Adam C. Henry

University of Pittsburgh

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Anuradha Ray

University of Pittsburgh

Charles G. Irvin

University of Vermont

Timothy B. Oriss

University of Pittsburgh

Andrew L. Mellor

Newcastle University

Jay K. Kolls

Tulane University

Prabir Ray

University of Pittsburgh

David H. Munn

Augusta University Health

SΜ

Steven Μ. Albelda

University of Pennsylvania

Barbro N. Melgert

University of Groningen

Peter DeLong

White River Junction VA Medical Center

Cooperative Institutions

University of Pittsburgh

University of Pennsylvania

University of Pittsburgh Medical Center

Children's Hospital of Pittsburgh

Pulmonary and Allergy Associates

Hospital of the University of Pennsylvania

Philadelphia University

UPMC Hillman Cancer Center

Boston Children's Hospital

Weatherford College

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Role of IL-17A, IL-17F, and the IL-17 Receptor in Regulating Growth-Related Oncogene-α and Granulocyte Colony-Stimulating Factor in Bronchial Epithelium: Implications for Airway Inflammation in Cystic Fibrosis

The Journal of Immunology (2005)

Florencia McAllister Adam C. Henry James L. Kreindler Patricia J. Dubin Lauren Ulrich

IL-17R signaling is critical for pulmonary neutrophil recruitment and host defense against Gram-negative bacteria through the coordinated release of G-CSF and CXC chemokine elaboration. In this study, we show that IL-17R is localized to basal airway cells in human lung tissue, and functional IL-17R signaling occurs on the basolateral surface of human bronchial epithelial (HBE) cells. IL-17A and IL-17F were potent inducers of growth-related oncogene-alpha and G-CSF in HBE cells, and significant synergism was observed with TNF-alpha largely due to signaling via TNFRI. The activities of both IL-17A and IL-17F were blocked by a specific anti-IL-17R Ab, but only IL-17A was blocked with a soluble IL-17R, suggesting that cell membrane IL-17R is required for signaling by both IL-17A and IL-17F. Because IL-17A and IL-17F both regulate lung neutrophil recruitment, we measured these molecules as well as the proximal regulator IL-23p19 in the sputum of patients with cystic fibrosis (CF) undergoing pulmonary exacerbation. We found significantly elevated levels of these molecules in the sputum of patients with CF who were colonized with Pseudomonas aeruginosa at the time of pulmonary exacerbation, and the levels declined with therapy directed against P. aeruginosa. IL-23 and the downstream cytokines IL-17A and IL-17F are critical molecules for proinflammatory gene expression in HBE cells and are likely involved in the proinflammatory cytokine network involved with CF pathogenesis.

10.4049/jimmunol.175.1.404

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TH17 Cells Mediate Steroid-Resistant Airway Inflammation and Airway Hyperresponsiveness in Mice

The Journal of Immunology (2008)

Laura McKinley John F. Alcorn Alanna Peterson Rachel DuPont Shernaaz B Kapadia

Abstract Steroid-resistant asthma comprises an important source of morbidity in patient populations. TH17 cells represent a distinct population of CD4+ Th cells that mediate neutrophilic inflammation and are characterized by the production of IL-17, IL-22, and IL-6. To investigate the function of TH17 cells in the context of Ag-induced airway inflammation, we polarized naive CD4+ T cells from DO11.10 OVA-specific TCR-transgenic mice to a TH2 or TH17 phenotype by culturing in conditioned medium. In addition, we also tested the steroid responsiveness of TH2 and TH17 cells. In vitro, TH17 cytokine responses were not sensitive to dexamethasone (DEX) treatment despite immunocytochemistry confirming glucocorticoid receptor translocation to the nucleus following treatment. Transfer of TH2 cells to mice challenged with OVA protein resulted in lymphocyte and eosinophil emigration into the lung that was markedly reduced by DEX treatment, whereas TH17 transfer resulted in increased CXC chemokine secretion and neutrophil influx that was not attenuated by DEX. Transfer of TH17 or TH2 cells was sufficient to induce airway hyperresponsiveness (AHR) to methacholine. Interestingly, AHR was not attenuated by DEX in the TH17 group. These data demonstrate that polarized Ag-specific T cells result in specific lung pathologies. Both TH2 and TH17 cells are able to induce AHR, whereas TH17 cell-mediated airway inflammation and AHR are steroid resistant, indicating a potential role for TH17 cells in steroid-resistant asthma.

