have the characteristic morphology of mature mast cells. Whether these early cells may by themselves have a physiologic role, remains to be determined. Mast cells persist in culture on fibroblast monolayers, in part due to the production of soluble factor(s) from the fibroblasts themselves. Final mast cell phenotype appears dependent upon the local tissue environment.

Animals↗
PubMed1991

Murine mast cells synthesize basement membrane components. A potential role in early fibrosis.

Mast cells are resident in tissues, particularly in association with endothelial and epithelial cell basement membranes, and increase at sites of inflammation, injury, and fibrosis. Although mast cells are known to both release and generate proinflammatory molecules in response to inflammatory stimuli, little is known about their normal biologic function. Here we demonstrate that IL-3-dependent mouse PT18 mast cells, mouse bone marrow-derived mast cells, and rat basophilic leukemia cells express large amounts of mRNA for collagen IV, laminin, and heparan sulfate proteoglycan. Western blot analysis confirmed that mast cells synthesize and secrete significant amounts collagen IV and laminin B1 and B2 chains. These data suggest that mast cells may contribute to normal tissue repair and/or the early overproduction of basement membrane components seen in a variety of fibrotic conditions.

Actins↗
PubMed1991

A preliminary assessment of behavioral problems in children with mastocytosis.

OBJECTIVE: The objectives of this study were to 1) review mastocytosis in terms of the behavioral pathology in adults, and 2) to assess a group of pediatric patients with mastocytosis to determine if similar behavioral pathology is evident. METHOD: Twelve children ages two to eleven referred to the NIH, a tertiary referral center for mastocytosis, were studied. Questionnaires were mailed for assessment of the child's behavior: parents completed the Childhood Behavior Checklist (CBCL) and children four years of age or more were evaluated by their teachers via the Child Behavior Checklist-Teacher Report form. Scores were compared to published normative data and to published data from other medically ill pediatric groups. Pathology was defined as present if the child scored greater than two standard deviations above published age and sex-matched norms. RESULTS: Mean factor scores on the CBCL for children with mastocytosis did not differ significantly from published norms, but individual ratings by parents were significantly elevated in four of ten subjects. Moreover, CBCL ratings by parents were similar to those seen in other medically ill pediatric groups. None of the teacher ratings were in the pathological range. CONCLUSIONS: The results of this study indicate that no clear excess of pathology exists in children with mastocytosis. Individual children treated with antihistamines for mastocytosis seem to have a nonspecific increase in behavioral difficulties at rates similar to other medically ill groups. No unique behavioral pattern implicating histamine overproduction was identified.

Child↗
PubMed1991

Pediatric mastocytosis.

The onset of mastocytosis occurs between birth and 2 years of age in approximately 55% of all cases; an additional 10% develop the disease before the age of 15 years. Mastocytosis in these age groups differs in many respects from mastocytosis that has its onset in adulthood. The typical presentation of pediatric-onset mastocytosis consists of cutaneous manifestations: either a solitary mastocytoma, urticaria pigmentosa, or, less commonly, diffuse cutaneous mastocytosis. Particularly in infants, bullous eruptions may occur. Mastocytosis in infants and children may involve internal organs, including the bone marrow and the gastrointestinal tract, although such manifestations appear to be less common in children than in adults. Plasma histamine levels may be elevated in pediatric-onset mastocytosis. Treatment usually involves the use of H1 and H2 antihistamines to control itching and to control the hypersecretion of gastric acid that may occur. The prognosis for children with mast cell disease is variable; approximately half of the children with urticaria pigmentosa may experience resolution of lesions and symptoms by adolescence.

Adolescent↗
PubMed1991

Mast cell adhesion to fibronectin.

