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Biomedical subjects

J H Butterfield

Publications and source records attributed to J H Butterfield.

At least 19 recordsLinked to original sources
PubMed2006

FIP1L1-PDGFRA in eosinophilic disorders: prevalence in routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature.

We previously studied clinico-pathologic features of 89 consecutive adult patients with moderate-to-severe eosinophilia, and reported a FIP1L1-PDGFRA prevalence of 12%. In that series, all 11 FIP1L1-PDGFRA+ patients receiving imatinib achieved a complete response. We now extend our observations through a study of 741 unselected patients with eosinophilia for FIP1L1-PDGFRA, and present longer term follow up data for the imatinib-treated cohort. We also include data for three previously unreported FIP1L1-PDGFRA+ patients. Among the 741 requests, only 21 (3%) were found to carry the FIP1L1-PDGFRA mutation. While all 14 FIP1L1-PDGFRA+ patients receiving imatinib achieved a complete response, the 4 patients who attempted to discontinue imatinib all relapsed. We also find that it is possible to maintain patients in clinical remission with an empirically derived schedule of low-dose (50-100 mg), intermittent (once daily to once weekly) imatinib. Lastly, we present a comprehensive review of the literature pertaining to FIP1L1-PDGFRA in order to address several key aspects of this mutation from a clinical standpoint.

Adult↗
PubMed2005

Interferon treatment for hypereosinophilic syndromes and systemic mastocytosis.

Hypereosinophilic syndromes (HES) and systemic mastocytosis (SMCD) are heterogeneous disorders with clinical symptoms from local and remote effects of excessive proliferation of eosinophils and mast cells, respectively. Interferon alpha (IFN-alpha), alone or in combination with other medications, can be a useful, and at times life-saving, treatment for patients with HES. Receptors for IFN-alpha are present on eosinophils, and clinical benefits are due to its effect on eosinophil proliferation, migration, activation, and survival. These effects are likely mediated through multiple pathways including, but not limited to, inhibition of eosinophil colony-forming cells, upregulation of IFN-gamma synthesis, and inhibition of production of eosinophil-active cytokines by T cells, mast cells, and mononuclear cells. IFN-alpha has been life-saving for patients with intractable HES that were resistant to prednisone, hydroxyurea, and other agents. Resistance to the eosinopenic effect of IFN-alpha does not develop and the dose of IFN-alpha necessary to maintain control of eosinophilia often decreases with time. The combination of IFN-alpha and hydroxyurea is very useful and allows dosage reduction of IFN-alpha and better control of hypereosinophilia than with either agent alone. The efficacy of IFN-alpha for treatment of SMCD has been more difficult to establish, with both favorable and unfavorable results reported. The disparate results may have resulted from the small number of patients with SMCD treated with IFN-alpha, the use of various criteria for a "successful" treatment outcome, short duration of treatment and follow-up, and the use of modest dosages. In reported series, side effects from IFN-alpha have frequently been dose-limiting. IFN-alpha improves many of the clinical symptoms of SMCD including dermatological, hematological, gastrointestinal, and systemic symptoms associated with histamine release. IFN-alpha has a beneficial effect on skeletal symptoms because of its ability to increase bone density and reduce painful episodes from vertebral fractures. No consistent improvement in bone marrow infiltration by mast cells has been demonstrated except in a recent study employing high dosages of IFN-alpha. A beneficial effect from the combination of IFN-alpha and prednisone has been reported for several patients, suggesting that combined use of these two medications may provide synergism in treatment outcomes.

Antineoplastic Agents↗
PubMed2004

Treatment of systemic mast cell disease with 2-chlorodeoxyadenosine.

We used three to six courses of 2-chlorodeoxyadenosine (2-CdA) (2-h infusion at 0.14 mg/kg per day x 5 days) given over a period of 3-36 months to treat four patients with aggressive systemic mast cell disease (SMCD) that was resistant to interferon-alpha (IFN-alpha). Treatment with 2-CdA resulted in a major response in two patients and a good partial response in one other patient (75% overall response). Treatment was well tolerated and duration of remission in responding patients ranges from 2 months to 4+ years since the completion of treatment with 2-CdA.

