Search PubMed⌕ Search

Biomedical subjects

Marc E Rothenberg

Publications and source records attributed to Marc E Rothenberg.

At least 73 records · Page 4Linked to original sources
PubMed2003

Immunotherapy of cytotoxic T cell-resistant tumors by T helper 2 cells: an eotaxin and STAT6-dependent process.

Currently most attempts at cancer immunotherapy involve the generation of CD8(+) cytotoxic T lymphocytes (CTLs) against tumor-associated antigens. Many tumors, however, have been immunoselected to evade recognition by CTLs and thus alternative approaches to cancer immunotherapy are urgently needed. Here we demonstrate that CD4(+) T cells that recognize a secreted tumor-specific antigen and exhibit a cytokine secretion profile characteristic of Th2 cells, are capable of clearing established lung and visceral metastases of a CTL-resistant melanoma. Clearance of lung metastases by the Th2 cells was found to be totally dependent on the eosinophil chemokine, eotaxin, and partially dependent on the transcription activator signal transducer and activator of transcription 6 (STAT6), with degranulating eosinophils within the tumors inducing tumor regression. In contrast, tumor-specific CD4(+) Th1 cells, that recruited macrophages into the tumors, had no effect on tumor growth. This work provides the basis for a new approach to adoptive T cell immunotherapy of cancer.

Animals↗
PubMed2003

Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism.

BACKGROUND & AIMS: Eosinophil infiltration into the esophagus occurs in a wide range of diseases; however, the underlying pathophysiologic mechanisms involved are largely unknown. We have previously reported that simultaneous delivery of allergen to the lung and gastrointestinal tract induces experimental eosinophilic esophagitis (EE). We aimed to determine whether delivery of a Th2 cytokine (interleukin [IL]-13) to the lung was sufficient for induction of EE. METHODS: IL-13 was delivered intratracheally to wild-type, signal transducer and activator of transcription (STAT) 6, eotaxin-1, or IL-5-deficient mice. Eosinophil levels and 5'-bromodeoxyuridine (BrdU) incorporation were examined by immunohistochemical staining. RESULTS: Intratracheal delivery of IL-13 induced dose-dependent eosinophil accumulation in the esophagus (but not the stomach). In addition, intratracheal IL-13 induced esophageal epithelial hyperplasia. The ability of IL-13 to induce EE was abolished in STAT6-deficient mice. IL-13-induced EE was nearly completely ablated in IL-5-deficient mice (37.3 +/- 11.6 vs. 3.3 +/- 3.2 eosinophils/mm(2) in wild-type and IL-5-deficient mice, respectively). Additionally, IL-13-induced EE was significantly diminished in eotaxin-1-deficient mice (48.7 +/- 10.3 vs. 14.1 +/- 12.5 eosinophils/mm(2) in wild-type and eotaxin-1-deficient mice, respectively). CONCLUSIONS: IL-13 delivery to the lung induces EE by an IL-5, eotaxin-1, and STAT6-dependent mechanism. These results further establish an intimate connection between respiratory and esophageal inflammation.

Animals↗
PubMed2003

Eotaxin-2 and IL-5 cooperate in the lung to regulate IL-13 production and airway eosinophilia and hyperreactivity.

