WO1992001465A1 - Inhibition par l'interleukine-8 de la liberation, induite par cytokine, des histamines contenues dans des basophiles - Google Patents

Inhibition par l'interleukine-8 de la liberation, induite par cytokine, des histamines contenues dans des basophiles Download PDF

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Publication number
WO1992001465A1
WO1992001465A1 PCT/US1991/005274 US9105274W WO9201465A1 WO 1992001465 A1 WO1992001465 A1 WO 1992001465A1 US 9105274 W US9105274 W US 9105274W WO 9201465 A1 WO9201465 A1 WO 9201465A1
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allergic
cells
hrf
histamine release
histamine
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PCT/US1991/005274
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English (en)
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Rafeul Alam
Michael A. Lett-Brown
J. Andrew Grant
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Board Of Regents, The University Of Texas System
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Priority to AU84124/91A priority Critical patent/AU661461B2/en
Priority to JP3514117A priority patent/JPH06502396A/ja
Publication of WO1992001465A1 publication Critical patent/WO1992001465A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2053—IL-8
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • Histamine releasing factors represent a group of cyto ines that release mediators from basophils and mast cells.
  • HRF Histamine releasing factors
  • Basophils and mast cells have been the subjects of scientific investigation since they were described by Paul Ehrlich in the 1870s. Mast cells are generally found in connective tissue; basophils, in the blood. The two cell types have many similarities. Both contain numerous metachromatically staining granules, both have cell surface receptors that bind IgE with high affinity, and both contain a myriad of diverse allergic mediators that can cause symptoms ranging from itching of the skin to the most life-threatening clinical situation, anaphylaxis. Basophils and mast cells collectively account for virtually all of the total body histamine and are collectively referred to as histamine-containing proallergic cells. There is convincing evidence that mast cells and basophils are essential for induction of allergic hypersensitivity reactions.
  • mast cells are the primary effector cell of such allergic diseases as asthma, allergic rhinitis, conjunctivitis, urticaria and anaphylaxis. Increased numbers of mast cells have been found in bronchoalveolar lavage fluid, respiratory mucosa, nasal mucosa, and biopsy specimens of urticarial lesions in these disorders.
  • mast cell mediators such as histamine and prostaglandin (PG) D 2 , have been recovered from serum, bronchoalveolar lavage fluid, nasal washings, and skin blister fluid during natural and provoked allergic reactions.
  • PG prostaglandin
  • mast cell granule-specific enzyme tryptase (not found in basophils) has been detected in serum from patients with allergic and anaphylactoid reactions.
  • mast cell-derived mediators alone or in combination, can evoke such typical allergic symptoms as bronchospasm, angioedema, cough, mucus secretion, rhinorrhea, sneezing, and wheal-and-flare skin reactions and mast cell-specific degranulating agents can induce allergic reactions in vivo.
  • mast cells are involved in the pathogenesis of a number of chronic inflammatory diseases. Increased numbers of mast cells have been detected in biopsy specimens from patients with rheumatoid arthritis, ulcerative colitis, Crohn's disease, sarcoidosis, hypersensitivity pneumonitis, pulmonary fibrosis, nasal polyps, atopic dermatitis, allergic contact dermatitis, bullous pemphigoid, keloid formation, scleroderma and progressive systemic sclerosis, acute and chronic graft vs. host disease, and parasitic infestation. Mast cells also have been implicated in regulation of nerve growth, and regulation of mast cell degranulation has proved useful in neurofibro atosis.
  • Cromolyn sodium a putative mast cell stabilizer, has been found beneficial to a subgroup of patients with ulcerative colitis, particularly those with proctitis.
