Prognostic impact of morphometric nuclear grade of endometrial carcinoma

BACKGROUND & AIMS: The pathogenesis of Clostridium difficile toxin A-induced intestinal inflammation is not completely understood. The aim of this study was to define the contribution of mast cells to the fluid secretion and neutrophil infiltration associated with toxin A-induced enteritis. METHODS: Fluid secretion and neutrophil infiltration in toxin A- or buffer-challenged ileal loops were assessed in normal, mast cell-deficient, and mast cell-deficient KitW/KitW-v mice that had undergone selective repair of their mast cell deficiency. The effect of a specific substance P-receptor antagonist was also studied. RESULTS: Intestinal fluid secretion and neutrophil recruitment were significantly diminished in mast cell-deficient KitW/KitW-v and mast cell-deficient MgfSl/MgfSl-d mice compared with the respective normal mice. Mast cell-reconstituted KitW/KitW-v mice showed responses similar to the normal congenic mice. Administration of a specific substance P-receptor antagonist (CP-96,345) reduced toxin A-induced intestinal fluid secretion and inhibited neutrophil infiltration in normal, mast cell-deficient KitW/KitW-v, and mast cell-reconstituted KitW/KitW-v mice. CONCLUSIONS: C. difficile toxin A elicits intestinal fluid secretion and neutrophil infiltration by both mast cell-dependent and -independent pathways, and substance P participates in both pathways.     

Mast cells mediate acute inflammatory responses to implanted biomaterials

Implanted biomaterials trigger acute and chronic inflammatory responses. The mechanisms involved in such acute inflammatory responses can be arbitrarily divided into phagocyte transmigration, chemotaxis, and adhesion to implant surfaces. We earlier observed that two chemokines-macrophage inflammatory protein 1alpha/monocyte chemoattractant protein 1-and the phagocyte integrin Mac-1 (CD11b/CD18)/surface fibrinogen interaction are, respectively, required for phagocyte chemotaxis and adherence to biomaterial surfaces. However, it is still not clear how the initial transmigration of phagocytes through the endothelial barrier into the area of the implant is triggered. Because implanted biomaterials elicit histaminic responses in the surrounding tissue, and histamine release is known to promote rapid diapedesis of inflammatory cells, we evaluated the possible role of histamine and mast cells in the recruitment of phagocytes to biomaterial implants. Using i.p. and s. c. implantation of polyethylene terephthalate disks in mice we find: (i) Extensive degranulation of mast cells, accompanied by histamine release, occurs adjacent to short-term i.p. implants. (ii) Simultaneous administration of H1 and H2 histamine receptor antagonists (pyrilamine and famotidine, respectively) greatly diminishes recruitment and adhesion of both neutrophils (<20% of control) and monocytes/macrophages (<30% of control) to implants. (iii) Congenitally mast cell-deficient mice also exhibit markedly reduced accumulation of phagocytes on both i.p. and s.c implants. (iv) Finally, mast cell reconstitution of mast cell-deficient mice restores "normal" inflammatory responses to biomaterial implants. We conclude that mast cells and their granular products, especially histamine, are important in recruitment of inflammatory cells to biomaterial implants. Improved knowledge of such responses may permit purposeful modulation of both acute and chronic inflammation affecting implanted biomaterials.     

Production of IL-13 by human lung mast cells in response to Fcepsilon receptor cross-linkage