BACKGROUND: Eotaxin-2 is a member of the eotaxin subfamily of CC chemokines that display eosinophil-specific, chemotactic properties and has been associated with allergic disorders. However, the contribution of eotaxin-2 to the development of defined pathogenic features of allergic disease remains to be defined. OBJECTIVE: We sought to determine whether eotaxin-2 was a cofactor with IL-5 for the regulation of pulmonary eosinophilia and to identify the combined role of these molecules in the induction of phenotypic characteristics of allergic lung disease. METHODS: We instilled recombinant eotaxin-2 into the airways of wild-type mice that had been treated systemically with IL-5 or into IL-5-transgenic mice and characterized pulmonary eosinophil numbers, IL-13 production, and airway hyperreactivity (AHR) to methacholine. Mice deficient in the IL-4 receptor alpha-chain, IL-13, and signal transducers and activators of transcription 6 or mice treated with anti-CCR3 monoclonal antibody were also used. RESULTS: Eotaxin-2 and IL-5 cooperatively promoted eosinophil accumulation, IL-13 production, and AHR to methacholine. Neither eotaxin-2 nor IL-5 alone induced these features of allergic disease. IL-13 production was critically dependent on eotaxin-2- and IL-5-regulated eosinophilia, which predisposed to the development of AHR. AHR was dependent on IL-13 and signaling through the IL-4R alpha-chain and signal transducers and activators of transcription 6 pathways and the presence of eosinophils in the lung. CONCLUSION: These investigations demonstrate important cooperativity between eotaxin-2, IL-5, and IL-13 signaling systems and eosinophils for the development of hallmark features of allergic disease of the lung.

Aerosols↗
PubMed2003

Molecular analysis of human Siglec-8 orthologs relevant to mouse eosinophils: identification of mouse orthologs of Siglec-5 (mSiglec-F) and Siglec-10 (mSiglec-G).

We recently identified a novel human sialic acid binding immunoglobulin-like lectin, Siglec-8, using mRNA from human eosinophils. To search for a mouse Siglec (mSiglec) ortholog of Siglec-8 and other mouse Siglec paralogs, we conducted public database searches with cDNA sequences of human Siglec-5 to -10 and identified two novel mSiglecs. One has significant sequence identity to human Siglec-5 and is a splice variant of mSiglec-F. The other has greatest sequence identity to human Siglec-10 (mSiglec-G). Both mSiglecs have extracellular Ig-like domains and intracellular tyrosine-based motifs. To determine whether these mSiglecs were relevant to mouse eosinophils, RT-PCR and Northern blot analysis were performed. We detected expression of mSiglec-5 (or -F), -10, and -E mRNA in purified mouse eosinophils, but Northern blot data comparing expression in tissues from normal, IL-5 transgenic, and allergen-sensitized and -challenged mice suggest that mSiglec-10 is probably most relevant to mouse eosinophils.

Amino Acid Sequence↗
PubMed2003

Chemokines in asthma: cooperative interaction between chemokines and IL-13.

The asthmatic response is characterized by elevated production of IgE, cytokines, chemokines, mucus hypersecretion, air-way obstruction, eosinophilia, and enhanced airway hyperreactivity to spasmogens. Clinical and experimental investigations have demonstrated a strong correlation between the presence of CD4+ TH2 cells, eosinophils, and disease severity, suggesting an integral role for these cells in the pathophysiology of asthma. TH2 cells are thought to induce asthma through the secretion of an array of cytokines (IL-4, -5, -9 -1),-13, -25) that activate inflammatory and residential effector pathways both directly and indirectly. In particular, IL-4 and IL-13 are produced at elevated levels in the asthmatic lung and are thought to be central regulators of many of the hallmark features of the disease. The potency of IL-13 in promoting airway hyperreactivity and mucus hypersecretion and the ability of IL-13 blockade to abrogate several critical aspects of experimental asthma have led to the view that this is a critical cytokine in disease pathogenesis. Extensive studies have also demonstrated a central role for chemokines in orchestrating multiple aspects of the asthmatic response. Chemokines are potent leukocyte chemoattractants, cellular activating factors, and histamine-releasing factors, which makes them particularly important in the pathogenesis of allergic inflammation. In particular, the eotaxin subfamily of chemokines and their receptor CC chemokine receptor 3 have emerged as central regulators of the asthmatic response. Recent studies have provided an integrated mechanism by which to explain the coordinate interaction between IL-13 and chemokines in the pathogenesis of asthma. In this regard, chemokines and IL-13 are attractive new therapeutic targets for the treatment of allergic disease. This article focuses on recently emerging data pertaining to the importance of chemokines, especially eotaxins, in promoting IL-13-associated allergic lung responses, as well as the potential for pharmacologically targeting these pathways.