  • Basophils appear to be particularly involved in some forms of allergic contact dermatitis, especially to poison ivy and, experimentally, to dinitrochlorobenzene. These cells represent 5% to 15% of the total infiltrating cells and are present within eight hours after application of the allergen to the skin. Given the number of inflammatory mediators released by mast cells and basophils, it is conceivable that sustained piecemeal degranulation of these cells contributes to the chronic inflammatory nature of the aforementioned disorders.
  • mast cells and basophils are stimulated to release histamine, leukotrienes, and other inflammatory mediators by the bridging of cell surface-bound IgE antibodies by appropriate allergens (or anti-IgE antibodies) , but the severity of a number of allergic diseases, for example bronchial asthma, rhinitis, and conjunctivitis, does not correlate with a patient's IgE level.
  • mast cells are believed to play a role in various other diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary fibrosis, and sarcoidosis, in the majority of these diseases, IgE antibody cannot be found.
  • HRA histamine releasing activity
  • HRF histamine releasing factor(s)
  • HRF is also synthesized by B- lymphocytes and T-lymphocytes, alveolar macrophages, platelets, neutrophils, and blood monocytes cultured in vitro.
  • B- lymphocytes and T-lymphocytes B- lymphocytes and T-lymphocytes
  • alveolar macrophages alveolar macrophages
  • platelets platelets
  • neutrophils neutrophils
  • blood monocytes cultured in vitro.
  • HRF has been shown to induce secretion of leukotrienes and to be chemotactic for basophils and monocytes.
  • HRF as a mediator of human allergic disease.
  • an HRF-like material has been obtained from skin blister fluid obtained during the late allergic reaction, now considered an important factor in the pathogenesis of chronic asthma and other allergic conditions.
  • HRF has also been recovered in nasal washings.
  • HRF induces bronchoconstriction on inhalation by asthmatic subjects and a wheal-and-flare reaction in humans and non-human primates.
  • Mononuclear cells from asthmatic patients have been shown to spontaneously produce relatively large amounts of HRF, and HRF production is enhanced on jln vitro incubation with specific allergen.
  • HRF-induced mediator release could provide a valuable tool in treating mast cell/basophil dependent disorders, which include the allergic diseases.
  • Our prior patent applications described a human histamine release inhibitory factor having a molecular weight of about 8,000 - 10,000 daltons.
  • IL-8 recombinant human Interleukin 8 (IL-8) (m.w. about 8,000 daltons) is an extremely potent inhibitor of HRF-induced histamine release.
  • HRIF and IL-8 specifically antagonize cytokine mediated histamine release.
  • IL-8 is secreted as a 79 amino acid peptide which then undergoes proteolytic cleavages yielding either a 77 or a 72 amino acid peptide both being active as neutrophil activator/attractant.
  • T. Yoshimura et al. Proc. Natl. Acad. Sci. USA 84:9233 (1987); Leonard, E.J., and T. Yoshimura, Am. J. Respir. Cell Mo. Biol. 2:479 (1990); M. Baggiolini et al., J. Clin. Invest. 84:1045 (1989)).
  • IL-8/NAP1 neurotrophil activating peptide alpha, beta and gamma for the 79, 77 and 72 amino acid peptides respectively
  • IL-8 is adopted herein as covering the each of those species.
  • IL-8 is produced by many cells including monocytes, macrophages, lymphocytes, endothelial cells, fibroblasts and keratinocytes.
  • Recombinant human IL-8 beta, a 77 amino acid peptide with alanine in its N-terminus was used in the studies described below.
  • a method for inhibiting HRF- induced release of an allergic mediator from pro-allergic cells comprising exposing the pro-allergic cells to interleukin 8.
  • the pro-allergic cells comprise mast cells, or basophils, and the allergic mediator is histamine.
  • the method may be performed either in vitro or in vivo, preferably using human interleukin 8 and human pro-allergic cells.
  • the interleukin 8 is present at a concentration of at least about lO'-t ⁇ .
  • the invention also includes a method for inhibiting release of allergic mediators from pro-allergic cells comprising exposing the pro-allergic cells to an effective concentration of interleukin 8 to inhibit histamine release.
  • histamine release may be inhibited by at least about 10 to at least about 60 percent, at least about 15 to at least about 60 percent, and more preferably, at least about 30 to at least about 60 percent, when measured according to the protocol set forth here.