BACKGROUND: Cross-linkage of the high affinity Fcepsilon receptors (FcepsilonRI) on the surface of the mast cell by the allergen-IgE complex is a central event in the induction of allergic inflammatory reactions. However, the precise roles of human mast cells in the perpetuation of allergic inflammation is not well known. IL-13 plays an important role in the regulation of allergic inflammation, especially being involved in the induction of IgE synthesis. OBJECTIVE: We investigated whether human lung mast cells have the capacity to produce IL-13 by cross-linking of the FcepsilonRI. METHODS: Lung mast cells were purified by affinity magnetic selection with monoclonal antibody YB5.B8 against c-kit to achieve a final mast cell purity of more than 93%. Purified mast cells were precultured with human myeloma IgE (3 microg/mL) for 16 h before challenge with stem cell factor (SCF) (50 ng/mL) and anti-IgE (1 microg/mL). By RT-PCR, ELISA and immunocytochemistry, we evaluated the capacity of human lung mast cells to express and produce IL-13. RESULTS: IgE-dependent activation of human lung mast cells caused an increase in IL-13 mRNA expression which persisted for up to 12 h. Immunoreactive IL-13 was detectable 24 h after activation of sensitized lung mast cells with SCF and anti-IgE in 6 of 13 non-asthmatic donors and a million of mast cells secreted 106.7 +/- 42.65 (mean +/- SE) pg of IL-13 into the culture supernatants. SCF alone induced 61.63 +/- 31.12 pg of IL-13 from 106 mast cells. This difference was statistically significant (P = 0.028, n = 13). Furthermore, we confirmed by immunocytochemistry that immunological activation induced an increase of intracellular IL-13. CONCLUSION: These findings demonstrate the capacity of human lung mast cells to transcribe IL-13 after IgE-dependent activation and to synthesize and release IL-13.     

Nutrition education in the medical school: factors critical to the development of a successful program

The phagocytosis by mononuclear phagocytes, neutrophils and eosinophils of mast cell granules which are released in the course of anaphylactic reactions was studied in the rat. Degranulation of rat peritoneal mast cells was induced either in vivo or in vitro after passive sensitization with homologous reaginic antiovalbumin serum by challenge with the antigen. The approximate extent of degranulation was assessed by determining histamine release. The anaphylactic reaction was stopped by fixation with glutaraldehyde and the cells were examined by electron microscopy. Phagocytosis was quantified in randomly selected thin section at the magnification of 1,800. Rapid and extensive phagocytosis of mast cell granules was observed both in vivo and in vitro. About one third of the mononuclear phagocytes and between 30 and 53% of the neutrophils present were engaged in phagocytosis and usually contained several mast cell granules. Phagocytosis by eosinophils was less prominent, both with respect to the proportion of phagocytosing cell (10-23%) and to the number of mast cell granules per cell profile. Examination of large numbers of cells indicates that the uptake process is highly efficient since both condensed and already disaggregated granule bodies were seen to adhere to the phagocytes and were taken up rapidly and without the need for opsonization. In the neutrophils, extensive fusion of azurophil granules (as evidenced by peroxidase cytochemistry) with phagosomes containing mast cell granules was observed. Occasionally, mast cell granules were seen within disrupted vacuoles, which could result from the swelling of the granule matrix following engulfment. The result of this study indicate that mononuclear and polymorphonuclear phagocytes have the capacity to scavenge important amounts of mast cell granule products released by anaphylaxis.     

Mast cell activation is not required for induction of airway hyperresponsiveness by ozone in mice

Exposure to ambient ozone (O3) is associated with increased exacerbations of asthma. We sought to determine whether mast cell degranulation is induced by in vivo exposure to O3 in mice and whether mast cells play an essential role in the development of pulmonary pathophysiological alterations induced by O3. For this we exposed mast cell-deficient WBB6F1-kitW/kitW-v (kitW/kitW-v) mice and the congenic normal WBB6F1 (+/+) mice to air or to 1 or 3 parts/million O3 for 4 h and studied them at different intervals from 4 to 72 h later. We found evidence of O3-induced cutaneous, as well as bronchial, mast cell degranulation. Polymorphonuclear cell influx into the pulmonary parenchyma was observed after exposure to 1 part/milllion O3 only in mice that possessed mast cells. Airway hyperresponsiveness to intravenous methacholine measured in vivo under pentobarbital anesthesia was observed in both kitW/kitW-v and +/+ mice after exposure to O3. Thus, although mast cells are activated in vivo by O3 and participate in O3-induced polymorphonuclear cell infiltration into the pulmonary parenchyma, they do not participate detectably in the development of O3-induced airway hyperresponsiveness in mice.     