Animals↗
PubMed2003

Receptor internalization is required for eotaxin-induced responses in human eosinophils.

BACKGROUND: CC chemokine receptor 3 (CCR3) is a major chemokine receptor involved in regulating eosinophil trafficking, and therefore the elucidation of ligand-induced CCR3 events has important implications in understanding the biologic and pathologic properties of eosinophils. After ligand binding to CCR3, cellular signals include stimulatory (ie, calcium mobilization, actin polymerization, shape change, and chemotaxis) and inhibitory (ie, desensitization of the receptor) events. We have previously demonstrated that CCR3 undergoes rapid and prolonged ligand-induced internalization. OBJECTIVE: Here we explore the role of internalization in downstream cellular processes, including shape change, actin polymerization, calcium mobilization, and desensitization. METHODS: Peripheral blood-derived human eosinophils were pretreated with 2 mechanistically distinct inhibitors of internalization, sucrose and phenylarsine oxide, and functional responses were monitored. RESULTS: We first demonstrate that ligand-induced internalization is required for chemokine-induced eosinophil shape change. To define which signaling components upstream of eosinophil shape change required internalization, we next studied the role of internalization in calcium mobilization and actin polymerization. Sucrose and phenylarsine oxide pretreatment inhibited actin polymerization, implicating receptor internalization in this early response. In contrast, calcium mobilization was not inhibited by blockade of internalization. Finally, we were interested in testing the role of internalization in receptor desensitization. We first demonstrated that preincubation with eotaxin induced a dose-dependent desensitization in eotaxin-induced eosinophil transepithelial migration. However, this phenomenon was not inhibited by blockade of internalization. CONCLUSION: These results establish that CCR3 internalization is critically involved in select eosinophil functional responses (ie, cellular shape change and actin polymerization) but not desensitization and calcium mobilization.

Eosinophils↗
PubMed2003

Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis.

Asthma is on the rise despite intense, ongoing research underscoring the need for new scientific inquiry. In an effort to provide unbiased insight into disease pathogenesis, we took an approach involving expression profiling of lung tissue from mice with experimental asthma. Employing asthma models induced by different allergens and protocols, we identified 6.5% of the tested genome whose expression was altered in an asthmatic lung. Notably, two phenotypically similar models of experimental asthma were shown to have distinct transcript profiles. Genes related to metabolism of basic amino acids, specifically the cationic amino acid transporter 2, arginase I, and arginase II, were particularly prominent among the asthma signature genes. In situ hybridization demonstrated marked staining of arginase I, predominantly in submucosal inflammatory lesions. Arginase activity was increased in allergen-challenged lungs, as demonstrated by increased enzyme activity, and increased levels of putrescine, a downstream product. Lung arginase activity and mRNA expression were strongly induced by IL-4 and IL-13, and were differentially dependent on signal transducer and activator of transcription 6. Analysis of patients with asthma supported the importance of this pathway in human disease. Based on the ability of arginase to regulate generation of NO, polyamines, and collagen, these results provide a basis for pharmacologically targeting arginine metabolism in allergic disorders.

Animals↗
PubMed2003

Mast cells are required for experimental oral allergen-induced diarrhea.

Gastrointestinal allergic disorders represent a diverse spectrum of inflammatory diseases that are occurring with increasing incidence and severity. An essential question concerning these disorders is to determine the specific cells and mediators responsible for specific clinical manifestations. With this in mind, we developed a murine model of oral allergen-induced intestinal inflammation accompanied by strong Th2-associated humoral and cellular responses and focused on the immunopathogenesis of allergic diarrhea. Exposure of OVA/alum-sensitized mice to repeated doses of intragastric OVA induced genetically restricted, dose-dependent, acute diarrhea associated with increased intestinal permeability, eosinophilia, and mastocytosis. Mice developed limited systemic manifestations of anaphylaxis, even though they developed marked intestinal mucosal mast cell degranulation. Notably, experiments involving mast cell depletion (with anti-c-kit mAb), anti-IgE treatment, and Fc epsilon RI-deficient mice indicated a critical effector role for mast cells in mediating allergic diarrhea. Furthermore, allergic diarrhea was dependent upon synergistic signaling induced by serotonin and platelet-activating factor (PAF), but not histamine. These results demonstrate that oral allergen-induced diarrhea associated with experimental Th2 intestinal inflammation is largely mast cell, IgE, serotonin, and PAF dependent.