  • FIGURE 1 Inhibition of HRF-induced histamine release from basophils by IL-8.
  • Leukocytes from 20 donors ten allergic and ten normal subjects
  • IL-8 IL-8 for 5 min
  • mononuclear cell-derived HRF The percent inhibition of histamine release from cells incubated with IL-8 as compared to buffer is shown.
  • Mean histamine release by HRF was 50+8% for cells from allergic individuals and 38+7% for cells from non-allergic individuals. The difference in the inhibition of histamine release between the two groups was statistically significant (*) at p ⁇ 0.04.
  • FIGURE 2 Effect of IL-8 on histamine release from basophils by MNC-HRF, anti-IgE, FMLP and C5a.
  • Leukocytes were preincubated with IL-8 (lO ⁇ ) for 5 min and then challenged with a predetermined dose of various secretagogues.
  • the number of experiments (N) is 20 for MNC-HRF, 10 for anti-IgE, and 3 for FMLP and C5a.
  • Asterisk indicates statistical difference compared to control release at p ⁇ 0.04.
  • FIGURE 3 The requirement for preincubation of leukocytes with IL-8 was investigated. Cells were separately preincubated with buffer or with IL-8 for 5 minutes and then challenged with HRF. In another set of experiments, IL-8 and HRF were added simultaneously to the cells or HRF was preincubated with cells first and IL-8 was added 5 min later. Results of one of three experiments are shown.
  • FIGURE 4 The effect of removal of IL-8 after preincubation on the inhibition of histamine release. After the preincubation with IL-8, leukocytes were washed 3x with 30 volumes of buffer. The cells were then challenged with HRF. In control experiments cells were preincubated with buffer and then treated as above. Results of one of three experiments are shown.
  • FIGURE 5 IL-8-induced histamine release from basophils. Leukocytes from 20 donors were incubated with various concentrations of IL-8 for 45 min and the released histamine was measured. Spontaneous histamine release in the presence of buffer was subtracted. Basophils from 6 of twenty donors (two normals and four allergic subjects) responded to IL-8 beta. Results shown are mean+SEM of histamine release by basophils from the six responder donors.
  • FIGURE 6 The effect of neutrophil depletion on IL-8- induced histamine release from basophils. Neutrophil-rich and neutrophil-depleted leukocytes from three donors were separated using sedimentation with hydroxyethyl starch and Ficoll-Hypaque gradient (sp. gr. 1.077) centrifugation respectively. The cells were then incubated with IL-8 and the released histamine was assayed.
  • FIGURE 7 The effect of preincubation with IL-8 on subsequent IL-8-induced histamine release from leukocytes.
  • Leukocytes from four preselected allergic donors were preincubated with different concentrations of IL-8 for 5 min and then challenged with IL-8 (lO- ⁇ ) . Error bars were omitted for clarity (SD ⁇ 1%).
  • FIGURE 8 The combined action of IL-3, IL-8 and GM- CSF on basophils and comparison with MNC-HRF.
  • Leukocytes from 7 allergic donors were incubated with IL-3 (1 ug/ml final concentration) , IL-8 (10" ⁇ ) and GM-CSF (1 ug/ml) added simultaneously to the cells.
  • the histamine release by these three cytokines was compared with that by MNC-HRF.
  • the histamine release by IL-3, IL-8 and GM-CSF were 30%, 7% and 7% in SC, 15%, 6% and 12% in TW and 12%, 6%, and 0% in BW respectively.
  • the release by the cytokines in other donors was negligible.
  • RPMI 1640 was obtained from GIBCO Laboratories, Grand Island, NY; human serum albumin, glutamine, Ficoll, Hypaque, Concanavalin A (Con A) , penicillin, streptomycin, FMLP and recombinant C5a from Sigma Chemicals Co. , St. Louis, MO; Hepes from Research Organics, Inc., Cleveland, OH; hydroxyethyl starch (HetaStarch) from American McGaw, Irvine, CA; human recombinant IL-3 and human recombinant endothelial IL-8 (77 amino acid peptide with alanine in its N-terminus) was obtained from Pepro Tech. Inc., Rocky Hills, NJ.
  • IL3 ⁇ xlO ⁇ /mg
  • GM-CSF 1.7xl0 7 U/mg
  • rabbit and-human IgE serum 460,000 IU/ml was from Behring Diagnostics, Somervilie, NY.
