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Biomedical subjects

J R Gordon

Publications and source records attributed to J R Gordon.

At least 55 records · Page 3Linked to original sources
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

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

Factors V and VII anticoagulant activities in the salivary glands of feeding Dermacentor andersoni ticks.

The salivary glands of Dermacentor andersoni ticks possess anticoagulant activities that can alter the clotting time of rabbit whole blood. Salivary gland extracts from female ticks inhibit both the intrinsic and extrinsic coagulation systems, and maximal activities against both pathways occur when the ticks attain about 250 mg feeding weight. These anticoagulants are directed against both coagulation factors V and VII, but they do not affect factors II or X. Despite this salivary anticoagulant activity, heavily tick-infested rabbits suffer no visible alteration of their peripheral blood coagulability and have no detectable circulating fibrin degradation products, suggesting that the ticks do not secrete a factor with fibrinolytic activity.

Animals↗
PubMed1991

Nonspecific activation of complement factor 5 by isolated Dermacentor andersoni salivary antigens.

Salivary gland extracts from feeding Dermacentor andersoni ticks contain an activity that activated both rabbit and human complement to produce inflammatory cell chemotactic activity. Purified salivary antigens (SGA), isolated from the glands of female ticks with anti-saliva immunoglobulins from tick-resistant rabbits, also induced chemotactin generation. It has been demonstrated previously that the intradermal injection of such SGA into normal animals induces nonspecific inflammatory reactions that mimic the responses accompanying tick feeding on normal animals. The chemotactic activity generated in serum by SGA was mediated either directly or indirectly by C5, as it could be abrogated by antisera directed against C5 but not by anti-C3 sera. That the in vitro generation of C5 by tick salivary proteins has relevance to tick feeding is suggested by the fact that many of the host inflammatory responses elicited by ixodid tick feeding also are effects known to be elicited by C5.

Animals↗
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

Schistosoma mansoni: analysis of the humoral and cellular basis of resistance in guinea-pigs vaccinated with radiation-attenuated cercariae.

This study addresses the humoral and cellular basis of specific acquired immunity in the guinea-pig irradiated vaccine model of schistosomiasis mansoni. Rodents vaccinated with 500 gamma-irradiated cercariae and then splenectomized 4.5 weeks later showed a 33% reduction in resistance to challenge as compared to vaccinated animals or vaccinated/sham splenectomized controls. Serum harvested from once vaccinated individuals conferred modest levels of resistance upon naive recipients in some experiments, but transfer was not achieved consistently. Serum from vaccinated and thrice boosted rodents (Vbbb) routinely transferred around 45% immunity, however, provided it was given in 4 ml aliquots on day 9 post-challenge; Vbbb serum thus transferred 50% of donor immunity. Interestingly, multiple doses of this protective serum given on and either side of day 9 did not enhance the protection achieved with a single 4 ml aliquot. Neither peripheral lymph node cells nor splenocytes from the polyvaccinated serum donors were able to transfer resistance to recipient guinea-pigs and they failed to augment the protection achieved with Vbbb serum. Foot-pad testing revealed no correlation between delayed hypersensitivity responses and immunity to challenge in vaccinated guinea-pigs. Although polyvaccine guinea-pig serum successfully protected homologous recipients, it failed to protect mice when administered either at the time of challenge (the optimal schedule for transfer of polyvaccine mouse serum), or around day 9 (the optimal schedule for guinea-pigs). Similarly, guinea-pigs could not be protected with polyvaccine rat serum that conferred 75% resistance upon naive recipient rats.

Animals↗
PubMed1989

Interleukin 3-dependent and -independent mast cells stimulated with IgE and antigen express multiple cytokines.

In response to IgE and specific multivalent antigen, mast cell lines (both growth factor-dependent and -independent) induce the transcription and/or secretion of a number of cytokines having a wide spectrum of activities. We have identified IL-1, IL-3, IL-5, IL-6, IFN-gamma, GM-CSF, JE, MIP1 alpha, MIP1 beta, and TCA3 RNA in at least two of four mast cell clones. The production of these products (except JE) is activation-associated and can be induced by IgE plus antigen. In selected instances cytokine expression can also be induced by activation with Con A or phorbol ester plus ionophore, albeit to levels less than those observed with IgE plus antigen. In addition, long-term mast cell clones and primary cultures of bone marrow-derived mast cells specifically release IL-1, IL-4, and/or IL-6 bioactivity after activation. These findings suggest that in addition to their inflammatory effector function mast cells may serve as a source of growth and regulatory factors. The relationship of mast cells to cells of the T lymphocyte lineage is discussed.

Animals↗
PubMed1989

Mast cells: immunologically specific effectors and potential sources of multiple cytokines during IgE-dependent responses.