Adult↗
PubMed2001

Diverse clinical outcomes of eosinophilic patients with T-cell receptor gene rearrangements: the emerging diagnostic importance of molecular genetics testing.

Abnormal clones of clusters of differentiation (CD)3(-)CD4(+) or CD3(+)CD4(-)CD8(-) phenotypically abnormal lymphocytes have been identified in some patients who have the idiopathic hypereosinophilic syndrome. This report illustrates the disparate clinical courses of six eosinophilic patients with evidence of abnormal T-cell clones based on the finding of a T-cell receptor gene rearrangement. The data suggest that molecular genetics testing for T-cell receptor gene rearrangements should be included in the routine work-up of patients with idiopathic eosinophilia.

Adult↗
PubMed2001

Inhibition of keratinocyte growth in cell culture and whole skin culture by mast cell mediators.

Mast cells are suggested to participate in regenerative processes, but their influence on epithelialization and wound healing has not been well studied. Since mast cells can be found in contact with epidermis in chronic inflammatory skin diseases and venous ulcers, the effect of mast cells on keratinocyte growth was studied. Keratinocytes were cultured in serum-free conditions with (complete medium) or without (basal medium) epidermal growth factor (EGF) and bovine pituitary extract (BPE) to reach subconfluence in a 24-well plate, and the cells were treated with different mast cell mediators histamine, heparin and tryptase, or lysate from HMC-1 cells, a human leukemic mast cell line. Whole skin cultures were used as a model for in vitro wounds to study the effect of mast cells on epithelial outgrowth from skin specimens. Histamine inhibited 3H-thymidine incorporation of keratinocytes dose-dependently by 29% at 1 mM, and 89% at 5 mM histamine. In whole skin culture, histamine inhibited epithelial outgrowth dose-dependently by 64% already at 0.1 mM histamine and maximally (91%) at 1 mM histamine. Heparin inhibited 3H-thymidine incorporation dose-dependently by up to 33% at 2 microg/ml in the absence, but not in the presence, of EGF/BPE. In contrast, in whole skin culture, heparin first inhibited the epithelial outgrowth by up to 27% at 2 microg/ml, but then reversed the inhibition to 30% stimulation at 200 microg/ml. Skin tryptase (0.0285 to 2.85 microg/ml) with or without heparin (0.5 to 20 microg/ml) did not affect thymidine incorporation in keratinocytes. Lysate from HMC-1 cells, but not that from control, neuroblastoma cells, inhibited 3H-thymidine incorporation in keratinocytes dose-dependently, and maximal (47%) inhibition was reached with 16,700 lysed HMC-1 cells/ml. In whole skin culture, HMC-1 lysate inhibited the epithelial outgrowth by up to 36% at 67,000 lysed cells/ml. The results show that mast cells and their mediators are inhibitory to keratinocyte 3H-thymidine incorporation and epithelial outgrowth in vitro, although, the inhibitory effect of histamine was seen at high concentrations suggesting a requirement for close morphologic vicinity of mast cells to keratinocytes. Thus, mast cells are assumed to control epidermal regeneration and to impair epithelialization of chronic ulcers.

Cell Division↗
PubMed2001

Eosinophil-associated inflammation and elaboration of eosinophil-derived proteins in 2 children with raccoon roundworm (Baylisascaris procyonis) encephalitis.