The MCP-5 murine mast cell line, as well as primary bone marrow-derived cultured mast cells (BMCMC), are demonstrated to bind to fibronectin, a ubiquitous adhesion protein of the extracellular matrix. BMCMC required activation by phorbol myristate acetate (PMA) to adhere to fibronectin, whereas MCP-5 displayed spontaneous adherence. The binding of both MCP-5 and BMCMC was dose dependent, with maximal adhesion at a fibronectin concentration of 20 micrograms/ml. The 120,000 molecular weight (MW) proteolytic fragment of fibronectin containing the RGDS cell attachment site was able to substitute for the native fibronectin molecule in promoting mast cell attachment. Mast cell adhesion to fibronectin, in addition, could be inhibited by the RGDS peptide alone. These data suggest that, in addition to the previously described mast cell-laminin interactions, mast cells also adhere to fibronectin, thus providing further insight into their tissue localization and possible roles in processes such as wound healing and fibrosis.

Animals↗
PubMed1991

Identification of an amino acid sequence in the laminin A chain mediating mast cell attachment and spreading.

PT18 mast cells and mouse bone marrow-derived mast cells have been shown to adhere and spread when in contact with a laminin substratum. Mouse bone marrow cells, however, first require activation with phorbol myristate acetate (PMA), ionophore, or antigen-specific IgE with antigen in order to exhibit these phenomena. Here, we have studied the interaction of these cells with three active synthetic peptides derived from different domains of laminin. PT18 cells and mouse bone marrow mast cells attached and spread on the 19 amino acid synthetic laminin A chain-derived peptide PA22-2, containing the active five amino acid sequence IKVAV, and this attachment did not require prior activation of the mouse bone marrow mast cells with PMA or IgE plus antigen. These cells did not adhere to the B1 chain peptide YIGSR-NH2 or the RGD-containing peptide from the A chain. PT18 cell adherence to laminin was inhibited by soluble peptide PA22-2, but not by either YIGSR-NH2, the RGD-containing, or control peptides. Antisera to the PA22-2 peptide completely abolished adherence to PA22-2, but only partially inhibited mast cell adherence to laminin. Antibody to the 67,000-32,000 MW laminin-binding protein receptor blocked cell adhesion to laminin and to the active A chain peptide. Thus, mast cell adhesion and spreading on laminin may be mediated by an interaction with the IKVAV sequence on the laminin A chain.

Amino Acid Sequence↗
PubMed1991

Classification and diagnosis of mastocytosis: current status.

Mastocytosis is a disease characterized by an abnormal increase in mast cells. Manifestations of the disease are provoked in large part by the resultant increase in mast cell-derived mediators, which have a variety of local and systemic effects. Mastocytosis is variable in respect to the organ systems involved, clinical manifestations, and association with hematologic diseases. This has suggested the need for an improved classification scheme to allow assessment of prognosis and therapy. The heterogeneity of the disease patterns in mastocytosis strongly suggests that more than one biologic lesion may occur in the developmental sequence that leads to placement of mature mast cells in tissues.

Humans↗
PubMed1991

The liver, spleen, and lymph nodes in mastocytosis.

In systemic mastocytosis the liver, spleen, and lymph nodes may be infiltrated by mast cells, with patterns of infiltration specific for each tissue. This may result in hepatosplenomegaly and enlarged lymph nodes. Extensive involvement with mast cells may also be associated with organ dysfunction. Specifically, in the case of liver, mast cell infiltration may result in fibrosis, portal hypertension, and abdominal ascites. Clinically significant involvement of the liver, spleen, and lymph nodes appears to be more common in patients with aggressive forms of mastocytosis, including those with a hematologic disorder.

Humans↗
PubMed1991

The treatment of mastocytosis: an overview.

The treatment of mastocytosis requires a recognition of specific disease patterns of involvement, with consequent institution of appropriate therapy based on the disease pattern manifested in a given patient. Treatment for most forms of mastocytosis is conservative and symptomatic. H1 and H2 antihistamines in combination or alone remain the primary drugs of choice. In specific cases, patients may require aspirin and/or steroids; some must be prepared to self-administer epinephrine for severe anaphylactic episodes. In patients with associated hematologic disorders, the treatment of the disorder will depend on the hematologic findings. In rare cases, and in aggressive forms of mastocytosis only, it may be necessary to consider limited forms of chemotherapy.

Humans↗
PubMed1990

Oxidative degradation of rat mast-cell heparin proteoglycan.

