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1.  Suppression of Inflammation in Ulcerative Colitis by Interferon-β-1a Is Accompanied by Inhibition of IL-13 Production 
Gut  2010;60(4):449-455.
Background and Aims
Ulcerative colitis (UC) is associated with increased IL-13 production by natural killer T cells. Taking advantage of the inhibitory actions of interferon-β on IL-13 expression, this proof-of-concept study aimed to show that decreasing IL-13 production is associated with clinical improvement of UC symptoms.
Adult patients with active UC were treated with 30 μg IM interferon-β-1a weekly for 12 weeks with 6 month follow-up. Clinical response was measured by the Short Clinical Colitis Activity Index, and cytokine production was measured in peripheral blood and lamina propria mononuclear cells (LPMC) before and after treatment.
11 of 16 patients were clinical responders, and 4 were in remission at the end of treatment. Rectal bleeding subscores improved dramatically by Week 4 (38% with frank bleeding vs 87% pretreatment). Increased IL-13 production by LPMC T cells fell significantly in responders (690±99 vs 297±58 pg/mL p=0.015) but was unchanged in non-responders (542±83 vs 510±39 pg/mL). In addition, non-responders had significantly higher production of IL-17 and IL-6 pretreatment compared to responders.
Interferon-β-1a induces clinical response and remission in a large subset of UC patients that is clearly associated with inhibition of IL-13 production. In addition, increased IL-17 and IL-6 production is associated with no response to interferon-β. These data provide a proof-of-concept that IL-13 is an effector cytokine in UC and should be a target for novel therapies.
PMCID: PMC3430969  PMID: 20971977
Ulcerative colitis; interferon-β; interleukin-13
2.  H. pylori Infection Inhibits Phagocyte Clearance of Apoptotic Gastric Epithelial Cells 
Increased apoptotic death of gastric epithelial cells is a hallmark of H. pylori infection, and altered epithelial cell turnover is an important contributor to gastric carcinogenesis. To address the fate of apoptotic gastric epithelial cells and their role in H. pylori mucosal disease, we investigated phagocyte clearance of apoptotic gastric epithelial cells in H. pylori infection. Human gastric mononuclear phagocytes were analyzed for their ability to take up apoptotic epithelial cells in vivo using immunofluorescence analysis. We then used primary human gastric epithelial cells induced to undergo apoptosis by exposure to live H. pylori to study apoptotic cell uptake by autologous monocyte-derived macrophages. We show that HLA-DR+ mononuclear phagocytes in human gastric mucosa contain cytokeratin-positive and TUNEL-positive apoptotic epithelial cell material, indicating that gastric phagocytes are involved in apoptotic epithelial cell clearance. We further show that H. pylori both increased apoptosis in primary gastric epithelial cells and decreased phagocytosis of the apoptotic epithelial cells by autologous monocyte-derived macrophages. Reduced macrophage clearance of apoptotic cells was mediated in part by H. pylori-induced macrophage TNF-α, which was expressed at higher levels in H. pylori-infected, compared to uninfected, gastric mucosa. Importantly, we show that H. pylori-infected gastric mucosa contained significantly higher numbers of apoptotic epithelial cells and higher levels of non-phagocytosed TUNEL-positive apoptotic material, consistent with a defect in apoptotic cell clearance. Thus, as shown in other autoimmune and chronic inflammatory diseases, insufficient phagocyte clearance may contribute to the chronic and self-perpetuating inflammation in human H. pylori infection.
PMCID: PMC3725581  PMID: 23686492
3.  Extracorporeal Photopheresis (ECP) in Patients with Steroid-Dependent Crohn’s Disease: An Open-Label, Multi-Center, Prospective Trial 
Inflammatory bowel diseases  2013;19(2):293-300.
ECP involves ex vivo leukocyte treatment with methoxsalen and UVA light to generate a tolerogenic response. A previous trial demonstrated that ECP permits corticosteroid withdrawal in steroid-dependent Crohn’s disease (CD) patients who were in clinical remission. We studied the effect of ECP on steroid withdrawal in steroid-dependent CD.
Patients with CD for ≥6 months, in remission at baseline while on steroids, but who had failed at ≥1 steroid withdrawal were included. Patients received 2 ECP treatments every 2 weeks for the 24-week steroid tapering period and underwent steroid-tapering. Patients completing steroid tapering could receive maintenance ECP (2 treatments/week) every month for 24 weeks.