Methacholine

10.4049/jimmunol.181.6.4089

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Critical role of IL-17R signaling in granulocyte recruitment and airway hyperreactivity in an Aspergillus model of asthma (96.7)

The Journal of Immunology (2007)

Shernaaz B Kapadia Laura McKinley Adam C. Henry Anuradha Ray Jay K. Kolls

Abstract Rationale IL-17 is a proinflammatory cytokine that enhances neutrophil recruitment in response to allergen in murine lung. In an Aspergillus fumigatus (Af)-induced asthma model, wild-type C57BL/6 mice develop bronchial inflammation and hyperreactivity. We hypothesized that, compared to C57BL/6, Af sensitized IL-17R KO mice would have reduced neutrophil recruitment to the lung, airway resistance and hyperreactivity. Methods C57BL/6 and IL-17R KO male mice, 6–8 wk old, were sensitized intraperitoneally with 40 ug Af extract and 2 mg Al(OH)3 on days 0 and 7, and intratracheally with 25 ug Af on days 21, 22, and 23. Bronchoalveolar lavage (BAL) differential cell counts and cytokine analysis were done at 24 and 72 hr. Flexivent was performed at 24 hr to assess airway physiology. Results WT mice had significant influx of both neutrophils and eosinophils in response to Af at 24 hr. In contrast, IL-17R KO mice showed reduced neutrophil and eosinophil emigration to the lung which was associated with lower KC and eotaxin levels in BAL fluid. Furthermore, Flexivent data showed lower airway resistance and bronchial hyperreactivity in IL-17R KO mice. Conclusion Our findings in Af treated IL-17R KO mice of decreased pulmonary neutrophil and eosinophil recruitment at 24 hr suggest that IL-17 promotes granulocyte recruitment as well as airway hyperreactivity. Funding: NHLBI

Proinflammatory cytokine

10.4049/jimmunol.178.supp.96.7

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A Role for Indoleamine 2,3‐Dioxygenase in Lung Dendritic Cell Activation in Response to Allergens Impacting Allergic Airways Disease

The FASEB Journal (2008)

Hui Xu Timothy B. Oriss Adam C. Henry Barbro N. Melgert Li Chen

Indoleamine 2,3 dioxgenase (IDO) has been shown to inhibit Th1‐mediated immune responses. However, the role of IDO in Th2 cell‐mediated diseases has not been adequately addressed. We have investigated the role of IDO in allergic airways disease. Interestingly, IDO protein expression was easily detected in lung myeloid DCs from naïve wild‐type (WT) mice which was not true for spleen DCs. Upon antigen sensitization via the lung, fewer mature DCs and fewer adoptively transferred CD4+ T cells from DO11.10 mice were recovered from lung‐draining lymph nodes (LNs) of IDO−/− mice compared to that from LNs of WT mice. In line with the lower net accumulation of adoptively transferred CD4+ T cells in the lung‐draining LNs of IDO−/− mice, Th2 cytokine levels in the lung tissue of these mice was also lower. In a chronic model of experimental asthma, all features of allergic airways disease were significantly attenuated in the IDO−/− mice. Collectively, these data show an important role for IDO in lung myeloid DC activation in response to allergens and suggest that the reduced Th2 type immune response in IDO−/− mice is due, at least in part, to less effective co‐stimulation between DCs and T cells. Supported by NIH grants HL 77430 (to A.R) and HL60207 (to P.R.)

Indoleamine 2,3-dioxygenase

Adoptive Cell Transfer

10.1096/fasebj.22.1_supplement.670.9

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Regulatory T cells and cytokines in malignant pleural effusions secondary to mesothelioma and carcinoma

Cancer Biology & Therapy (2005)