Mast cells are critical effectors in many IgE-dependent responses, and the numbers and phenotype of certain mast cell populations can be influenced, through IL-3 and IL-4, by the same T cells that regulate IgE production. However, IgE can interact with cells other than mast cells, and different mast cell populations express significant variation in multiple important aspects of their phenotype, including mediator content and responses to cytokines and stimuli of activation. As a result it may be difficult to define the unique contributions of mast cells to IgE-dependent reactions. One approach for analysing the roles of various mast cell populations in individual biological responses is to attempt to elicit these reactions in mice in which the presence or absence of specific mast cell populations can be regulated experimentally. We have used genetically mast cell-deficient and mast cell-reconstituted mice to demonstrate that mast cells provide essential effector function in certain IgE-dependent responses involving the skin, stomach or lungs but are not necessary for the pulmonary alterations and death associated with active anaphylaxis. Similar approaches can be used to investigate the biological significance of the production, by mast cells stimulated with IgE and specific antigen, of cytokines similar or identical to IL-1, IL-3, IL-4, IL-5, IL-6, TNF-alpha/cachectin, IFN-gamma, GM-CSF, JE, MIP-1 alpha, MIP-1 beta and TCA3.

Animals↗
PubMed1989

What's at stake.

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Drug Industry↗
PubMed1988

Functional role of specific secreted and cell surface molecules in tumour cell invasion and metastasis.

The invasion and metastatic spread of tumour cells are complex biological processes involving an array of cell surface and secreted protein molecules which function as specific recognition and catalytic agents in each step of the malignant cascade. In order to begin to identify these molecules and implicate them as true functioning agents, our laboratory has developed selected panels of monoclonal antibodies that have been screened for their ability to inhibit specific manifestations of the malignant phenotype in various model systems. Since monoclonal antibodies recognize only single and unique determinants, it is hypothesized that any monoclonal antibody which is specifically antifunctional will allow for the identification and isolation of relevant protein molecules.

Animals↗
PubMed1988

A review of Ontario's revised drug cost programs.

Ontario's PARCOST program was introduced in 1970. This paper examines the changes wrought in the program since its inception and the economic and political reasons for those changes. It describes the components of the pharmacist's claim, the nature of price controls, and the problems with formulary decisions. The authors suggest that the driving force behind budget restraints is cost containment through lower drug prices with little emphasis on therapeutic considerations.

Cost Control↗
PubMed1988

Immunity to Schistosoma mansoni in guinea-pigs vaccinated with radiation-attenuated cercariae. T-cell activation of macrophages for larval killing.

This study addresses macrophage activation in guinea-pigs vaccinated with radiation-attenuated cercariae of Schistosoma mansoni. Peritoneal exudate macrophages elicited in vaccinated animals by mineral oil injection were activated to kill larval schistosomes in vitro. Killing efficiency is dependent upon the cell: target ratio employed and is enhanced by, but is not strictly dependent on, the presence of specific antibodies. Macrophages co-cultured with parasites release superoxide radicals and hydrogen peroxide, but the use of inhibitors has shown that neither of these reactive oxygen intermediates are the causal agents of cellular cytotoxicity in this system. Oil-elicited macrophages from naive guinea-pigs do not show comparable activation; they can, however, be activated in vitro by incubation with culture supernatant fluids from schistosome antigen-stimulated spleen, or lymph node cells harvested from vaccinated guinea-pigs. Naive macrophages activated in this way kill schistosomula in vitro and release the activation markers IL-1 and superoxide anion. The macrophage-activating factor (MAF) present in spleen cell culture supernatant fluids has a MW of 35,000-55,000, but does not have the chemical characteristics of gamma-interferon. In this study MAF is shown to be released by a population of lymph node cells that does not adhere to nylon-wool columns, that responds well in proliferation assays to schistosome antigens and to the T-cell mitogen concanavalin A, but does not respond to the B-cell mitogen lipopolysaccharide. These cells have been identified as small lymphocytes.

Animals↗
PubMed1987

Pericardial effusion in women with breast cancer.

Ninety patients with a history of breast cancer and pericardial effusion detected on echocardiography were identified and divided on a clinical basis into three groups. Group 1 consisted of 20 patients who had progressive metastatic breast cancer and echocardiography performed on a routine basis as a part of a clinical trial involving 38 patients. All 20 had small unexpected effusions, and only one patient developed symptomatic malignant pericardial disease late in her clinical course. Group 2 consisted of 32 patients who were without evidence of metastatic disease at the time of positive echocardiography and the etiology was considered benign in all patients. Six patients required pericardiectomy, five for severe radiation induced pericarditis and one for amyloid. No patient developed proven or suspected malignant pericardial disease. Group 3 comprised 38 patients who had known metastatic disease outside the pericardium at the time of positive echocardiography. Nineteen patients in Group 3 had histologically proven malignant involvement during life or at autopsy, and five more had suspected malignant pericardial disease. Ten patients initially were treated with pericardiectomy and 28 patients were managed with systemic therapy alone (24 patients) or with pericardiocentesis (four patients). Among the 12 patients with malignant effusion treated without surgery, proven local progression of pericardial disease occurred in six, with sudden death in two of those patients. No patient treated initially with surgery suffered progression of her pericardial disease. It was concluded that: small, clinically unsuspected pericardial effusions appear to be relatively common in women with metastatic breast cancer; no patient with clinical pericardial disease confirmed on echocardiography and no evidence of metastatic breast cancer developed malignant pericardial involvement; 50% of patients with known metastatic disease and a clinically apparent pericardial effusion had malignant pericardial disease; and nonsurgical therapy in patients with histologically proven or clinically suspected malignant pericardial effusion was associated with a high incidence of progressive pericardial disease.

Adult↗