31 patients (CDAI 91; IBDQ 172.5) were enrolled (baseline corticosteroid dose − 20 mg/day). 65% were refractory to/intolerant of anti-TNF agents or immunosuppressants. After 24 weeks of ECP, 7 of 31 (22.6%) patients discontinued steroids while maintaining a CDAI of < 150. At Week 24, the steroid dose for the remaining patients on corticosteroids was 10 mg (p < 0.003 vs. baseline) with a CDAI of 110 and an IBDQ of 179. Following maintenance treatment, 3 patients remained in steroid-free remission. The 10 patients in the study and receiving ECP at Week 48 had a steroid dose of 3.5 mg with a CDAI of 40 and an IBDQ of 188.
ECP permitted discontinuation or reduction of steroids in a population of refractory steroid-dependent CD patients. ECP may be useful in permitting steroid withdrawal in selected steroid-dependent CD patients. Ideally, these results need to be confirmed in a “sham-controlled” clinical trial.
PMCID: PMC3437245  PMID: 22573600
Extracorporeal Photopheresis; Crohn’s Disease; Steroid Dependent
4.  A framework for human microbiome research 
Methé, Barbara A. | Nelson, Karen E. | Pop, Mihai | Creasy, Heather H. | Giglio, Michelle G. | Huttenhower, Curtis | Gevers, Dirk | Petrosino, Joseph F. | Abubucker, Sahar | Badger, Jonathan H. | Chinwalla, Asif T. | Earl, Ashlee M. | FitzGerald, Michael G. | Fulton, Robert S. | Hallsworth-Pepin, Kymberlie | Lobos, Elizabeth A. | Madupu, Ramana | Magrini, Vincent | Martin, John C. | Mitreva, Makedonka | Muzny, Donna M. | Sodergren, Erica J. | Versalovic, James | Wollam, Aye M. | Worley, Kim C. | Wortman, Jennifer R. | Young, Sarah K. | Zeng, Qiandong | Aagaard, Kjersti M. | Abolude, Olukemi O. | Allen-Vercoe, Emma | Alm, Eric J. | Alvarado, Lucia | Andersen, Gary L. | Anderson, Scott | Appelbaum, Elizabeth | Arachchi, Harindra M. | Armitage, Gary | Arze, Cesar A. | Ayvaz, Tulin | Baker, Carl C. | Begg, Lisa | Belachew, Tsegahiwot | Bhonagiri, Veena | Bihan, Monika | Blaser, Martin J. | Bloom, Toby | Vivien Bonazzi, J. | Brooks, Paul | Buck, Gregory A. | Buhay, Christian J. | Busam, Dana A. | Campbell, Joseph L. | Canon, Shane R. | Cantarel, Brandi L. | Chain, Patrick S. | Chen, I-Min A. | Chen, Lei | Chhibba, Shaila | Chu, Ken | Ciulla, Dawn M. | Clemente, Jose C. | Clifton, Sandra W. | Conlan, Sean | Crabtree, Jonathan | Cutting, Mary A. | Davidovics, Noam J. | Davis, Catherine C. | DeSantis, Todd Z. | Deal, Carolyn | Delehaunty, Kimberley D. | Dewhirst, Floyd E. | Deych, Elena | Ding, Yan | Dooling, David J. | Dugan, Shannon P. | Dunne, Wm. Michael | Durkin, A. Scott | Edgar, Robert C. | Erlich, Rachel L. | Farmer, Candace N. | Farrell, Ruth M. | Faust, Karoline | Feldgarden, Michael | Felix, Victor M. | Fisher, Sheila | Fodor, Anthony A. | Forney, Larry | Foster, Leslie | Di Francesco, Valentina | Friedman, Jonathan | Friedrich, Dennis C. | Fronick, Catrina C. | Fulton, Lucinda L. | Gao, Hongyu | Garcia, Nathalia | Giannoukos, Georgia | Giblin, Christina | Giovanni, Maria Y. | Goldberg, Jonathan M. | Goll, Johannes | Gonzalez, Antonio | Griggs, Allison | Gujja, Sharvari | Haas, Brian J. | Hamilton, Holli A. | Harris, Emily L. | Hepburn, Theresa A. | Herter, Brandi | Hoffmann, Diane E. | Holder, Michael E. | Howarth, Clinton | Huang, Katherine H. | Huse, Susan M. | Izard, Jacques | Jansson, Janet K. | Jiang, Huaiyang | Jordan, Catherine | Joshi, Vandita | Katancik, James A. | Keitel, Wendy A. | Kelley, Scott T. | Kells, Cristyn | Kinder-Haake, Susan | King, Nicholas B. | Knight, Rob | Knights, Dan | Kong, Heidi H. | Koren, Omry | Koren, Sergey | Kota, Karthik C. | Kovar, Christie L. | Kyrpides, Nikos C. | La Rosa, Patricio S. | Lee, Sandra L. | Lemon, Katherine