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Biomedical subjects

S J Galli

Publications and source records attributed to S J Galli.

At least 127 records · Page 7Linked to original sources
PubMed1991

Mouse splenic and bone marrow cell populations that express high-affinity Fc epsilon receptors and produce interleukin 4 are highly enriched in basophils.

Splenic and bone marrow cells from normal mice, and from mice that have been polyclonally activated by injection of anti-IgD antibody, contain cells that produce interleukin 4 (IL-4) in response to crosslinkage of Fc epsilon receptors (Fc epsilon R) or Fc gamma R or to ionomycin. Isolated Fc epsilon R+ cells have recently been shown to contain all of the IL-4-producing capacity of the nonlymphoid compartment of spleen and bone marrow. Here, purified Fc epsilon R+ cells are shown to be enriched in cells that contain histamine and express alcian blue-positive cytoplasmic granules. By electron microscopy, the vast majority of cytoplasmic granule-containing cells are basophils; they constitute approximately 25% and approximately 50%, respectively, of Fc epsilon R+ spleen and bone marrow cells from anti-IgD-injected mice. The Fc epsilon R- populations contain cells that form colonies typical of mast cells. The Fc epsilon R+ populations also contain cells that, upon culture with IL-3, form colonies of alcian blue-positive cells, but (in contrast to colonies derived from Fc epsilon R- populations) the colonies are small, and all the cells die within 2-3 weeks. The Fc epsilon R+ cells synthesize histamine during a 60-hr culture with IL-3, while the Fc epsilon R- cells do not. These results indicate that IL-4-producing Fc epsilon R+ cells are highly enriched in basophils.

Animals↗
PubMed1991

Mast cells in rat dermis and jejunal lamina propria show a five-fold difference in unit granule volume.

The cytoplasmic granules of mast cells have a periodic multimodal size distribution in which the volumes of individual granules are integral multiples of the intermodal distance, a volume defined as the "unit granule" or v1. In this study, we used two 3-month-old male rats to analyze two classical mast cell subpopulations, dermal "connective tissue-type mast cells" and jejunal lamina propria "mucosal mast cells", for the morphometric characteristics of their cytoplasmic granules. Both v1 and the mean volume of individual cytoplasmic granules were much smaller in dermal than in jejunal mast cells (ratios of 1:5.5 and 1:4.2, respectively), but dermal mast cells contained 150% more granules per cell than did jejunal mast cells. The two types of mast cells did not differ significantly in total cell volume, nucleus volume, aggregate volume of cytoplasmic granules per cell or numbers of unit granules comprising a granule of mean volume. These findings add unit granule volume to the list of phenotypic characteristics which express significant variation in anatomically distinct populations of mast cells.

Animals↗
PubMed1991

Stem cell factor (SCF), a novel hematopoietic growth factor and ligand for c-kit tyrosine kinase receptor, maps on human chromosome 12 between 12q14.3 and 12qter.

Recently a novel hematopoietic growth factor, stem cell factor (SCF), was cloned and demonstrated to be the ligand for the c-kit tyrosine kinase receptor. In the mouse, SCF is encoded by Sl (steel), a gene critical to the development of several distinct cell lineages during embryonic life and which has important effects on hematopoiesis in the adult animal. The Sl/SCF locus maps to the distal region of mouse chromosome 10, in the vicinity of genes that have been mapped to human chromosome 12. Here we report the use of somatic cell hybrid lines to localize SCF to the long arm of human chromosome 12, between 12q14.3 and 12qter. In addition to localizing the Sl homolog in man, these data provide further evidence for the conservation of synteny between the long arm of human chromosome 12 and the distal end of mouse chromosome 10.

Animals↗
PubMed1991

Cytokine production by mast cells and basophils.

Mast cells and/or basophils have been implicated in the expression of a wide variety of biological responses, including immediate hypersensitivity reactions, host responses to parasites and neoplasms, angiogenesis, tissue remodeling, and immunologically non-specific inflammatory and fibrotic conditions. Recent findings suggest that an important mechanism by which mast cells influence such biological responses is through the production of a broad panel of multifunctional cytokines. In contrast, the extent to which basophils can produce cytokines is uncertain.