  • Leukocytes were isolated from buffy coats obtained from normal blood bank donors. MNC were isolated by Ficoll-Hypaque gradient centrifugation as previously described (R. Alam et al., J. Clin. Invest. 82:2056 (1988)) and pulsed with Con A (25ug/ml in RPMI 1640 medium) for 4 hr, washed twice with Hanks' balanced salt solution, resuspended in RPMI 1640 medium, and then cultured for 72 hr. Supernatants were harvested and concentrated 5Ox using an Amicon ultrafiltration chamber with YM-5 filters (MW cut-off 5,000) and ultracentrifuged.
  • Spontaneous histamine release was assessed by incubating the cells in HACM buffer alone. The total histamine content of the cells was measured by lysing the cells with 3% perchloric acid. The percentage of histamine release was calculated according to the formula: [(histamine in the supernatant) lOO]/(total histamine in the cells).
  • Spontaneous histamine release from the cells was usually less than 5%.
  • the values of spontaneous histamine release were subtracted from the calculated histamine release.
  • E. Histamine release inhibition assay For the inhibition assay, 50 ul aliquots of cells were first incubated with various dilutions of IL-8 (10" n to 10" * -M) for 5 min at room temperature and then challenged with 50 ul of HRF, anti-IgE (1:3000 dilution), IL3 (1 ug/ml), C5a (1 ug/ml) or FMLP (1:3000 dilution) separately (all concentrations shown are final) . The cells were then further incubated for 45 min in a water bath at 37 * C and the supernatants were separated by centrifugation. Histamine content of the supernatant and total cellular content were determined as described above.
  • a typical experimental protocol includes: Preincubation Challenge a. leukocytes + buffer + buffer b. leukocytes + buffer + HRF* c. leukocytes + IL-8 + buffer d. leukocytes + IL-8 + HRF*
  • IL-8 In order to assess the inhibitory activity of IL-8, the e fect of preincubation of leukocytes with the cytokine on histamine release by MNC-HRF was studied on cells from 10 allergic and 10 non-allergic donors. IL-8 inhibited HRF-induced histamine release from basophils obtained from 17 of 20 subjects (Fig. 1) . Two of the non-inhibited leukocyte samples were obtained from allergic donors; the other was obtained from a non-allergic donor. As shown in Section III below, however, leukocytes from the two allergic donors released low levels of histamine upon exposure to IL-8 alone, but cells from the normal donor did not.
  • IL-8 inhibited IL-3-induced histamine release from two donors.
  • the release by IL-3 (1 ug/ml) from leukocytes preincubated with buffer were 40+1% and 15+0.5% from donor 1 and donor 2 respectively.
  • IL-8 (10" 10 10' 6 M)
  • the release of by IL-3 were 31+1% and 7+0.3% respectively at the highest concentration of IL-8.
  • the third donor did not show any inhibition. This particular donor is a possible non-responder to IL-8 since there was no inhibition of HRF- induced histamine release by IL-8 from this donor, either.
  • IL-8 did not show any inhibitory activity when added to the cells simultaneously with MNC-HRF or added five min after MNC-HRF
  • IL-8 In order to determine whether continued presence of IL-8 is necessary after preincubation with the cells, leukocytes were preincubated with IL-8 for five minutes, washed 3 times with 30 volumes of buffer, and then challenged with MNC-HRF. As shown in Figure 4, that procedure did not abrogate the inhibitory effect of IL-8.
  • IL-8 acts as a strong inhibitor of cytokine-induced histamine release at concentrations as low as 10 ⁇ 9 -10" 8 M.
  • Neutrophils have high affinity receptors for IL-8 (also described as neutrophil activating peptide 1) (T. Yoshimura et al., Proc. Natl. Acad. Sci. USA 84:9233 (1987)). Since our leukocyte preparation contained neutrophils, we postulated that the low histamine release from basophils by IL-8 might be due to the avid binding of the cytokine to neutrophils. Therefore we have compared IL-8 activity using neutrophil-depleted mononuclear cell preparations that contained 2-3% of basophils with leukocyte preparations containing approximately 60% neutrophils.
  • Neutrophil-depleted mononuclear cells (less than 3% neutrophils) were purified by Ficoll-Hypaque gradient (sp. gr. 1.077). As shown in Figure 6, simultaneous experiments done with neutrophils-depleted and neutrophil-rich preparations did not show any difference in histamine release. Since IL-8 did release a low amount of histamine from cells of selected donors, we performed the following experiment in order to determine whether inhibition of HRF- induced histamine release by IL-8 could be due to specific desensitization (down regulation of receptors) . For that experiment, leukocytes obtained from selected IL-8 responder donors were preincubated with various concentrations of IL-8 and then challenged with 10" ⁇ of IL-8.