Allergens↗
PubMed2002

Constitutive overexpression of IL-5 induces extramedullary hematopoiesis in the spleen.

The differentiation of eosinophils from hematopoietic precursors and their subsequent maturation, chemotaxis, and activation is primarily regulated by interleukin-5 (IL-5). To examine the effect of chronic IL-5 exposure on hematopoiesis, IL-5 transgenic (IL-5trg) mice and wild-type BALB/c (WT) mice were examined. In comparison to WT mice, a significant alteration in bone marrow hematopoiesis was observed in IL-5trg mice. Although the total number of myeloid progenitors in the bone marrow of IL-5trg mice was not significantly altered, the number of long-term culture-initiating cells (LTC-ICs) was 1.5-fold lower than that observed in WT mice. Furthermore, IL-5trg mice failed to demonstrate hematopoietic activity in long-term bone marrow cultures, which correlated with a significant decrease in the number of bone marrow mesenchymal/stromal progenitor (MSP) cells in these mice. In comparison to WT mice, a 10-fold decrease was observed in the number of fibroblast colony-forming units (CFU-Fs) in IL-5trg bone marrow. Hematopoietic activity of IL-5trg bone marrow cells was rescued by cultivation on preestablished layers of bone marrow-derived stromal cells. However, in contrast to bone marrow, increased hematopoietic activity was observed in the spleen and peripheral blood of IL-5trg mice. Likewise, the numbers of LTC-ICs and granulocyte-macrophage, macrophage, eosinophil, B-lymphocyte progenitors in the peripheral blood and spleen of IL-5trg mice were approximately 20-fold higher than in WT mice. A significant increase in CFU-F numbers was also observed in the spleens of IL-5trg mice compared with WT mice. Overall, our results suggest that constitutive overexpression of IL-5 can potentially induce colonization of spleen with MSP cells, which provides the necessary microenvironment for establishment of hematopoiesis in extramedullary sites.

Animals↗
PubMed2002

Defective T cell development and function in calcineurin A beta -deficient mice.

The calcium-dependent phosphatase calcineurin and its downstream transcriptional effector nuclear factor of activated T cells (NFAT) are important regulators of inducible gene expression in multiple cell types. In T cells, calcineurin-NFAT signaling represents a critical event for mediating cellular activation and the immune response. The widely used immunosuppressant agents cyclosporin and FK506 are thought to antagonize the immune response by directly inhibiting calcineurin-NFAT signal transduction in lymphocytes. To unequivocally establish the importance of calcineurin signaling as a mediator of the immune response, we deleted the gene encoding the predominant calcineurin isoform expressed in lymphocytes, calcineurin A beta (CnA beta). CnA beta(-/-) mice were viable as adults, but displayed defective T cell development characterized by fewer total CD3 cells and reduced CD4 and CD8 single positive cells. Total peripheral T cell numbers were significantly reduced in CnA beta(-/-) mice and were defective in proliferative capacity and IL-2 production in response to PMA/ionomycin and T cell receptor cross-linking. CnA beta(-/-) mice also were permissive to allogeneic tumor-cell transplantation in vivo, similar to cyclosporin-treated wild-type mice. A mechanism for the compromised immune response is suggested by the observation that CnA beta(-/-) T cells are defective in stimulation-induced NFATc1, NFATc2, and NFATc3 activation. These results establish a critical role for CnA beta signaling in regulating T cell development and activation in vivo.