Animals↗
PubMed1991

Immediate and late inflammatory responses to ragweed antigen challenge of the peripheral airways in allergic asthmatics. Cellular, mediator, and permeability changes.

Asthma may represent the clinical manifestations of a unique form of chronic airway inflammation and is often associated with allergy. To better define the components of allergic inflammation in the lung, fluids obtained by bronchoalveolar lavage (BAL) were examined for cells, inflammatory mediators, and markers of airway permeability 5 min and 19 h following instillation of ragweed antigen directly into an airway segment of allergic asthmatic subjects. The 5-min response to antigen challenge (n = 10) was characterized by 17- to 208-fold increases in histamine, prostaglandin D2 (PGD2), and its metabolite, 9 alpha,11 beta-PGF2, thromboxane B2, and 6-keto-PGF1 alpha compared with a saline-challenged segment (0.004 less than p less than 0.017). The increases in most of these mediators were significantly correlated with each other (0.0001 less than p less than or equal to 0.01), and the magnitude of all significant mediator increases was directly correlated with skin test sensitivity to ragweed antigen (0.007 less than or equal to p less than or equal to 0.05). There was also a slight increase in kinins (p = 0.04). Changes in cells and airway permeability were not detected. In contrast, the 19-h response to antigen challenge (n = 9) was characterized by a 13-fold increase in total cells recovered by BAL. Eosinophils, basophils, and lymphocytes were significantly increased and comprised 38, 1, and 9% of total cells, respectively. A neutrophil influx was also observed but was not specific for antigen challenge since a similar change was observed in a sham, saline-challenged site.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Recruitment of neutrophils during IgE-dependent cutaneous late phase reactions in the mouse is mast cell-dependent. Partial inhibition of the reaction with antiserum against tumor necrosis factor-alpha.

Much of the clinically important pathology associated with IgE-dependent disorders is thought to reflect the actions of the blood-borne leukocytes recruited during these responses. To evaluate the extent to which mast cells are responsible for the leukocyte infiltration associated with IgE-dependent cutaneous reactions, we attempted to elicit these responses in normal mice, genetically mast cell-deficient W/Wv mice, and in W/Wv mice selectively repaired of their mast cell deficiency by the intradermal injection of cultured mast cells derived from the congenic normal (+/+) mice. We found that the tissue swelling associated with IgE-dependent passive cutaneous anaphylaxis reactions developed rapidly and diminished markedly from 2 to 4 h after antigen challenge, but remained detectable for at least 24 h after elicitation of the responses. Infiltration of leukocytes (predominantly neutrophils) also occurred at these sites, but reached maximal levels 6-12 h after antigen challenge, persisted at high levels for 24 h, and largely waned by 48 h. Virtually all of the tissue swelling and leukocyte infiltration associated with IgE-dependent cutaneous reactions was mast cell dependent. Intradermal injection of 40 U of recombinant murine TNF-alpha (rmTNF-alpha) elicited neutrophil infiltration similar in magnitude and kinetics to that observed after IgE-dependent mast cell degranulation. A rabbit anti-rmTNF-alpha (R anti-rmTNF-alpha) antiserum, which was able to inhibit 84% of the neutrophil infiltration observed after i.d. injection of rmTNF-alpha, inhibited IgE-, and mast cell-dependent leukocyte infiltration by 47 +/- 7% in three separate experiments. These findings indicate that TNF-alpha contributes to mast cell-dependent recruitment of leukocytes during IgE-dependent cutaneous late phase reactions, but suggest that other mast cell-associated mediators probably also contribute to this response.

Animals↗
PubMed1991

Role of mast cells in ion transport abnormalities associated with intestinal anaphylaxis. Correction of the diminished secretory response in genetically mast cell-deficient W/Wv mice by bone marrow transplantation.