  • IL-3 alone (25 ng/ml) released 8+0.2% of histamine.
  • Preincubation with IL-3 followed by incubation with IL-8 cause 20+0.5% and 32+1% of histamine release respectively.
  • This particular allergic donor is highest "releaser 1 * of histamine among our donors, and he is also one of few donors who responds to both IL-3 and IL-8.
  • IL-3 and GM-CSF release histamine from basophils of selected donors at high concentrations (1 ug/ml) (R. Alam et al., J. Immunol. 142:3431 (1989)). We, therefore, asked whether the combined action of IL-3, IL-8 and GM-CSF would mimic the activity of mononuclear cell-derived HRF in cells from those donors. Seven patients were studied using relatively high concentrations of IL-3 (final concentration of 1 ug/ml), IL- ⁇ flO- ⁇ M) and GM-CSF (1 ug/ml). Three allergic patients released significant amounts of histamine, although less than MNC-derived HRF.
  • MNC-derived HRF released histamine from basophils obtained from most normal donors.
  • the Interleukin 8 will prove to be useful in treating numerous diseases in which mast cells and basophils are involved, especially the allergic disorders.
  • these include, but are not limited to, bronchial asthma, allergic rhinitis, conjunctivitis, and urticaria.
  • the best mode of administering the factor will depend on the particular clinical situation, it is believed that the factor may be most easily administered by formulating it together with a suitable pharmaceutical excipient and administering the formulation topically.
  • the factor could be formulated as a component of an aerosol for intranasal or intrabronchial administration. These delivery devices might be modified to be powered by freon.
  • This mode of administration may be particularly useful in treating certain allergic diseases, for example, allergic rhinitis and bronchial asthma.
  • the factor could also be administered topically to the skin or eye; this formulation might prove effective for allergic disorders at these sites.
  • the factor could be formulated for intravenous, intramuscular, subcutaneous, intradermal, or intraarticular injection; such injections might be used to treat inflammatory reactions at these sites in which the triggering of mediator release from basophils and mast cells is involved in the pathogenesis of the illness.
  • suitable excipients for example, saline or physiologic buffers, are known to those of skill in the art and may be used. Of course, in some cases, it may be desirable to incorporate a preservative into this excipient. Methods for incorporating therapeutic agents into pharmaceutical vehicles are believed to be well within the skill of the art.
  • the invention has not yet been used in clinical settings.
  • the inventors have relied upon the published results with other cytokines in predicting the acceptable pharmaceutical dosage for Interleukin 8.
  • the most relevant studies of an aerosol were the use of intranasal alpha 2-interferon to prevent viral upper respiratory infections. Douglas, et al., (New Engl. J. Med.. 314:65 (1986)) and Hayden, et al. , (New Engl. J. Med.. 314:71 (1986)) administered 5 X 10 6 international units (IU) per day for an effective response.
  • This cytokine is currently licensed for treatment of hairy cell leukemia at a dose of 3 X 10 6 IU per day by intramuscular or subcutaneous administration.
  • Interleukin 8 recently injected G/M CSF by continuous infusion at doses of 1.5 to 25 X 10 6 units/M 2 of body surface for an effective response in patients with myelodysplasia. Therefore, the inventors would propose that the effective dose of Interleukin 8 will be from about 10 4 to about 10 7 units. Furthermore, the inventors would define a unit in the traditional manner: 1 unit causes 50% inhibition of near maximal histamine release from HRF-stimulated basophils. The exact doses of Interleukin 8 to be used in a particular clinical application must be determined by accepted pharmaceutical methods known to those skilled in the pharmaceutical arts.