Peter DeLong Richard G. Carroll Adam C. Henry Tomoyuki Tanaka Sajjad Ahmad

Immunotherapy against a variety of malignancies, including pleural-based malignancies, has shown promise in animal models and early human clinical trials, but successful efforts will need to address immuno-suppressive factors of the tumor and host, particularly certain cytokines and CD4+ CD25+ regulatory T cells (Treg). Here, we evaluated the cellular and cytokine components of malignant pleural effusions from 44 patients with previously diagnosed mesothelioma, non-small cell lung cancer (NSCLC), or breast cancer and found significant differences in the immune profile of pleural effusions secondary to mesothelioma vs. carcinoma. Although a high prevalence of functionally suppressive CD4+ CD25+ T cells was found in carcinomatous pleural effusions, mesothelioma pleural effusions contained significantly fewer CD4+ CD25+ T cells. Activated CD8+ T cells in pleural fluid were significantly more prevalent in mesothelioma than carcinoma. However, there is clear patient-to-patient variability and occasional mesothelioma patients with high percentages of CD4+ CD25+ pleural effusion T cells and low percentages of CD8+ CD25+ pleural effusion T cells can be identified. Mesothelioma pleural effusions contained the highest concentrations of the immuno-suppressive cytokine transforming growth factcor (TGF)-beta. Thus, the contribution of cellular and cytokine components of immuno-suppression associated with malignant pleural effusions varies by tumor histology and by the individual patient. These results have implications for the development of immunotherapy directed to the malignant pleural space, and suggest the need to tailor immunotherapy to overcome immunosuppressive mechanisms in tumor environments.

Pleural disease

10.4161/cbt.4.3.1644

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Citations (120)

Pore Occlusion in Compacted Mixtures of Sand and Kaolinite Due to Bioclogging

Sailaja Tumuluri Lakshmi N. Reddi George L. Marchin Adam C. Henry

Biokinetics in engineered soils is a subject of relatively recent interest. In this paper, results are presented from experimental studies to address the bioclogging mechanisms. The primary focus of this study is to assess the relative importance of biomass growth vs. biogas generated in the soil pores. Experiments were conducted using Pseudomonas aeruginosa as the bacterial culture and compacted mixtures of kaolinite and Ottawa sand as porous media. Results indicated about one order-of-magnitude reduction of permeabilities when the bacteria were introduced through a nutrient solution in the influent chamber. Compacted specimens prepared using a bacterial inoculum and permeated with nutrient solution alone showed that growth kinetics prevented the specimens from ever reaching the saturated hydraulic conductivities with respect to distilled deionized water. Bacterial counts in the influent and in the effluent revealed that the kinetic processes were similar in soil media and in the pure nutrient solution medium. Reductions in permeabilities were attributed to the biogas generated during bacteria permeation. Pore-size distributions of bioclogged specimens showed lager pores, which was also consistent with visual observations of specimen cracking and gas bubble accumulation at the surface of the specimens, particularly in the case of specimens prepared with bacteria inoculum.

Distilled water

Biogas

Bacterial growth

10.1061/40789(168)20

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Treatment of Lung Cancer Using Clinically Relevant Oral Doses of the Cyclooxygenase-2 Inhibitor Rofecoxib

Annals of Surgery (2005)

Tomoyuki Tanaka Peter DeLong Kunjlata M. Amin Adam C. Henry Robert Kruklitis

In Brief Objective: To investigate the uses and limitations of cyclooxygenase- (COX) 2 inhibition using clinically relevant doses of oral rofecoxib in the treatment of murine models of non–small-cell lung cancer (NSCLC). Summary Background Data: Overexpression of COX-2 has been reported in lung cancer. Several studies have demonstrated that high doses of COX-2 inhibitors could inhibit the growth of rodent and human lung cancer cell lines. The potential uses and limitations of COX-2 inhibition at doses equivalent to those currently approved for use in humans have not been well studied. Methods: Three murine NSCLC cell lines were injected into the flanks of mice to establish tumor xenografts. Mice were treated orally with low doses of a COX-2 inhibitor (rofecoxib chow, 0.0075%). Mechanisms were evaluated by analysis of tumor-infiltrating lymphocytes. To study rofecoxib as adjuvant therapy, large established tumors (14–18 days after tumor inoculation) were surgically debulked and animals were treated with rofecoxib starting 3 days before surgery. Recurrence of the tumor after debulking was monitored. Results: Rofecoxib significantly slowed the growth of small (0-120 mm3) tumors (P < 0.01-0.05) in all 3 cell lines, with higher efficacy in the more immunogenic tumors. Minimal responses were noted in larger tumors. Rofecoxib appeared to augment CD8+ T cell infiltration in immunogenic tumors. Rofecoxib significantly reduced the recurrence rate after debulking (P < 0.01). Conclusions: Clinically relevant doses of the COX-2 inhibitor rofecoxib given orally were effective in inhibiting the growth of small (but not large) tumors in 3 murine NSCLC cell lines tested and in preventing recurrences after surgical debulking. Depending on the immunogenicity of human tumors, COX-2 inhibition might be useful as adjuvant therapy for surgically resectable NSCLC. Clinically relevant doses of the cyclooxygenase-2 (COX-2) inhibitor rofecoxib given orally were effective in inhibiting the growth of small tumors and in preventing recurrence after debulking in non–small-cell lung cancer (NSCLC). These data suggest that COX-2 inhibition may be useful as adjuvant therapy for surgical resectable NSCLC.