Requirements for allergen-induced airway hyperreactivity in T and B cell-deficient mice

BACKGROUND: The pathogenesis of asthma is believed to reflect antigen-induced airway inflammation leading to the recruitment of eosinophils and activation of mast cells through cell-associated IgE. Controversies persist however, regarding the relative importance of different pathogenic cells and effector molecules. MATERIALS AND METHODS: A variety of gene-targeted mice were examined for the induction of cholinergic airway hyperresponsiveness (AH), allergic airway inflammation, mucus production, and serum IgE reactivity following intratracheal challenge with a potent allergen. AH was determined using whole-body plethysmography following acetylcholine challenge. Where possible, results were confirmed using neutralizing antibodies and cell-specific reconstitution of immune deficient mice. RESULTS: T and B cell-deficient, recombinase-activating-gene-deficient mice (RAG -/-) failed to develop significant allergic inflammation and AH following allergen challenge. Reconstitution of RAG -/- mice with CD4+ T cells alone was sufficient to restore allergen-induced AH, allergic inflammation, and goblet cell hyperplasia, but not IgE reactivity. Sensitized B cell-deficient mice also developed airway hyperreactivity and lung inflammation comparable to that of wild-type animals, confirming that antibodies were dispensable. Treatment with neutralizing anti-IL-4 antibody or sensitization of IL-4-deficient mice resulted in loss of airway hyperreactivity, whereas treatment with anti-IL-5 antibody or sensitization of IL-5-deficient mice had no effect. CONCLUSIONS: In mice, CD4+ T cells are alone sufficient to mediate many of the pathognomonic changes that occur in human asthma by a mechanism dependent upon IL-4, but independent of IL-5, IgE, or both. Clarification of the role played by CD4+ T cells is likely to stimulate important therapeutic advances in treatment of asthma.     

Induction of a selective and persistent extravasation of neutrophils into the peritoneal cavity by tryptase mouse mast cell protease 6

Recombinant mouse mast cell protease 6 (mMCP-6) was generated to study the role of this tryptase in inflammatory reactions. Seven to forty-eight hours after the i.p. injection of recombinant mMCP-6 into BALB/c, mast cell-deficient WCB6F1-Sl/Sl(d), C5-deficient, or mMCP-5-null mice, the number of neutrophils in the peritoneal cavity of each animal increased significantly by >50-fold. The failure of the closely related recombinant tryptase mMCP-7 to induce a comparable peritonitis indicates that the substrate specificities of the two tryptases are very different. Unlike most forms of acute inflammation, the mMCP-6-mediated peritonitis was relatively long lasting and neutrophil specific. Mouse MCP-6 did not induce neutrophil chemotaxis directly in an in vitro assay, but did promote chemotaxis of the leukocyte in the presence of endothelial cells. Mouse MCP-6 did not induce cultured human endothelial cells to express TNF-alpha, RANTES, IL-1alpha, or IL-6. However, the tryptase induced endothelial cells to express large amounts of IL-8 continually over a 40-h period. Neither enzymatically active mMCP-7 nor enzymatically inactive pro-mMCP-6 was able to induce endothelial cells to increase their expression of IL-8. Although the mechanism by which mMCP-6 induces neutrophil accumulation in tissues remains to be determined, the finding that mMCP-6 induces cultured human endothelial cells to selectively release large amounts of IL-8 raises the possibility that this tryptase regulates the steady state levels of neutrophil-specific chemokines in vivo during mast cell-mediated inflammatory events.     

Requirement for gammadelta T cells in allergic airway inflammation

The factors that contribute to allergic asthma are unclear but the resulting condition is considered a consequence of a type-2 T helper (TH2) cell response. In a model of pulmonary allergic inflammation, mice that lacked gammadelta T cells had decreases in specific immunoglobulin E (IgE) and IgG1 and pulmonary interleukin-5 (IL-5) release as well as in eosinophil and T cell infiltration compared with wild-type mice. These responses were restored by administration of IL-4 to gammadelta T cell-deficient mice during the primary immunization. Thus, gammadelta T cells are essential for inducing IL-4-dependent IgE and IgG1 responses and for TH2-mediated airway inflammation to peptidic antigens.     