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Abstract

La présente invention a permis d'observer l'inhibition, par l'interleukine-8 (IL-8), de la libération induite par HRF (facteur de libération d'histamines) des histamines contenues dans des basophiles chez 17 donneurs d'une population de 20 donneurs, selon des concentrations de niveaux aussi bas que 10?-9 à 10-8¿ M. On a observé une inhibition de la libération d'histamines par IL-8 notablement plus élevée chez les sujets normaux que chez les patients atteints d'allergies (59 ± 8 % contre 31 ± 7 %, p<0,04). L'IL-8 n'a eu une action inhibitrice que sur la libération d'histamines induite par cytokine et n'a pas influé sur la libération d'histamines par anti-IgE par FMLP et par C5a. Un procédé permettant d'inhiber la libération d'agents vecteurs d'allergies grâce à l'interleukine 8 est revendiqué.
PCT/US1991/005274 1990-07-25 1991-07-25 Inhibition par l'interleukine-8 de la liberation, induite par cytokine, des histamines contenues dans des basophiles WO1992001465A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU84124/91A AU661461B2 (en) 1990-07-25 1991-07-25 Interleukin 8 inhibition of cytokine-induced histamine release from bosophils or mast cells
JP3514117A JPH06502396A (ja) 1990-07-25 1991-07-25 好塩基球からのサイトカイン誘導ヒスタミン放出のインターロイキン８阻害

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US55800490A 1990-07-25 1990-07-25
US558,004 1990-07-25

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WO1992001465A1 true WO1992001465A1 (fr) 1992-02-06

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CA (1) CA2087979A1 (fr)
WO (1) WO1992001465A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994021277A1 (fr) * 1993-03-15 1994-09-29 The Research Foundation Of State University Of New York Procede pour inhiber la liberation de mediateurs stimulant l'inflammation, par des cellules basophiles et des mastocytes
US5436222A (en) * 1993-03-15 1995-07-25 The Research Foundation Of State University Of New York Use of platelet factor 4 to treat inflammatory diseases
US5554590A (en) * 1992-08-19 1996-09-10 East Carolina University Method of treating asthma
US6520173B2 (en) * 2000-05-02 2003-02-18 Robert Martin Lautner Portable solid-fuel camp-stove

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4571952B2 (ja) * 2004-02-05 2010-10-27 アクセス ビジネス グループ インターナショナル リミテッド ライアビリティ カンパニー 抗アレルギー組成物及び関連方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE68926743T2 (de) * 1988-01-12 1997-01-09 Univ Texas Die freisetzung des histamin hemmenden faktors sowie diesen enthaltende präparate
AU2348492A (en) * 1991-07-19 1993-02-23 East Carolina University Method of treating asthma

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Clinical Research, Vol. 38, No. 2, 1990 E S Schulman et al.: "Differential Effects of interleukin-8 on human basophil and human lung mast cell histamine release ", *
Dialog Information Services, file 5, BIOSIS 1969-91,Dialog Accession no. 7904975, Kuna P et al: "IL-8 inhibits histamine release induced by histamine releasing factors HRF-S connective tissue activa- ting peptide III CTAP-III and IL-3 from human basu- phils, & Immunol 87 (i PART 2). 1991. 207 *
Dialog Information Services, file 5, BIOSIS 1969-91,Dialog accession no. 7905110, Alam, R et al: "Agonistic- antagonistic property of interleukin 8 on basophils identification of IL-8 as a potent inhibitor of cytokine-induced histamine release" Immunol 87 (i PART 2). 1991. 241 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5554590A (en) * 1992-08-19 1996-09-10 East Carolina University Method of treating asthma
WO1994021277A1 (fr) * 1993-03-15 1994-09-29 The Research Foundation Of State University Of New York Procede pour inhiber la liberation de mediateurs stimulant l'inflammation, par des cellules basophiles et des mastocytes
US5436222A (en) * 1993-03-15 1995-07-25 The Research Foundation Of State University Of New York Use of platelet factor 4 to treat inflammatory diseases
US5474983A (en) * 1993-03-15 1995-12-12 The Research Foundation Of State University Of New York Method of inhibiting pro-inflammatory mediator release from basophils and mast cells
US6520173B2 (en) * 2000-05-02 2003-02-18 Robert Martin Lautner Portable solid-fuel camp-stove

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AU8412491A (en) 1992-02-18
JPH06502396A (ja) 1994-03-17
CA2087979A1 (fr) 1992-01-26
EP0540663A1 (fr) 1993-05-12

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