Animals↗
PubMed2002

Intrinsic defect in T cell production of interleukin (IL)-13 in the absence of both IL-5 and eotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma.

Interleukin (IL)-5 and IL-13 are thought to play key roles in the pathogenesis of asthma. Although both cytokines use eotaxin to regulate eosinophilia, IL-13 is thought to operate a separate pathway to IL-5 to induce airways hyperreactivity (AHR) in the allergic lung. However, identification of the key pathway(s) used by IL-5 and IL-13 in the disease process is confounded by the failure of anti-IL-5 or anti-IL-13 treatments to completely inhibit the accumulation of eosinophils in lung tissue. By using mice deficient in both IL-5 and eotaxin (IL-5/eotaxin(-/-)) we have abolished tissue eosinophilia and the induction of AHR in the allergic lung. Notably, in mice deficient in IL-5/eotaxin the ability of CD4(+) T helper cell (Th)2 lymphocytes to produce IL-13, a critical regulator of airways smooth muscle constriction and obstruction, was significantly impaired. Moreover, the transfer of eosinophils to IL-5/eotaxin(-/-) mice overcame the intrinsic defect in T cell IL-13 production. Thus, factors produced by eosinophils may either directly or indirectly modulate the production of IL-13 during Th2 cell development. Our data show that IL-5 and eotaxin intrinsically modulate IL-13 production from Th2 cells and that these signaling systems are not necessarily independent effector pathways and may also be integrated to regulate aspects of allergic disease.

Adoptive Transfer↗
PubMed2002

IL-5 promotes eosinophil trafficking to the esophagus.

Eosinophil infiltration into the esophagus occurs in a wide range of diseases; however, the underlying pathophysiological mechanisms involved are largely unknown. We now report that the Th2 cytokine, IL-5, is necessary and sufficient for the induction of eosinophil trafficking to the esophagus. We show that transgenic mice overexpressing IL-5 under the control of a T cell (CD2) or a small intestinal enterocyte (fatty acid-binding protein) promoter have markedly increased eosinophil numbers in the esophagus. For example, esophageal eosinophil levels are 1.9 +/- 0.9 and 121 +/- 14 eosinophils/mm(2) in wild-type and CD2-IL-5-transgenic mice, respectively. Consistent with this effect being mediated by a systemic mechanism, pharmacological administration of IL-5 via a miniosmotic pump in the peritoneal cavity resulted in blood and esophageal eosinophilia. To examine the role of IL-5 in oral Ag-induced esophageal eosinophilia, eosinophilic esophagitis was induced by allergen exposure in IL-5-deficient and wild-type mice. Importantly, IL-5-deficient mice were resistant to eosinophilic esophagitis. Finally, we examined the role of eotaxin when IL-5 was overproduced in vivo. Esophageal eosinophil levels in CD2-IL-5-transgenic mice were found to decrease 15-fold in the absence of the eotaxin gene; however, esophageal eosinophil numbers in eotaxin-deficient IL-5-transgenic mice still remained higher than wild-type mice. In conclusion, these studies demonstrate a central role for IL-5 in inducing eosinophil trafficking to the esophagus.

Administration, Oral↗
PubMed2002

Eosinophil-associated gastrointestinal disorders: a world-wide-web based registry.

A world wide web database was established that tracked features of eosinophil-associated gastrointestinal disorders; 80% had coexisting atopic disease, 62% had food sensitization, and 16% had an immediate family member with a similar disorder. Developmental delay, seizure disorders, and congenital anomalies were seen in a proportion of respondents. The world wide web has proven to be an efficient tool to gather patient information, allowing us to define distinguishing features of various eosinophil-associated gastrointestinal disorders and to establish that these disorders have strong genetic and allergic components.

Adolescent↗
PubMed2002

Experimental analysis of eosinophil-associated gastrointestinal diseases.