OBJECTIVE: Eosinophil-associated proteins, especially eosinophil-derived neurotoxin, may be important contributors to the neurologic pathology and symptoms caused by Baylisascaris procyonis infection. METHODS: Two cases of severe B procyonis encephalitis with evidence of marked eosinophil degranulation in the central nervous system are presented. Serial cerebrospinal fluid (CSF) specimens were collected from each patient during the course of their illness. Antibodies against B procyonis were measured in the patients' serum and CSF. Levels of the eosinophilopoietin interleukin-5 (IL-5) and 2 important eosinophil proteins, eosinophil-derived neurotoxin and major basic protein, were assayed in the CSF. RESULTS: Both patients had rapidly progressive central nervous system disease with evidence of eosinophilic meningoencephalitis. Both tested positive for antibodies to B procyonis in serum and CSF and had progressively worsening deep white matter changes on magnetic resonance images of the brain. CSF levels of IL-5, eosinophil-derived neurotoxin, and major basic protein were markedly elevated over controls. CONCLUSIONS: This is the first report of the measurement of IL-5, eosinophil-derived neurotoxin, and major basic protein in human CSF. In addition to traumatic damage and necrosis caused by migrating larvae, eosinophil-derived neurotoxin from associated eosinophilic inflammation may be an important contributory factor in the pathogenesis of B procyonis encephalitis. parasite, eosinophil-derived-neurotoxin, major basic protein, eosinophilia, hypereosinophilia, interleukin-5, encephalitis, child.

Animals↗
PubMed2001

Urticaria and angioedema from cyclooxygenase-2 inhibitors.

Cyclooxygenase-2 (COX-2) inhibitors celecoxib and rofecoxib have generally been well tolerated. It has been unclear if specific COX-2 inhibitors would cross react with acetylsalicylic acid and typical nonsteroidal antiinflammatory drugs to cause urticaria or angioedema. There are no reports in the literature of hives or angioedema resulting from their use. We describe 3 patients who developed urticaria and/or angioedema from COX-2 inhibitors. With the increasing use of COX-2 inhibitors, one needs to be aware of these side effects and of possible cross reactivity between celecoxib and rofecoxib.

Adult↗
PubMed1999

5-Lipoxygenase upregulation by dexamethasone in human mast cells.

In spite of intensive research, our understanding of the regulation of expression of 5-LO (the key enzyme in the leukotriene metabolism) remains fragmentary. We investigated the effects of dexamethasone on the expression of this gene in a binary model consisting of two clones of the human mast cell line HMC-1, one with a 5-LO-negative and the other with a 5-LO-positive phenotype, respectively. When dexamethasone was included in the culture medium at a physiologically relevant concentration, biosynthesis of 5-LO derivatives increased considerably not only in the 5-LO-negative HMC-1 cells (approx 10-fold) but also in the 5-LO-positive cells, characterized by an already substantial enzyme activity. Consistently, Northern blot analysis revealed that a dramatic increase in the abundance of 5-LO mRNA occurred when the cells were exposed to dexamethasone. Likewise, a significant increase in the immunoreactive 5-LO protein was detected by Western blotting. In contrast, dexamethasone seemed to have no effect on the expression of two other genes of pivotal importance in leukotriene biosynthesis, viz. FLAP and LTC(4) synthase. We conclude that in human mast cells glucocorticoids effectively and selectively upregulate the expression of 5-LO.

5-Lipoxygenase-Activating Proteins↗
PubMed1999

Epidemiology of anaphylaxis in Olmsted County: A population-based study.