The susceptibility of rat mast-cell heparin to oxidative degradation was examined. Heparin as a component of intact mast-cell granules (MCG) was degraded following ingestion by normal human neutrophils. In contrast, neutrophils from patients with chronic granulomatous disease (CGD), which do not respond to stimulation with respiratory-burst activity, exhibited a greatly diminished ability to degrade phagocytosed MCG heparin. MCG-associated heparin also was cleaved by H2O2 plus Fe2+ (Fenton's reagent). Isolated heparin proteoglycan (average Mr approx. 750,000) was rapidly cleaved to smaller molecules similar in size to commercial pig heparin upon exposure to Fenton's reagent. This cleavage was inhibited by catalase and by the hydroxyl-radical (OH.)-scavenger mannitol, but not by superoxide dismutase (SOD). The cleavage products retained approx. 26% of the anticoagulant activity of the native molecule. The heparin proteoglycan was also cleaved by acetaldehyde/xanthine oxidase/FeSO4, a system that generates superoxide (O2.-), H2O2 and OH.. Whereas the cleavage at relatively high iron ion concentrations was inhibited by catalase and mannitol but not by SOD, at lower iron ion concentrations the cleavage was inhibited by catalase, mannitol and SOD. These findings suggest the involvement of OH., which at high Fe2+ concentrations is generated by Fenton's reagent (H2O2 plus Fe2+), and at low iron ion concentrations is generated by the iron-ion-catalysed interaction between O2.- and H2O2 (Haber-Weiss reaction). These studies suggest that oxygen radicals generated by activated phagocytes may contribute to the degradation in vivo of both solubilized and granule-associated proteoglycan heparin.

Animals↗
PubMed1990

Regulation of adhesion of mouse bone marrow-derived mast cells to laminin.

We have reported that mast cells adhere to laminin after activation with PMA. In this study, we demonstrate that the cross-linking of cell surface high-affinity IgE-R on mast cells derived from mouse bone marrow cultured for 3 wk in the presence of WEHI-3-conditioned media acts as a highly sensitive physiologic stimulus for this attachment and that receptor activation is also induced by calcium ionophore A23187. Adherence occurred at threefold log concentrations less of A23187 and Ag than required for histamine release in a selective subpopulation comprising 20 to 30% of the total cells. At higher concentrations of agonist that permitted histamine release, the time course for degranulation was shown to be more rapid than that of adherence. Adherence was inhibited by antibodies to laminin and laminin receptor and was calcium ion and temperature dependent. Treatment of cells with dibutyryl cAMP, which activates protein kinase A, inhibited both adherence and histamine release induced by Ag or calcium ionophore. Treatment of cells with staurosporin, which inhibits protein kinase C, also inhibited adherence and histamine release induced by calcium ionophore, but was not significantly active against either adherence or histamine release induced by Ag. It thus appears that agents which modulate intracellular signaling mechanisms are equally effective toward histamine release and adherence, suggesting these two events are intimately linked in stimulus secretion coupling. Specific cytokines stimulating mast cell adhesion to laminin could not be found; however, culture of mast cells with TGF-beta 1 was determined to enhance IgE-mediated adherence to laminin. Hence, the high-affinity IgE-R on the mast cell functions not only in exocytosis but also facilitates the process of mast cell adherence to laminin.

Animals↗
PubMed1990

Arthritis and mast cell activation.

The significance of the mast cell in the pathogenesis of rheumatic diseases continues to receive attention. Increased numbers of mast cells are found in the synovial tissue and fluid of patients with inflammatory arthritides, and these mast cells can be activated by many of the substances found in inflammatory synovial fluid. This activation results in the release of mediators that are capable of amplifying the inflammatory process within the joint space. Recent research has shown that mast cells also produce a variety of cytokines and hematopoietic growth factors that may have paracrine and autocrine functions that are important to the development of the inflammatory cell infiltrate. Increased numbers of mast cells are also found in many fibrotic conditions, including scleroderma. These mast cells, directly or through mediator generation, affect the function of endothelial cells, fibroblasts, and growth factors important to the proliferation and function of these cells. A clearer understanding of mast cell involvement in the inflammatory arthritides and fibrotic processes should lead to new therapeutic strategies.

