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Faustman, Denise

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Faustman

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Denise

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Faustman, Denise
Author's Publications: search.filters.isAuthorOfPublication.78165beb-4619-4b5a-a829-acbd6026116b

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    Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations
    (Nature Publishing Group UK, 2018) Kuhtreiber, Willem; Tran, Lisa; Kim, Taesoo; Dybala, Michael; Nguyen, Brian; Plager, Sara; Huang, Daniel; Janes, Sophie; Defusco, Audrey; Baum, Danielle; Zheng, Hui; Faustman, Denise
    Mycobacterium are among the oldest co-evolutionary partners of humans. The attenuated Mycobacterium bovis Bacillus Calmette Guérin (BCG) strain has been administered globally for 100 years as a vaccine against tuberculosis. BCG also shows promise as treatment for numerous inflammatory and autoimmune diseases. Here, we report on a randomized 8-year long prospective examination of type 1 diabetic subjects with long-term disease who received two doses of the BCG vaccine. After year 3, BCG lowered hemoglobin A1c to near normal levels for the next 5 years. The BCG impact on blood sugars appeared to be driven by a novel systemic and blood sugar lowering mechanism in diabetes. We observe a systemic shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, a state of high glucose utilization. Confirmation is gained by metabolomics, mRNAseq, and functional assays of cellular glucose uptake after BCG vaccinations. To prove BCG could induce a systemic change to promote accelerated glucose utilization and impact blood sugars, murine data demonstrated reduced blood sugars and aerobic induction in non-autoimmune mice made chemically diabetic. BCG via epigenetics also resets six central T-regulatory genes for genetic re-programming of tolerance. These findings set the stage for further testing of a known safe vaccine therapy for improved blood sugar control through changes in metabolism and durability with epigenetic changes even in advanced Type 1 diabetes.
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    The Hippo signaling pathway is required for salivary gland development and its dysregulation is associated with Sjogren's-like disease
    (2013) Enger, Tone Berge; Samad-Zadeh, Arman; Bouchie, Meghan; Skarstein, Kathrine; Galtung, Hilde Kanli; Mera, Toshiyuki; Walker, Janice; Menko, A. Sue; Varelas, Xaralabos; Faustman, Denise; Jensen, Janicke Liaaen; Kukuruzinska, Maria
    Sjogren's syndrome (SS) is a complex autoimmune disease that primarily affects salivary and lacrimal glands and is associated with high morbidity. Although the prevailing dogma is that immune system pathology drives SS, increasing evidence points to structural defects, including defective E-cadherin adhesion, to be involved in its etiology. We have shown that E-cadherin plays pivotal roles in the development of the mouse salivary submandibular gland (SMG) by organizing apical-basal polarity in acinar and ductal progenitors and by signaling survival for differentiating duct cells. Recently, E-cadherin junctions have been shown to interact with effectors of the Hippo signaling pathway, a core pathway regulating organ size, cell proliferation and differentiation. We now show that Hippo signaling is required for SMG branching morphogenesis and is involved in the pathophysiology of SS. During SMG development, a Hippo pathway effector, TAZ, becomes increasingly phosphorylated and associated with E-cadherin and α-catenin, consistent with the activation of Hippo signaling. Inhibition of Lats2, an upstream kinase that promotes TAZ phosphorylation, results in dysmorphogenesis of the SMG and impaired duct formation. SMGs from NOD mice, a mouse model for SS, phenocopy the Lats2-inhibited SMGs and exhibit a reduction in E-cadherin junctional components, including TAZ. Importantly, labial specimens from human SS patients display mislocalization of TAZ from junctional regions to the nucleus, coincident with accumulation of extracellular matrix components, fibronectin and CTGF, known downstream targets of TAZ. Our studies show that Hippo signaling plays a crucial role in SMG branching morphogenesis and provide evidence that defects in this pathway are associated with SS in humans.
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    TNF Receptor 2 and Disease: Autoimmunity and Regenerative Medicine
    (Frontiers Media S.A., 2013) Faustman, Denise; Davis, Miriam
    The regulatory cytokine tumor necrosis factor (TNF) exerts its effects through two receptors: TNFR1 and TNFR2. Defects in TNFR2 signaling are evident in a variety of autoimmune diseases. One new treatment strategy for autoimmune disease is selective destruction of autoreactive T cells by administration of TNF, TNF inducers, or TNFR2 agonism. A related strategy is to rely on TNFR2 agonism to induce T-regulatory cells (Tregs) that suppress cytotoxic T cells. Targeting TNFR2 as a treatment strategy is likely superior to TNFR1 because of its more limited cellular distribution on T cells, subsets of neurons, and a few other cell types, whereas TNFR1 is expressed throughout the body. This review focuses on TNFR2 expression, structure, and signaling; TNFR2 signaling in autoimmune disease; treatment strategies targeting TNFR2 in autoimmunity; and the potential for TNFR2 to facilitate end organ regeneration.