P. | Lennon, Niall | Lewis, Cecil M. | Lewis, Lora | Ley, Ruth E. | Li, Kelvin | Liolios, Konstantinos | Liu, Bo | Liu, Yue | Lo, Chien-Chi | Lozupone, Catherine A. | Lunsford, R. Dwayne | Madden, Tessa | Mahurkar, Anup A. | Mannon, Peter J. | Mardis, Elaine R. | Markowitz, Victor M. | Mavrommatis, Konstantinos | McCorrison, Jamison M. | McDonald, Daniel | McEwen, Jean | McGuire, Amy L. | McInnes, Pamela | Mehta, Teena | Mihindukulasuriya, Kathie A. | Miller, Jason R. | Minx, Patrick J. | Newsham, Irene | Nusbaum, Chad | O’Laughlin, Michelle | Orvis, Joshua | Pagani, Ioanna | Palaniappan, Krishna | Patel, Shital M. | Pearson, Matthew | Peterson, Jane | Podar, Mircea | Pohl, Craig | Pollard, Katherine S. | Priest, Margaret E. | Proctor, Lita M. | Qin, Xiang | Raes, Jeroen | Ravel, Jacques | Reid, Jeffrey G. | Rho, Mina | Rhodes, Rosamond | Riehle, Kevin P. | Rivera, Maria C. | Rodriguez-Mueller, Beltran | Rogers, Yu-Hui | Ross, Matthew C. | Russ, Carsten | Sanka, Ravi K. | Pamela Sankar, J. | Sathirapongsasuti, Fah | Schloss, Jeffery A. | Schloss, Patrick D. | Schmidt, Thomas M. | Scholz, Matthew | Schriml, Lynn | Schubert, Alyxandria M. | Segata, Nicola | Segre, Julia A. | Shannon, William D. | Sharp, Richard R. | Sharpton, Thomas J. | Shenoy, Narmada | Sheth, Nihar U. | Simone, Gina A. | Singh, Indresh | Smillie, Chris S. | Sobel, Jack D. | Sommer, Daniel D. | Spicer, Paul | Sutton, Granger G. | Sykes, Sean M. | Tabbaa, Diana G. | Thiagarajan, Mathangi | Tomlinson, Chad M. | Torralba, Manolito | Treangen, Todd J. | Truty, Rebecca M. | Vishnivetskaya, Tatiana A. | Walker, Jason | Wang, Lu | Wang, Zhengyuan | Ward, Doyle V. | Warren, Wesley | Watson, Mark A. | Wellington, Christopher | Wetterstrand, Kris A. | White, James R. | Wilczek-Boney, Katarzyna | Wu, Yuan Qing | Wylie, Kristine M. | Wylie, Todd | Yandava, Chandri | Ye, Liang | Ye, Yuzhen | Yooseph, Shibu | Youmans, Bonnie P. | Zhang, Lan | Zhou, Yanjiao | Zhu, Yiming | Zoloth, Laurie | Zucker, Jeremy D. | Birren, Bruce W. | Gibbs, Richard A. | Highlander, Sarah K. | Weinstock, George M. | Wilson, Richard K. | White, Owen
Nature  2012;486(7402):215-221.
A variety of microbial communities and their genes (microbiome) exist throughout the human body, playing fundamental roles in human health and disease. The NIH funded Human Microbiome Project (HMP) Consortium has established a population-scale framework which catalyzed significant development of metagenomic protocols resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 to 18 body sites up to three times, which to date, have generated 5,177 microbial taxonomic profiles from 16S rRNA genes and over 3.5 Tb of metagenomic sequence. In parallel, approximately 800 human-associated reference genomes have been sequenced. Collectively, these data represent the largest resource to date describing the abundance and variety of the human microbiome, while providing a platform for current and future studies.
PMCID: PMC3377744  PMID: 22699610
5.  The Effect of Intermittent IL-2 Therapy on CD4 T Cells in the Gut in HIV-1 Infected Patients 
We sought to determine the effects of interleukin-2 administered in combination with antiretroviral therapy (ART) on CD4+ T cells in the gut. Lymphocytes from whole blood, colon and terminal ileum of HIV infected adults treated with interleukin-2 and ART or ART alone were examined. There were no differences between groups in the proportion of CD4+ T cells or in expression of CD25 or Ki67 by CD4+T cells in the gut. Although IL-2 administration leads to expansion of peripheral blood CD4+ T cells, there is no alteration in the proportion or activation of CD4+ T cells in the gut mucosa.