BACKGROUND: Awareness of the clinical features of anaphylaxis and its causative triggers is important if recurrent episodes are to be avoided. The incidence of anaphylaxis in the general population is often underreported, and epidemiologic studies are few. Because an accurate profile of anaphylaxis could heighten awareness of this problem, we investigated the epidemiology of anaphylaxis in the general population of Olmsted County, Minn. OBJECTIVE: The purpose of this study was to describe the epidemiology of anaphylaxis in Olmsted County residents from 1983 through 1987. METHODS: This was a retrospective population-based cohort study. The medical records of 1255 Olmsted County residents identified by computer-linked, medical diagnostic indices (the Rochester Epidemiology Study) were reviewed retrospectively to identify residents whose clinical episodes met the criteria for anaphylaxis. We determined the incidence and rate of occurrence of anaphylaxis, rate of recurrence, prevalence of atopy, cause of anaphylaxis, frequency of referral to an allergy specialist, hospital admission rate, and case-fatality rate. RESULTS: There were 133 residents who experienced 154 anaphylactic episodes during the 5-year period: 116 residents had 1 episode of anaphylaxis, 13 residents had 2 episodes, and 4 residents had 3 episodes. The anaphylaxis occurrence rate was 30 per 100,000 person-years (95% confidence interval, 25-35). There were 110 residents who had a first lifetime episode of anaphylaxis (that was medically evaluated) during the years 1983 to 1987. The average annual incidence rate of anaphylaxis was 21 per 100,000 person-years (95% confidence interval, 17-25). Atopy was present in 53% of the cohort, and allergy consultation was obtained in 52%. A suspect allergen was identified in 68% of the cohort, most frequently a food, medication, or insect sting. The hospitalization rate was 7%, and 1 patient died. CONCLUSION: The incidence of anaphylaxis is less than 1%, and death rarely occurs. People with atopy experience anaphylaxis more frequently than people without atopy. Anaphylaxis frequently is not recognized by patients and physicians.

Anaphylaxis↗
PubMed1999

ATP modulates anti-IgE-induced release of histamine from human lung mast cells.

Adenosine 5'-triphosphate (ATP) is released from the cytoplasm under physiologic and pathophysiologic conditions and enters the extracellular space, where it acts on a group of recently cloned cell-surface receptors termed P2-purinoceptors (subtypes P2X and P2Y). We examined the effects of extracellular ATP, uridine triphosphate (UTP), the stable ATP analogues alpha,betamethylene-ATP (alpha,betamATP), beta,gammamethylene-ATP (beta,gammamATP), and 2-methylthio-ATP (2mSATP), and adenosine (10(-6)-10(-3) M) on histamine release from human lung mast cells (HLMC) induced by anti-IgE and the calcium ionophore A23187. None of the nucleotides or adenosine directly induced histamine release. Adenosine exhibited a bimodal effect, enhancing histamine release at 10(-6) to 10(-4) M (P > 0.05, NS) and inhibiting it at 10(-3) M (P < 0.05). ATP (10(-4) M) enhanced anti-IgE-induced histamine release (10.9 +/- 2.7% to 19. 2 +/- 2.9%, n = 20, P < 0.01), but not ionophore A23187-induced histamine release (n = 10). The adenine nucleotides consistently enhanced anti-IgE-induced histamine release; the rank order for this action was: ATP > 2mSATP > alpha,betamATP > beta,gammamATP, suggesting mediation by a P2Y-purinoceptor subtype. The selective P2X purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2', 4'-disulfonic acid failed to influence the effect of ATP, further supporting P2Y-purinoceptor mediation of anti-IgE-induced histamine release. UTP, an agonist at P2Y-purinoceptors, also significantly enhanced anti-IgE-induced histamine release. Application of the reverse transcription-polymerase chain reaction indicated that HLMC constitutively express the messenger RNAs encoding the P2Y1- and P2Y2-purinoceptor subtypes, and not that encoding the P2X7-purinoceptor (i.e., P2Z), a subtype implicated in ATP-induced histamine release in rodent peritoneal mast cells. The data produced in the study suggest that ATP plays an important modulatory role in histamine release from HLMC, and that it may therefore be mechanistically involved in human allergic/asthmatic reactions.

Adenine Nucleotides↗
PubMed1998

Lectin histochemistry of human leukaemic mast cells (HMC-1) transplanted into severe combined immunodeficient (scid) mice.