To investigate the role of mast cells in transport abnormalities during intestinal anaphylaxis, we examined responses to antigen in isolated intestinal preparations from ovalbumin-sensitized genetically mast cell-deficient WBB6F1-W/Wv (W/Wv) mice and congenic normal WBBGF1(-)+/+ (+/+) mice. Changes in ion transport (primarily secretion of chloride ions) were indicated by increases in short-circuit current (Isc). In tissues from +/+ mice, antigen caused increases in Isc which were significantly inhibited by antagonists to histamine (diphenhydramine) and serotonin (ketanserin), by a cyclooxygenase inhibitor (piroxicam) and by a neurotoxin (tetrodotoxin). In preparations from W/Wv mice, antigen-stimulated responses were approximately 30% of that in +/+ mice and were inhibited only by piroxicam. Responses to electrical transmural stimulation of nerves were approximately 50% in W/Wv versus +/+ mice, and were inhibited by antagonists of mast cell mediators in +/+ but not W/Wv mice. Reconstitution of mast cells in W/Wv mice by intravenous injection of +/+ bone marrow cells restored the normal responses to both antigen and nerve stimulation. Our results indicate that mast cell-dependent mechanisms are primarily responsible for the ion secretion associated with intestinal anaphylaxis, but that other cells are also involved. In addition, our data provide evidence for the functional importance of bidirectional communication between nerves and mast cells in the regulation of ion transport in the gastrointestinal tract.

Anaphylaxis↗
PubMed1991

Differences in the expression of the cardiopulmonary alterations associated with anti-immunoglobulin E-induced or active anaphylaxis in mast cell-deficient and normal mice. Mast cells are not required for the cardiopulmonary changes associated with certain fatal anaphylactic responses.

We compared the changes in heart rate (HR), pulmonary dynamic compliance (Cdyn), and pulmonary conductance (GL) associated with three different models of anaphylaxis in genetically mast cell-deficient WBB6F1-W/Wv and congenic normal (+/+) mice. Intravenous infusion of a monoclonal rat anti-mouse IgE produced a marked tachycardia, diminutions in Cdyn and GL, and death in +/+ but not W/Wv mice, and +/+ mice sensitized to develop high circulating levels of IgE exhibited HR, Cdyn, and GL responses to rat anti-IgE challenge which were significantly less intense than those in nonimmunized +/+ mice. By contrast, virtually identical cardiopulmonary responses were observed in either +/+ or W/Wv mice challenged to elicit pure active anaphylactic responses or simultaneous active and anti-IgE-dependent anaphylaxis. These findings show that anaphylactic responses associated with significant tachycardia, reductions in Cdyn and GL, and death can occur in the virtual absence of tissue mast cells. This is true even though, in normal mice, such responses are associated with extensive degranulation of tissue mast cells. By contrast, certain models of anaphylaxis, such as that induced in nonsensitized mice by anti-mouse IgE, can not be elicited in the absence of mast cells.

Anaphylaxis↗
PubMed1991

Gastrointestinal mast cells. New approaches for analyzing their function in vivo.

Mast cells have been implicated in a variety of physiologic or pathologic responses in the gastrointestinal tract; however, the precise contributions of the mast cell to these reactions have been difficult to define. This article discusses general aspects of mast cell biology, outlines new approaches for the analysis of mast cell function in vivo, and reviews recent evidence indicating that mast cells can produce a wide spectrum of multifunctional cytokines.

Animals↗
PubMed1990

[125I]fibrin deposition occurs at both early and late intervals of IgE-dependent or contact sensitivity reactions elicited in mouse skin. Mast cell-dependent augmentation of fibrin deposition at early intervals in combined IgE-dependent and contact sensitivity reactions.