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    Homogeneous Expansion of Human T-Regulatory Cells Via Tumor Necrosis Factor Receptor 2
    (Nature Publishing Group, 2013) Okubo, Yoshiaki; Mera, Toshiyuki; Wang, Limei; Faustman, Denise
    T-regulatory cells (Tregs) are a rare lymphocyte subtype that shows promise for treating infectious disease, allergy, graft-versus-host disease, autoimmunity, and asthma. Clinical applications of Tregs have not been fully realized because standard methods of expansion ex vivo produce heterogeneous progeny consisting of mixed populations of CD4 + T cells. Heterogeneous progeny are risky for human clinical trials and face significant regulatory hurdles. With the goal of producing homogeneous Tregs, we developed a novel expansion protocol targeting tumor necrosis factor receptors (TNFR) on Tregs. In in vitro studies, a TNFR2 agonist was found superior to standard methods in proliferating human Tregs into a phenotypically homogeneous population consisting of 14 cell surface markers. The TNFR2 agonist-expanded Tregs also were functionally superior in suppressing a key Treg target cell, cytotoxic T-lymphocytes. Targeting the TNFR2 receptor during ex vivo expansion is a new means for producing homogeneous and potent human Tregs for clinical opportunities.
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    Strategic internal covalent cross-linking of TNF produces a stable TNF trimer with improved TNFR2 signaling
    (BioMed Central, 2015) Ban, Liqin; Kuhtreiber, Willem; Butterworth, John; Okubo, Yoshiaki; Vanamee, Éva S.; Faustman, Denise
    Background: Soluble TNF superfamily (TNFSF) ligands are less stable and less active than their transmembrane (tm) analogues. This is a problem for the therapeutic use of recombinant TNFSF ligands in diverse diseases including cancer and autoimmunity. Creating TNFSF ligand analogues with improved targeting of their respective receptors is important for research and therapeutic purposes. Findings: Covalent internal cross-linking of TNF monomers by double mutations, S95C/G148C, results in stable trimers with improved TNFR2 function. The resulting mutein induced the selective death of autoreactive CD8 T cells in type-1 diabetic patients and demonstrates targeted proliferation and expansion of human CD4 Tregs. Conclusions: Stable TNF trimers, created by internal covalent cross-linking, show improved signaling. The high structural homology within the TNF superfamily provides an opportunity to extend internal cross-linking to other TNF superfamily proteins to produce active trimers with improved stability and receptor signaling, and with potential applications for cancer, autoimmunity, infections, and transplantation. Electronic supplementary material The online version of this article (doi:10.1186/s40591-015-0044-4) contains supplementary material, which is available to authorized users.
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    Treg activation defect in type 1 diabetes: correction with TNFR2 agonism
    (Nature Publishing Group, 2016) Okubo, Yoshiaki; Topley, Heather; Butterworth, John; Zheng, Hui; Faustman, Denise
    Activated T-regulatory cells (aTregs) prevent or halt various forms of autoimmunity. We show that type 1 diabetics (T1D) have a Treg activation defect through an increase in resting Tregs (rTregs, CD4+CD25+Foxp3+CD45RA) and decrease in aTregs (CD4+CD25+Foxp3+CD45RO) (n= 55 T1D, n=45 controls, P=0.01). The activation defect persists life long in T1D subjects (T1D=45, controls=45, P=0.01, P=0.04). Lower numbers of aTregs had clinical significance because they were associated with a trend for less residual C-peptide secretion from the pancreas (P=0.08), and poorer HbA1C control (P=0.03). In humans, the tumor necrosis factor receptor 2 (TNFR2) is obligatory for Treg induction, maintenance and expansion of aTregs. TNFR2 agonism is a method for stimulating Treg conversion from resting to activated. Using two separate in vitro expansion protocols, TNFR2 agonism corrected the T1D activation defect by triggering conversion of rTregs into aTregs (n=54 T1D, P<0.001). TNFR2 agonism was superior to standard protocols and TNF in proliferating Tregs. In T1D, TNFR2 agonist-expanded Tregs were homogeneous and functionally potent by virtue of suppressing autologous cytotoxic T cells in a dose-dependent manner comparable to controls. Targeting the TNFR2 receptor for Treg expansion in vitro demonstrates a means to correct the activation defect in T1D.