It is difficult to isolate and impossible to propagate human mast cells in tissue culture. As an alternative to the use of human differentiated mast cells, a human leukaemic mast cell line (HMC-1), which can be propagated in vitro, has been employed in a number of studies. Carbohydrate binding proteins, lectins, have been used to characterise the terminal sugar residues of human mast cells in situ. The aim of the present study is to characterise the lectin binding sites of HMC-1 cells transplanted into severe combined immunodeficient (scid) mice. Lectins specific for the complex carbohydrates, neuraminic acid and N-acetylglucosamine residues showed generally a strong uniform binding pattern, whereas mannose and glucose specific yielded lectins a greater heterogeneity. This glycotope expression pattern has some similarities with those of human mast cells in situ, and therefore HMC-1 cells grown in scid mice constitute a valuable model system for the study of carbohydrate expression in human mast cells.

Animals↗
PubMed1998

Response of severe systemic mastocytosis to interferon alpha.

Six patients with documented systemic mast cell disease were enrolled in a 1-year, phase I study to determine the possible benefits of interferon alpha-2b (IFN-alpha). IFN-alpha therapy was begun at a dosage of 0.5 million units/day (MU/day) by subcutaneous injection and increased, as tolerated, to 3.0 MU/day. Subsequent dose modifications were made based on clinical tolerance and response. No immediate, adverse reactions to IFN-alpha occurred. Several patients showed symptomatic improvement. In two patients ascites resolved and did not recur. Two other patients reported improved energy levels and had decreased size of retroperitoneal, measenteric and retrocrural nodes. One patient failed to benefit and died shortly after completing 12 months of therapy. Bone marrow mastocytosis decreased by 5% to 10% after 12 months of therapy with IFN-alpha. Although five of the six patients had a decrease in the urinary excretion of 1-methyl-4-imidazole acetic acid, serum tryptase values did not appreciably change in any patient. Side-effects from IFN-alpha included hypothyroidism, thrombocytopenia and depression. It is concluded that although treatment with IFN-alpha was associated with a decline in bone marrow mastocytosis and reduced excretion of histamine metabolites, prolonged therapy may be needed and dose-limiting side-effects are frequent.

Aged↗
PubMed1998

Induction of L-histidine decarboxylase in a human mast cell line, HMC-1.

Histamine is an important mediator in allergic reactions, gastric acid secretions, and neurotransmission in the central nervous system. Basophils and mast cells are the main sources of histamine, which is formed from L-histidine by histidine decarboxylase (HDC). However, the regulatory mechanism of HDC in these cells remains unclear. We examined the regulation of HDC activity and gene expression using a unique human mast cell line, HMC-1, after stimulation with phorbol 12-myristate 13-acetate (PMA) or ionomycin. HDC activity was increased from 52.1+/-0.4 (mean+/-standard deviation) to 154+/-6.9, or 105.6+/-6.2 pmol/min/mg protein (n = 3), 4 hours after stimulation with PMA (10 ng/mL) or ionomycin (10[-6] M). Although actinomycin D had no effect on this increase, cycloheximide completely inhibited the increase caused by these stimuli. The population of HMC-1 cells containing HDC protein was increased after stimulation with either PMA or ionomycin as evaluated by immunocytochemical analysis with anti-HDC antibody as a marker. HMC-1 constitutively expressed HDC mRNA, and its level was not increased with these stimuli. These results suggest that the increase of HDC activity in HMC-1 induced by PMA or ionomycin is regulated at the translational level.

Cell Line↗
PubMed1997

The HMC-1 human mast cell line expresses the hepatocyte growth factor receptor c-met.

Hepatocyte growth factor (HGF) was originally characterized as a strong inducer of liver regeneration. However, it is now clear that HGF and its receptor, the proto-oncogene c-met, can be expressed in many other tissues, and that HGF can mediate diverse biological activities. We investigated the expression and function of c-met in a human mast cell line (HMC-1). We found that HMC-1 cells express c-met and that c-met expression can be upregulated by treatment of the cells with phorbol 12-myristate 13-acetate (PMA). Although HGF did not detectably influence the proliferation or morphology of HMC-1 cells, HGF inhibited the cells' ability to release tumor necrosis factor-alpha (TNF-alpha) in response to stimulation with PMA and the calcium ionophore, A23187. These results add the inhibition of TNF-alpha production to the other recognized effects of HGF/c-met on cellular function.