When elicited in the skin of mice, either IgE-dependent immediate hypersensitivity reactions or T cell-dependent contact sensitivity (CS) reactions result in local extravasation of [125I]fibrinogen and deposition of [125I]fibrin. However, these two types of reaction differ in kinetics and in requirement for IgE, mast cells, or T cells. In the present study, we investigated the kinetics and magnitude of [125I]fibrin deposition in combined IgE-dependent and CS reactions elicited simultaneously at the same site and compared the results with those obtained when the two reactions were elicited at separate sites. We found that [125I]fibrin deposition in pure IgE-dependent reactions was greater at 2 or 6 h after challenge than at 24 h, but that significant fibrin deposition persisted at those sites 24 h after challenge. In CS reactions, [125I]fibrin deposition was detected as early as 2 h after challenge, indicating that fibrin deposition accompanies the "early component" of CS detected by Van Loveren et al. with the use of measurements of tissue swelling. But much more [125I]fibrin deposition was present in CS reactions at 24 h than at 2 or 6 h after Ag challenge. When IgE-dependent and CS reactions were elicited at the same site, [125I]fibrin deposition at early intervals (2 to 6 h) after challenge was increased three- to 25-fold compared with that seen in isolated CS reactions, but at 24 h the results in the combined reactions were virtually identical to those in CS responses. Studies in genetically mast cell-deficient and congenic normal mice indicated that mast cells were required for expression of the IgE-dependent augmentation of [125I]fibrin deposition observed at early intervals in combined IgE-dependent and CS reactions, but not for the [125I]fibrin deposition associated with "pure" CS reactions. These findings indicate that the net effect of IgE-dependent mast cell activation on CS responses is to increase the fibrin deposition associated with these responses, but this effect is appreciated only at early intervals after elicitation of the reaction.

Animals↗
PubMed1990

Human eosinophils express transforming growth factor alpha.

Transforming growth factor alpha (TGF-alpha) is a pleuripotential cytokine with diverse biological effects, including the ability to influence the proliferation of normal cells or neoplastic epithelial cells. Eosinophils are a subset of granulocytes that normally enter the peripheral tissues, particularly those beneath gastrointestinal, respiratory, and urogenital epithelium, where they reside in close proximity to the epithelial elements. In this study, we demonstrate that the great majority of eosinophils infiltrating the interstitial tissues adjacent to two colonic adenocarcinomas and two oral squamous cell carcinomas labeled specifically by in situ hybridization with a 35S-riboprobe for human TGF-alpha (hTGF-alpha). No other identifiable leukocytes in these lesions contained detectable hTGF-alpha mRNA. We also examined leukocytes purified from a patient with the idiopathic hypereosinophilic syndrome. 80% of these eosinophils, but none of the patient's neutrophils or mononuclear cells, were positive for hTGF-alpha mRNA by in situ hybridization, and 55% of these eosinophils were positive by immunohistochemistry with a monoclonal antibody directed against the COOH terminus of the mature hTGF-alpha peptide. Finally, the identification of the purified eosinophil-associated transcript as hTGF-alpha was confirmed by polymerase chain reaction product restriction enzyme analysis followed by Southern blot hybridization. In contrast to eosinophils from the patient with hypereosinophilic syndrome, the peripheral blood eosinophils from only two of seven normal donors had detectable TGF-alpha mRNA and none of these eosinophils contained immunohistochemically detectable TGF-alpha product. Taken together, these findings establish that human eosinophils can express TGF-alpha, but suggest that the expression of TGF-alpha by eosinophils may be under microenvironmental regulation. Demonstration of TGF-alpha production by tissue-infiltrating eosinophils and the eosinophils in the hypereosinophilic syndrome identifies a novel mechanism by which eosinophils might contribute to physiological, immunological, and pathological responses.

Adenocarcinoma↗
PubMed1990

Mast cells as a source of both preformed and immunologically inducible TNF-alpha/cachectin.

Tumour necrosis factor-alpha (TNF-alpha)/cachectin is a multifunctional cytokine that has effects in inflammation, sepsis, lipid and protein metabolism, haematopoiesis, angiogenesis and host resistance to parasites and malignancy. TNF-alpha was first described in activated macrophages, but certain mouse or rat mast cell populations (reviewed in refs 4,5) and some in vitro-derived human cells with cytochemical features of mast cells-basophils may also contain products similar to TNF-alpha. Here we present evidence that resident mouse peritoneal mast cells constitutively contain large amounts of TNF-alpha bioactivity, whereas cultured, immature mast cells vary in their TNF-alpha content. IgE-dependent activation of cultured or peritoneal mast cells induces extracellular release of TNF-alpha and augments levels of TNF-alpha messenger RNA and bioactivity. These findings identify mouse mast cells as an important source of both preformed and immunologically inducible TNF-alpha, and suggest that release of TNF-alpha by mast cells may contribute to host defence, the pathophysiology of allergic diseases and other processes dependent on TNF-alpha.