Intramuscular injection of hrRANTES causes mast cell recruitment and increased transcription of histidine decarboxylase in mice: lack of effects in genetically mast cell-deficient W/WV mice

RANTES (regulated upon activation, normal T cell expressed and presumably secreted) and other chemoattractant proteins are members of the intercrine or chemokine family of proinflammatory basic polypeptides. RANTES is a prototype of the C-C chemokine subfamily that acts as a selective chemoattractant for human monocytes and CD4-positive lymphocytes and increases the adherence of monocytes to endothelial cells. However, the role of RANTES in white cells is still unclear. We report here that hrRANTES at 20 ng/50 microl in mice causes mast cell recruitment 4 h after intramuscular injection, an effect inhibited by anti-RANTES, as evidenced by 0.1% Toluidine blue, a specific dye for coloring mast cells. Injections of PBS (50 microl) vehicle (negative control) did not produce any appreciable inflammatory response, whereas injection of lipopolysaccharide 20 ng/50 microl (positive control) generated a marked inflammatory state. When RANTES was injected intramuscularly in genetically mast cell-deficient W/Wv mice, the inflammatory effect was not present. The RANTES injection sites were then excised and studied under an optical and electron microscope. A Northern blot analysis was performed using a probe that was prepared to detect mRNA encoding the histidine decarboxylase (HDC) gene on excised muscle tissue. We found that hrRANTES provoked generation of HDC mRNA from muscle tissue after 4 h. These effects were inhibited by an anti-RANTES antibody and were absent in genetically mast cell-deficient mice. The increasing number of mast cells in the RANTES injection sites led to an augmentation of histamine content compared to controls (PBS). The injection of hrRANTES 20 ng/20 microl into the sole of a rat paw confirmed the inflammatory and the mast cell recruitment potential of this chemokine. In these studies, hrRANTES injections in muscle tissue provided direct in vivo evidence that RANTES has a significant effect on mast cell recruitment and HDC mRNA generation.     

Tumour necrosis factor-alpha expression and cell recruitment in Sephadex particle-induced lung inflammation: effects of dexamethasone and cyclosporin A

1. Tumour necrosis factor-alpha (TNF-alpha) is a cytokine with diverse properties consistent with a possible role in inflammatory disease. We investigated whether TNF-alpha is induced during the progression of lung inflammation elicited by a particulate non-antigenic stimulus, and whether pharmacological control of TNF-alpha expression influences recruitment of specific inflammatory cell types. 2. A single intravenous injection of Sephadex particles into rats led to extensive granulomatous inflammation in lung alveolar and bronchial tissue that peaked in intensity after 24-72 h. Mononuclear cells were the principal component of granulomas, but neutrophils and eosinophils were also abundant. Numbers of mononuclear cells, neutrophils and eosinophils recovered by bronchoalveolar lavage (BAL) peaked at 72 h, 48 h and 72 h, respectively. 3. Messenger RNA encoding TNF-alpha was induced in lung epithelial cells, lung granulomas and BAL cells 6 h after Sephadex administration and remained elevated for 72 h before declining to baseline by 7 days. In BAL cell populations TNF-alpha protein was localized to mononuclear cells at all times points pre- and post-Sephadex administration. 4. Treatment of rats with dexamethasone significantly reduced the Sephadex-induced recruitment of mononuclear cells, neutrophils and eosinophils into the bronchoalveolar cavity, and significantly reduced TNF-alpha mRNA expression by BAL cells. 5. Treatment of rats with cyclosporin A was without effect on Sephadex-induced elevations of mononuclear cell numbers and expression of TNF-alpha, but did reduce significantly recruitment of neutrophils and eosinophils to BAL cell populations. 6. These results show that a sequential asthma-like recruitment of neutrophils, eosinophils and mononuclear cells into lung tissue can be induced by single exposure to a non-antigenic stimulus. Pharmacological and histological studies reveal that mononuclear cell mobilization relates closely to induced TNF-alpha expression, whereas mobilization of neutrophils and eosinophils appears secondary to expression of the cytokine.     