Animals↗
PubMed1990

Mast cells in cutaneous mastocytosis: accumulation of the MCTC type.

Lesional (n = 15) and non-lesional (n = 10) skin of subjects with mastocytosis was analysed for the distribution and concentration of trypase positive, chymase negative mast cells (MCT) and tryptase positive, chymase positive mast cells (MCTC) cells and compared to normal skin (n = 23) and non-lesional skin of subjects with unexplained anaphylaxis or flushing episodes (n = 6). Skin biopsies were fixed in Carnoy's fluid and subjected to double immunohistochemical staining with biotinylated mouse monoclonal anti-chymase antibody followed by alkaline phosphatase-conjugated mouse monoclonal anti-tryptase antibody. MCTC cells were the only type of mast cells seen in all specimens analysed and in each case were more numerous in superficial compared to deep regions of dermis. The concentration (mean +/- s.d.) of mast cells in the superficial dermis of mastocytosis lesions (40 985 +/- 21 772 mast cells/mm3) was significantly increased over that in corresponding areas of non-lesional skin from subjects with mastocytosis (7178 +/- 3607 mast cells/mm3), skin from subjects with idiopathic anaphylaxis or flushing episodes (6974 +/- 3873 mast cells/mm3) and normal skin (7347 +/- 2973 mast cells/mm3). The exclusive presence of MCTC cells in skin lesions of mastocytosis which are characterized by non-malignant hyperplasia of mast cells suggests involvement of local tissue factors in mast cell recruitment and differentiation.

Biopsy↗
PubMed1990

Sequential appearance of basophils and mast cells from human bone marrow in long-term suspension culture.

Human bone marrow cells grown in liquid culture in the presence of conditioned medium from concanavalin A stimulated peripheral blood mononuclear cells, from mixed lymphocyte reactions, or from an osteogenic sarcoma tumor line gave rise to basophils which were maximal in number at 1-3 weeks. Basophils had a multilobed nucleus, contained large cytoplasmic granules of variable size which stained metachromatically with acid, but not neutral toluidine blue, were negative for chloroacetate esterase, and did not contain human mast cell tryptase. In long-term cultures, mast cells were detected after 5-6 weeks. Mast cells had cytoplasmic granules that stained with acid and neutral toluidine blue, were positive for chloroacetate esterase, and contained human mast cell tryptase. It, therefore, appears that in liquid cultures even in the absence of feeder layers, human bone marrow cell cultures can give rise initially to basophils, and then to mast cells.

Animals↗
PubMed1990

Early expression of high-affinity receptor for immunoglobulin E (Fc epsilon RI) during differentiation of mouse mast cells and human basophils.

Immediate hypersensitivity is due to the release of mediators from mast cells and basophils after the crosslinking of Fc epsilon RI. The appearance of such receptors was examined during differentiation of human and mouse bone marrow cells cultured in the presence of IL-3. As already reported, mouse bone marrow yield cultures of greater than 95% mast cells by 3 wk, whereas human bone marrow develop into cultures comprising 25% basophils by 3 wk. Here we show that transcripts for Fc epsilon RI subunits and membrane-associated receptors are apparent by 1 wk in both human and murine IL-3-dependent bone marrow cells. These cells contain few, if any, granules. The expression of transcripts and the number of receptor-positive cells continue to increase over 3 wk of culture. In parallel, a progressively larger number of cells become increasingly granulated to finally resemble either basophils or mast cells. Mature peripheral human basophils also contain transcripts for Fc epsilon RI and, therefore, may have the potential to synthesize de novo receptors. The early appearance of Fc epsilon FI during cell differentiation may be important for these cells to respond to IgE-mediated stimuli before granulation. The physiologic role of Fc epsilon RI could be to mediate lymphokine production (IL-3, IL-4, IL-6, and granulocyte/macrophage colony-stimulating factor) without inducing cellular degranulation.

Animals↗