Animals↗
PubMed1990

Phorbol 12-myristate 13-acetate-induced development of functionally active mast cells in W/Wv but not Sl/Sld genetically mast cell-deficient mice.

The normal skin and other tissues of adult genetically mast cell-deficient WBB6F1-W/Wv or WCB6F1-Sl/Sld mice contain less than 1.0% the number of mast cells present in the corresponding tissues of the congenic normal (+/+) mice. We previously reported that mature dermal mast cells developed locally in the skin of W/Wv, but not Sl/Sld, mice at sites of chronic idiopathic dermatitis. We now report that the repeated application of phorbol 12-myristate 13-acetate (PMA) to the ear skin of either W/Wv or +/+ mice induces both dermatitis and a striking and dose-dependent increase in the number of dermal mast cells. The number of dermal mast cells at sites treated for 6 weeks with 5 micrograms PMA, three times per week, was 39 +/- 7/mm2 and 305 +/- 34/mm2 for W/Wv and +/+ mice, respectively; the corresponding values for vehicle-treated skin were 1.5 +/- 1.0/mm2 and 145 +/- 8/mm2, respectively. The PMA-induced dermal mast cells in W/Wv mice appeared mature by morphology, stained with the heparin-binding fluorescent dye, berberine sulfate, and were competent to express IgE-dependent passive cutaneous anaphylaxis responses. The development of mast cells was a local, not systemic, effect of PMA treatment. PMA treatment also induced dermatitis in both WCB6F1-Sl/Sld and +/+ mice, but was associated with increased numbers of dermal mast cells only in the WCB6F1(-)+/+ mice. PMA treatment had no detectable effect on the ability of bone marrow-derived cultured mast cells to survive in the skin of Sl/Sld mice. These findings establish a convenient model system for analyzing factors associated with the development of endogenous populations of mast cells in genetically mast cell-deficient W/Wv mice.

Administration, Cutaneous↗
PubMed1990

Mast cells as a source of multifunctional cytokines.

Mast cells have been implicated in the expression of a wide variety of biological responses, including immediate hypersensitivity reactions, host responses to parasites and neoplasms, immunologically non-specific inflammatory and fibrotic conditions, angiogenesis, and tissue remodeling and wound healing. However, the molecular basis for the action of the mast cell in many of these responses is obscure. In this review, John Gordon, Parris Burd and Stephen Galli suggest that the production of a broad panel of multifunctional cytokines may represent an important mechanism by which mast cells influence physiological, immunological and pathological processes.

Animals↗
PubMed1990

Production of transforming growth factor alpha by hamster eosinophils.

Previously it was demonstrated that malignant transformation of the Syrian hamster cheek pouch mucosa is associated with the expression of TGF-alpha. Therefore in situ hybridization and immunohistochemistry was used to investigate the cellular sources of TGF-alpha production in this model system. Surprisingly one cell type in the inflammatory infiltrate present in the connective tissue adjacent to the transformed epithelium represented a major source of TGF-alpha mRNA. Detailed analysis of these cells revealed that they were eosinophils. In addition to TGF-alpha mRNA, about 40% of the eosinophils associated with the oral tumors exhibited TGF-alpha product reactive with a monoclonal antibody against the C terminus of the mature TGF-alpha peptide. Normal hamster bone marrow eosinophils also exhibited TGF-alpha mRNA and product by in situ hybridization and immunohistochemistry. These results suggest that the eosinophil represents a biologically significant source of TGF-alpha.

9,10-Dimethyl-1,2-benzanthracene↗