Intrathoracic vagal nerve schwannoma preoperative diagnosis is correct because of clinical and characteristic CT findings--a case report and review of the literature

BACKGROUND: Blister formation and tissue damage in bullous pemphigoid have been attributed to the release of eosinophil granule proteins--namely, to eosinophil derived cationic protein (ECP) and major basic protein (MBP). In the present investigation these eosinophil granule proteins were studied in the conjunctiva of patients with ocular cicatricial pemphigoid (OCP). METHODS: Conjunctival biopsy specimens obtained from patients with subacute (n = 8) or chronic conjunctival disease (n = 13) were analysed histologically and immunohistochemically using antibodies directed against EG1 (stored and secreted ECP), EG2 (secreted ECP), MBP, CD45 (common leucocyte antigen), CD3 (pan T cell marker), and HLA-DR (class II antigen). RESULTS: Subepithelial mononuclear cells, mast cells, and neutrophils were detected in all specimens. The number of mononuclear cells, neutrophils, CD45+ cells, CD3+ cells, and the HLA-DR expression were significantly higher in the subacute than in the chronic disease group. Some eosinophils were found in specimens from five of eight patients with subacute OCP, but in none of the patients with chronic disease. The eosinophil granule proteins (ECP and MBP) were found in the epithelium and substantia propria in patients with subacute conjunctivitis. CONCLUSIONS: Subepithelial cell infiltration in the conjunctiva greatly differs between subacute and chronic ocular cicatricial pemphigoid specimens. The findings suggest that eosinophil granule proteins may participate in tissue damage in acute phase of inflammation in OCP.     

Identification of a committed precursor for the mast cell lineage

Mast cells originate from hematopoietic stem cells, but the mast cell-committed precursor has not been identified. In the study presented here, a cell population in murine fetal blood that fulfills the criteria of progenitor mastocytes was identified. It is defined by the phenotype Thy-1loc-Kithi, contains cytoplasmic granules, and expresses RNAs encoding mast cell-associated proteases but lacks expression of the high-affinity immunoglobulin E receptor. Thy-1loc-Kithi cells generated functionally competent mast cells at high frequencies in vitro but lacked developmental potential for other hematopoietic lineages. When transferred intraperitoneally, this population reconstituted the peritoneal mast cell compartment of genetically mast cell-deficient W/Wv mice to wild-type levels.     

Topical cyclosporine inhibits mast cell-mediated conjunctivitis

PURPOSE: Allergic conjunctivitis is a common condition caused by a mast cell-mediated hypersensitivity reaction to immunoglobulin E-bound allergens. The purpose of this study was to investigate the effect of topical cyclosporine A on the development of mast cell-mediated conjunctivitis in mice. METHODS: Allergic conjunctivitis was induced in C57BL/6 mice by topical applications of compound 48/80, a mast cell degranulating agent. In two separate experiments, mice were treated with topical cyclosporine A (0.05%, 0.2%, or 0.4%), prednisolone acetate 1%, or phosphate-buffered saline. Twenty-four hours after compound 48/80 instillation, the number of neutrophils, eosinophils, lymphocytes, macrophages, and the number of preserved goblet cells and undegranulated mast cells in the conjunctiva were counted by a masked observer. RESULTS: In both experiments, treatment with all three doses of cyclosporine A resulted in a statistically significant reduction in the number of infiltrating neutrophils and eosinophils compared to saline-treated controls. There was no significant difference in the treatment effect of cyclosporine and prednisolone acetate. In addition, there was increased preservation of goblet cells in the cyclosporine A-treated animals. Immunohistochemical staining showed a reduction in infiltrating lymphocytes and a smaller reduction in infiltrating macrophages in animals treated with cyclosporine compared to saline-treated controls. CONCLUSIONS: Topical cyclosporine A was effective in inhibiting the development of mast cell-mediated allergic conjunctivitis in mice. This study suggests that topical cyclosporine A may be effective in treating allergic conjunctivitis in humans.     