Tumor Debulking

10.1097/01.sla.0000149427.84712.d9

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Insulin-Like Growth Factor Binding Proteins 3 and 5 Are Overexpressed in Idiopathic Pulmonary Fibrosis and Contribute to Extracellular Matrix Deposition

American Journal Of Pathology (2005)

Joseph M. Pilewski Lixin Liu Adam C. Henry Alycia V. Knauer Carol Feghali‐Bostwick

Pathogenesis

10.1016/s0002-9440(10)62263-8

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Citations (221)

Indoleamine 2,3-Dioxygenase is not required for tolerance induction in the airways but is important for allergic airway disease (39.8)

The Journal of Immunology (2007)

Hui Xu Timothy B. Oriss Barbro N. Melgert Adam C. Henry Li Chen

Abstract Indoleamine 2,3 dioxgenase (IDO) has emerged as an important negative regulator of immune responses. However, the role of IDO in Th2 cell-mediated diseases is not completely clear. We investigated the role of IDO in the induction of inflammation or tolerance in the airways in response to ovalbumin (OVA). The results of these experiments show that IDO−/− mice are susceptible to tolerance induction. However, IDO−/− mice displayed significantly lower airway hyperresponsiveness (AHR), lower serum OVA-specific IgE and lower Th2 type cytokines (IL-5 and IL-13) in comparison to wt mice. In an OVA-induced chronic airway inflammation model, the IDO−/− mice also showed lower AHR and Th2 type cytokines in the lung and less infiltration of inflammatory cells in the airways. To dissect the mechanism underlying IDO-mediated promotion of allergic airway disease, we stimulated lung DC by allergens in vitro. The expression of important co-stimulatory molecules and MHC-II was lower in DCs from IDO−/− mice in comparison to those in DCs from wt control mice suggesting that the reduced airway Th2 type immune response in IDO−/− mice may be due, at least in part, to less effective co-stimulation between DCs and T cells. In summary, our data suggest that IDO is not required for the induction of airway tolerance, but may play a role in promoting Th2-induced allergic airway disease. Supported by NIH grants HL 77430 (to A.R) and HL60207 (to P.R.)

Regulatory T cell

Indoleamine 2,3-dioxygenase

10.4049/jimmunol.178.supp.39.8

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Use of cyclooxygenase-2 inhibition to enhance the efficacy of immunotherapy.

PubMed (2003)

Peter DeLong Tomoyuki Tanaka Robb Kruklitis Adam C. Henry Veena Kapoor

Antitumor effects of cyclooxygenase-2 (COX-2) inhibition have been reported in a wide variety of tumor models and in human cancers, both as chemoprevention and therapy. Human mesothelioma tumors have been shown to overexpress COX-2 and high levels of COX-2 protein have been demonstrated to be a prognostic factor, indicating poor outcome in this tumor. In this study, we determined that inhibition of COX-2 by oral administration of Rofecoxib significantly slowed but did not cure the growth of small tumors in mesothelioma-bearing mice. Large tumors were unaffected. This effect was dependent on the presence of CD8+ T cells and was associated with increased tumor-infiltrating lymphocytes. Because these activities are consistent with a mechanism that results in a decrease in the immunosuppressive environment of the tumor, we additionally examined the effect of COX-2 blockade combined with Ad.IFN-beta therapy, a treatment that we have previously demonstrated results in expansion of antitumor CD8+ CTLs and cures a high percentage of small mesothelioma tumors in mice. Ad.IFN-beta therapy combined with COX-2 inhibition was associated with an increased number of T cells within tumors and resulted in cures of small tumors, significant inhibition of the growth of large established tumors, and inhibition of the growth of metastatic tumor foci after surgical debulking. The additive effects of these modes of treatment suggests that it would be rational to combine COX-2 inhibition with immuno- and immunogene therapy approaches (perhaps in conjunction with surgical debulking) in human clinical trials of treatment of mesothelioma and other tumors.

Debulking

Growth inhibition

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Citations (85)