PMCID: PMC3073743  PMID: 21350367
gastrointestinal tract; mucosa; IL-2; HIV; CD4
6.  Cycling of Gut Mucosal CD4+ T Cells Decreases after Prolonged Anti-Retroviral Therapy and is Associated with Plasma LPS Levels 
Mucosal immunology  2009;3(2):172-181.
The gut mucosa is an important site of HIV immunopathogenesis, with severe depletion of CD4+ T cells occurring during acute infection. The effect of prolonged anti-retroviral therapy (ART) on cycling and restoration of T lymphocytes in the gut remains unclear. Colon and terminal ileal biopsies and peripheral blood samples were collected from viremic, untreated, HIV-infected participants, patients treated with prolonged ART (>5 years), and uninfected controls and analyzed by flow cytometry. In the gut, the proportion of cycling T cells decreased and the number of CD4+ T cells normalized in treated patients in parallel with β7 expression on CD4+ T cells in blood. Cycling of gut T cells in viremic patients was associated with increased plasma LPS levels, but not colonic HIV-RNA. These data suggest that gut T cell activation and microbial translocation may be interconnected while prolonged ART may decrease activation and restore gut CD4+ T cells.
PMCID: PMC2830855  PMID: 19956090
7.  Anti-IgE Treatment of Eosinophil Associated Gastrointestinal Disorders 
Eosinophil Associated Gastrointestinal Disorders (EGIDs) are commonly associated with atopy and are being recognized with increasing frequency. Current therapy for EGIDs is inadequate.
We sought to determine the efficacy of anti-IgE therapy in EGIDs and investigate the role of IgE in disease pathogenesis.
Nine subjects with EGIDs received omalizumab every 2 weeks for 16 weeks while other therapy was held constant. Blood absolute eosinophil counts, tissue eosinophil counts, symptom scores, and free IgE were serially measured. Allergen skin testing, and flow cytometry for basophil activation and FcεRI were determined at baseline and at week 16.
Omalizumab was associated with a decrease in absolute eosinophil count at both the 16 week (34%, p=0.004) and combined weeks 12–16 (42%, p=0.012) time points. Tissue eosinophils decreased in the duodenum (59%) and gastric antrum (69%), but did not reach statistical significance (p=0.074 and 0.098, respectively). Esophageal eosinophil counts remained unchanged. Basophil and dendritic cell FcεRI expression, and free IgE were all significantly decreased (p<0.005). Omalizumab increased the concentration of allergen required to trigger half-maximal basophil activation by 170-fold. Allergen skin test wheal and erythema responses decreased by 78% and 82%, respectively. Symptom scores were decreased at both the midstudy (63%) and end of study (70%) time points (p<0.005 for both).
These results demonstrate that IgE-mediated processes contribute to the generation of eosinophilic inflammation in EGIDs, and suggest that anti-IgE therapy may be effective in these disorders.
Clinical implications
Anti-IgE may be a potential therapy for EGIDs.
PMCID: PMC2768344  PMID: 17765756
Eosinophil; eosinophilic gastroenteritis; eosinophilic esophagitis; omalizumab; IgE; food allergy; basophil
8.  Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway 
Journal of Clinical Investigation  1999;104(12):1693-1701.
The renin-angiotensin system (RAS) is a key regulator of vascular tone and blood pressure. In addition, angiotensin II also has a number of cellular effects that may contribute to disease pathogenesis. Using Agtr1a–/– mice, which lack AT1A receptors for angiotensin II, we have identified a novel function of the RAS to modulate the immune system. We find that angiotensin II, acting through type 1 (AT1) receptors on immune cells, triggers the proliferation of splenic lymphocytes. These actions contribute to the vigor of cellular alloimmune responses. Within lymphoid organs, sufficient components of the RAS are present to activate AT1 receptors during an immune response, promoting cell growth. These actions require activation of calcineurin phosphatase. In an in vivo model of cardiac transplantation, the absence of AT1 signaling accentuates the immunosuppressive effects of the calcineurin inhibitor cyclosporine. We conclude that inhibition of AT1 receptor signaling should be useful as an anti-inflammatory and immunosuppressive therapy. Furthermore, the actions of the RAS to promote lymphocyte activation may contribute to inflammation that characterizes a number of diseases of the heart and the vascular system.
J. Clin. Invest. 104:1693–1701 (1999).
PMCID: PMC409880  PMID: 10606623

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