Intraepithelial infiltration by mast cells with both connective tissue-type and mucosal-type characteristics in gut, trachea, and kidneys of IL-9 transgenic mice

IL-9 transgenic mice were analyzed for the presence of mast cells in different tissues. In these mice, increased mast cell infiltration was found in the gastric and intestinal epithelium as well as in the upper airways and kidney epithelium, but not in other organs, such as skin. IL-9 transgenic mast cells do not show signs of massive degranulation such as that found in IL-4 transgenic mice and are not involved in spontaneous pathologic changes. Gastric mast cells showed a phenotype related to connective-type mast cells, since they were stained by safranin, and strong expression of mouse mast cell protease-4 and -5 was found in this organ. However, they also expressed proteases related to the mucosal cell type, such as mouse mast cell protease-1 and -2. In vitro, although IL-9 by itself did not induce mast cell development from bone marrow progenitors, it strongly synergized with stem cell factor for the growth and differentiation of mast cells expressing the same protease pattern as that observed in IL-9 transgenic mice. Since constitutive stem cell factor expression was observed in vivo, and anti-c-Kit Abs inhibited IL-9 transgenic mastocytosis in the gut, this synergistic combination of factors is likely to be responsible for the mastocytosis observed in IL-9 transgenic mice. Taken together, these data demonstrate that IL-9 induces the in vivo amplification of a nonclassical mast cell subset with a mucosal localization but expressing proteases characteristic of both connective tissue-type and mucosal mast cells.     

Inhibitory mechanisms of beta-adrenoceptor agonists for immunoglobulin E-mediated experimental allergic reactions in rats

Inhibitory mechanisms of isoproterenol and clenbuterol for immunoglobulin E (IgE)-mediated experimental allergic reactions in rats were studied. IgE-mediated passive cutaneous anaphylaxis, histamine-induced cutaneous reaction and serotonin-induced cutaneous reaction were evoked at the same time in the same rats. Isoproterenol administered intravenously immediately before challenge inhibited all these reactions significantly. Clenbuterol administered intravenously 0-3 h before challenge also significantly inhibited the three cutaneous reactions. The inhibition was maximum when the drug was given 1 h before challenge. Passive cutaneous anaphylaxis was always inhibited more potently than histamine-induced cutaneous reaction and serotonin-induced cutaneous reaction by these beta-adrenoceptor agonists. Passive peritoneal anaphylaxis was caused by injecting an antigen intravenously. Isoproterenol administered intravenously immediately before challenge inhibited the reaction significantly. Clenbuterol administered intravenously 0-3 h before challenge also significantly inhibited passive peritoneal anaphylaxis, maximally so when given 1 h before challenge. In vitro IgE-dependent histamine release from sensitized peritoneal mast cells or mesenteric mast cells was not affected by isoproterenol and clenbuterol. Mouse monoclonal IgE, a foreign protein, administered intravenously decreased rapidly in the circulation. About 50% of the mouse IgE given disappeared in 20 min. The decrease of mouse IgE was partly but significantly inhibited by the beta-adrenoceptor agonists, and the inhibition was abolished by simultaneous treatment with propranolol. These results indicate that direct inhibition of mast cell activation does not contribute to the potent inhibition of in vivo allergic reactions in rats by beta-adrenoceptor agonists, and that inhibition of the allergic cutaneous reaction is partially explained by the inhibition of vascular permeability increases caused by mast cell mediators. Penetration of intravenously administered antigen from blood vessels to peripheral tissues to cause mast cell activation might be inhibited by beta-adrenoceptor agonists, and this could play some role in inhibiting intravenous antigen-induced allergic reactions in rats. Clenbuterol exhibited its maximum action with some latency in vivo, suggesting that some time-requiring process may be involved in the manifestation of its action.     

Leukocyte common antigen (CD45) is required for immunoglobulin E-mediated degranulation of mast cells

We demonstrate using primary mast cell cultures derived from wild-type and CD45-deficient mice that mast cell triggering through the high-affinity immunoglobulin E (IgE) receptor requires the cell surface tyrosine phosphatase CD45. Unlike wild-type cells, cross-linking of surface-bound IgE in mast cells deficient in CD45 does not induce degranulation. Degranulation in these mutant cells does occur after treatment with the calcium ionophore A23187 indicating that the degranulation machinery is intact in these cells. We also demonstrate that the tyrosine phosphatase inhibitors orthoVanadate and perVanadate inhibit degranulation in wild-type mast cells, as does cross-linking of CD45 by anti-CD45 antibodies. Finally, we show that CD45-deficient mice are resistant to IgE-dependent systemic anaphylaxis. These results show that, like the T cell receptor and the antigen receptor on B cells, there is an absolute requirement for CD45 in signaling via the high affinity IgE receptor, expanding the number of receptors for which CD45 is an essential component.     