Calcimycin↗
PubMed1997

Expression of functional TrkA receptor tyrosine kinase in the HMC-1 human mast cell line and in human mast cells.

Nerve growth factor (NGF) can influence mast cell development and function in murine rodents by interacting with its receptors on mast cells. We now report the identification of mRNA transcripts of full-length tyrosine kinase-containing trkA, trkB, and trkC neurotrophin receptor genes in HMC-1 human mast cell leukemia cells. Although HMC-1 cells lacked p75 mRNA, they expressed transcripts for the exon-lacking splice variant of trkA (trkAI), truncated trkB (trkB.T1), and truncated trkC. By flow cytometry, HMC-1 cells exhibited expression of TrkA, TrkB, and TrkC receptor proteins containing full-length tyrosine kinase domains. NGF stimulation of HMC-1 cells induced tyrosine phosphorylation of TrkA protein, increased expression of the early response genes c-fos and NGF1-A, and activation of ERK-mitogen-activated protein (MAP) kinase, results which indicate that TrkA receptors in HMC-1 cells are fully functional. Highly purified populations of human lung mast cells expressed mRNAs for trkA, trkB and trkC, whereas preparations of human umbilical cord blood-derived mast cells expressed mRNAs for trkA and trkC, but not trkB. Moreover, preparations of human umbilical cord blood-derived immature mast cells not only expressed mRNA transcript and protein for TrkA, but exhibited significantly higher numbers of chymase-positive cells after the addition of NGF to their culture medium for 3 weeks. In addition, HMC-1 cells expressed mRNAs for NGF, brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), the cognate ligands for TrkA, TrkB, and TrkC, whereas NGF and BDNF transcripts were detectable in human umbilical cord blood mast cell preparations. Taken together, our findings show that human mast cells express a functional TrkA receptor tyrosine kinase and indicate that NGF may be able to promote certain aspects of mast cell development and/or maturation in humans. Our studies also raise the possibility that human mast cells may represent a potential source for neurotrophins.

Cell Line↗
PubMed1997

Production of macrophage inflammatory protein-1alpha by human mast cells: increased anti-IgE-dependent secretion after IgE-dependent enhancement of mast cell IgE-binding ability.

The contributions of mast cells to the pathology of allergic diseases, as well as to the expression of immunoglobulin E (IgE)-dependent host responses to parasites, reflect both the amounts and types of cytokines and other mediators that are released by these cells in such settings. Whereas mast cells cannot intrinsically express immunologically specific functions, the binding of IgE to high-affinity IgE receptors (Fc epsilonRI) on the surface of mast cells primes these cells to secrete cytokines and other biologically active products upon subsequent exposure to specific antigens. We now report that both HMC-1, a growth factor-independent human mast cell leukemia cell line, and growth factor-dependent human umbilical cord blood-derived mast cells can secrete the multifunctional C-C chemokine, macrophage inflammatory protein-1alpha (MIP-1alpha). In addition, we found that in vitro exposure of human umbilical cord blood-derived mast cells to concentrations of IgE within the range observed in the serum of subjects with allergic diseases or parasite infections, which markedly up-regulates the ability of these cells to bind IgE to their surface, also significantly enhances the ability of the cells to secrete MIP-1alpha upon subsequent passive sensitization with IgE and challenge with anti-IgE. Thus, IgE-dependent enhancement of human mast cell IgE-binding ability permits these cells to respond to Fc epsilonRI-dependent challenge with significantly increased secretion of MIP-1alpha, a chemokine that can have diverse functions in inflammation, allergic reactions, and host responses to infection.

Antibodies, Anti-Idiotypic↗