Eosinophil infiltration into the gastrointestinal tract occurs in a wide range of diseases. However, the underlying cellular and molecular mechanisms involved in eosinophil migration and the role of eosinophils in disease pathogenesis are largely unknown. Recent studies using experimental models of eosinophil-associated gastrointestinal allergy have revealed differential roles for IL-5 and eotaxin in the modulation of eosinophil accumulation into various regions of the gastrointestinal tract. Furthermore, such studies have revealed a possible role for eosinophils in the pathogenesis of gastrointestinal disorders. The present review describes the clinical manifestations of various eosinophil-associated gastrointestinal disorders and the current understanding of the role of IL-5 and eotaxin in the allergic inflammatory response, and the participation of the eosinophilic granulocyte in the expression of disease.

Animals↗
PubMed2001

Enterocyte expression of the eotaxin and interleukin-5 transgenes induces compartmentalized dysregulation of eosinophil trafficking.

Eosinophils accumulate in the gastrointestinal tract in a number of medical disorders, but the mechanisms involved are largely unknown. To understand the significance of cytokine expression by enterocytes, enterocyte transgenic mice that overexpressed the eosinophil-selective cytokines eotaxin and interleukin (IL)-5 were generated. Transgenic mice, generated by utilizing the rat intestinal fatty acid-binding protein promoter (Fabpi), overexpressed the mRNA for these cytokines in the small intestine. Overexpression of IL-5 resulted in marked increases of eosinophils in the bone marrow and blood, whereas eotaxin overexpression resulted in similar levels compared with nontransgenic control mice. In contrast, both IL-5 and eotaxin transgenic mice had significant accumulation of eosinophils in the gastrointestinal mucosa compared with control mice. Eotaxin-induced gastrointestinal eosinophilia was substantially higher than that induced by IL-5 and was especially prominent within the lamina propria of the villi. Interestingly, genetic rescue of eotaxin deficiency (by transgenic overexpression of eotaxin in eotaxin gene-targeted mice) resulted in significant restoration of gastrointestinal eosinophil levels. Finally, the intestinal eosinophilia induced by the eotaxin transgene was beta(7) integrin-dependent. Taken together, these results demonstrate that expression of eotaxin and IL-5 in intestinal epithelium induces compartmentalized dysregulation of eosinophil trafficking and the important role of the beta(7) integrin in gastrointestinal allergic responses.

Animals↗
PubMedDate not supplied

Allergen induced TFF2 is expressed by mucus-producing airway epithelial cells but is not a major regulator of inflammatory responses in the murine lung.

Asthma is a complex pulmonary disorder characterized by reversible airflow obstruction, airway hyperresponsiveness, mucus cell metaplasia, and inflammation. Employing animal models of pulmonary inflammation induced by different allergens and Th2 cytokines, the authors have previously described the up-regulation of trefoil factor 2 (TFF2) in the lung. Given the known biological role of trefoil factors in epithelial restitution, it has been postulated that allergen-induced TFF2 might have an important role in asthmatic responses. Here the authors show that TFF2 is induced early and maintained for 2 weeks following allergen challenge in the mouse lung. In situ mRNA hybridization demonstrated expression of TFF2 primarily in a subset of bronchial epithelial cells and TFF2 immunohistochemistry identified expression in alcian blue-positive bronchial epithelial cells. TFF2 gene-deleted mice inoculated with allergen displayed a 10-fold increase in total cellularity compared with saline controls. Although this response was modestly attenuated compared to wild type controls, the loss of TFF2 did not affect gross levels of tissue inflammation. Furthermore, the loss of TFF2 did not affect induction or resolution of mucus cell metaplasia as measured by periodic acid-Schiff (PAS) or alcian blue staining. Thus, TFF2 is an allergen-induced gene, which is expressed in mucus-positive airways, but is not a major contributor to allergen-induced goblet cell metaplasia, mucus production, or inflammatory responses in the lung.

Allergens↗