Role of gamma interferon in Helicobacter pylori-induced gastric inflammatory responses in a mouse model

The immune responses to Helicobacter pylori infection play important roles in gastroduodenal diseases. The contribution of gamma interferon (IFN-gamma) to the immune responses, especially to the induction of gastric inflammation and to protection from H. pylori infection, was investigated with IFN-gamma gene knockout (IFN-gamma-/-) mice. We first examined the colonizing abilities of eight H. pylori strains with a short-term infection test in order to select H. pylori strains which could colonize the mouse stomach. Only three strains (ATCC 43504, CPY2052, and HPK127) colonized C57BL/6 wild-type mice, although all of the strains except for ATCC 51110 could colonize IFN-gamma-/- mice. The number of H. pylori organisms colonizing the stomach in wild-type mice was lower than that in IFN-gamma-/- mice. Oral immunization with the CPY2052 sonicate and cholera toxin protected against infection with strain CPY2052 in both types of mouse. These findings suggested that IFN-gamma may play a protective role in H. pylori infection, although the degree of its protective ability was estimated to be low. In contrast, in a long-term infection test done to examine the contribution of IFN-gamma to gastric inflammation, CPY2052-infected wild-type mice developed a severe infiltration of mononuclear cells in the lamina propria and erosions in the gastric epithelium 15 months after infection, whereas CPY2052-infected IFN-gamma-/- mice showed no inflammatory symptoms. This result clearly demonstrated that IFN-gamma plays an important role in the induction of gastric inflammation caused by H. pylori infection.     

Successful induction of adjuvant arthritis in mice by treatment with a monoclonal antibody against IL-4

Adjuvant arthritis (AA) is an experimental model of autoimmune disease in rats induced by immunization with Mycobacterium tuberculosis (MT). Induction of AA in other species, including mice, has been shown to be difficult. In the present study, we found that AA could be induced in mice if the animals were treated with a mAb (11B11 mAb) against IL-4. Histologically, the joints exhibited synovial edema with infiltration of many neutrophils in the early phase of inflammation. In its late phase, there were proliferation of synovium, cell infiltrate in which mononuclear cells predominated, and destruction of cartilage and subchondral bone. The joint inflammation was passively transferred to normal syngeneic recipient mice with lymphoid cells but not with sera from mice immunized with MT followed by treatment with the anti-IL-4 Ab. Delayed-type hypersensitivity (DTH) and proliferative responses of lymphoid cells to purified protein derivative were markedly augmented in 11B11 mAb-treated mice. Furthermore, the induction of arthritis was associated with a marked decrease in IL-4 secretion but a significant increase in IFN-gamma and IL-2 production. Thus, the neutralization of IL-4 by an anti-IL-4 Ab appears to be required for the induction of AA in mice.     

Immunologic basis of chronic allergic diseases: clinical messages from the laboratory bench

During the past decade there have been significant advances in our understanding of the mechanisms underlying allergic responses. Immediate hypersensitivity reactions are mediated primarily by mast cells in an IgE-dependent manner. After the local release of various mediators, proinflammatory cytokines, and chemokines, there is a cell-mediated response that is dominated by eosinophils and T lymphocytes. The majority of T cells in early allergic reactions are memory T cells secreting helper type 2 (TH2)-like cytokines, i.e. IL-4, IL-5, and IL-13, but not interferon-gamma. These cytokines regulate IgE synthesis and promote eosinophil differentiation and cell survival, thus contributing to allergic inflammatory responses. Failure to control immune activation early in the course of allergic inflammation may blunt the response to glucocorticoid therapy and contribute to long-term morbidity of disease. The identification of key cells and cytokines involved in the initiation and maintenance of allergic inflammation is likely to become an important therapeutic target in the future management of this important group of diseases.