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    31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two: National Harbor, MD, USA. 9-13 November 2016
    (BioMed Central, 2016) Ager, Casey; Reilley, Matthew; Nicholas, Courtney; Bartkowiak, Todd; Jaiswal, Ashvin; Curran, Michael; Albershardt, Tina C.; Bajaj, Anshika; Archer, Jacob F.; Reeves, Rebecca S.; Ngo, Lisa Y.; Berglund, Peter; ter Meulen, Jan; Denis, Caroline; Ghadially, Hormas; Arnoux, Thomas; Chanuc, Fabien; Fuseri, Nicolas; Wilkinson, Robert W.; Wagtmann, Nicolai; Morel, Yannis; Andre, Pascale; Atkins, Michael B.; Carlino, Matteo S.; Ribas, Antoni; Thompson, John A.; Choueiri, Toni; Hodi, F. Stephen; Hwu, Wen-Jen; McDermott, David; Atkinson, Victoria; Cebon, Jonathan S.; Fitzharris, Bernie; Jameson, Michael B.; McNeil, Catriona; Hill, Andrew G.; Mangin, Eric; Ahamadi, Malidi; van Vugt, Marianne; van Zutphen, Mariëlle; Ibrahim, Nageatte; Long, Georgina V.; Gartrell, Robyn; Blake, Zoe; Simoes, Ines; Fu, Yichun; Saito, Takuro; Qian, Yingzhi; Lu, Yan; Saenger, Yvonne M.; Budhu, Sadna; De Henau, Olivier; Zappasodi, Roberta; Schlunegger, Kyle; Freimark, Bruce; Hutchins, Jeff; Barker, Christopher A.; Wolchok, Jedd D.; Merghoub, Taha; Burova, Elena; Allbritton, Omaira; Hong, Peter; Dai, Jie; Pei, Jerry; Liu, Matt; Kantrowitz, Joel; Lai, Venus; Poueymirou, William; MacDonald, Douglas; Ioffe, Ella; Mohrs, Markus; Olson, William; Thurston, Gavin; Capasso, Cristian; Frascaro, Federica; Carpi, Sara; Tähtinen, Siri; Feola, Sara; Fusciello, Manlio; Peltonen, Karita; Martins, Beatriz; Sjöberg, Madeleine; Pesonen, Sari; Ranki, Tuuli; Kyruk, Lukasz; Ylösmäki, Erkko; Cerullo, Vincenzo; Cerignoli, Fabio; Xi, Biao; Guenther, Garret; Yu, Naichen; Muir, Lincoln; Zhao, Leyna; Abassi, Yama; Cervera-Carrascón, Víctor; Siurala, Mikko; Santos, João; Havunen, Riikka; Parviainen, Suvi; Hemminki, Akseli; Dalgleish, Angus; Mudan, Satvinder; DeBenedette, Mark; Plachco, Ana; Gamble, Alicia; Grogan, Elizabeth W.; Krisko, John; Tcherepanova, Irina; Nicolette, Charles; Dhupkar, Pooja; Yu, Ling; Kleinerman, Eugenie S.; Gordon, Nancy; Grenga, Italia; Lepone, Lauren; Gameiro, Sofia; Knudson, Karin M.; Fantini, Massimo; Tsang, Kwong; Hodge, James; Donahue, Renee; Schlom, Jeffrey; Evans, Elizabeth; Bussler, Holm; Mallow, Crystal; Reilly, Christine; Torno, Sebold; Scrivens, Maria; Foster, Cathie; Howell, Alan; Balch, Leslie; Knapp, Alyssa; Leonard, John E.; Paris, Mark; Fisher, Terry; Hu-Lieskovan, Siwen; Smith, Ernest; Zauderer, Maurice; Fogler, William; Franklin, Marilyn; Thayer, Matt; Saims, Dan; Magnani, John L.; Gong, Jian; Gray, Michael; Fromm, George; de Silva, Suresh; Giffin, Louise; Xu, Xin; Rose, Jason; Schreiber, Taylor H.; Gameiro, Sofia R.; Clavijo, Paul E.; Allen, Clint T.; Hodge, James W.; Tsang, Kwong Y.; Grogan, Jane; Manieri, Nicholas; Chiang, Eugene; Caplazi, Patrick; Yadav, Mahesh; Hagner, Patrick; Chiu, Hsiling; Waldman, Michelle; Klippel, Anke; Thakurta, Anjan; Pourdehnad, Michael; Gandhi, Anita; Henrich, Ian; Quick, Laura; Young, Rob; Chou, Margaret; Hotson, Andrew; Willingham, Stephen; Ho, Po; Choy, Carmen; Laport, Ginna; McCaffery, Ian; Miller, Richard; Tipton, Kimberly A.; Wong, Kenneth R.; Singson, Victoria; Wong, Chihunt; Chan, Chanty; Huang, Yuanhiu; Liu, Shouchun; Richardson, Jennifer H.; Kavanaugh, W. Michael; West, James; Irving, Bryan A.; Jaini, Ritika; Loya, Matthew; Eng, Charis; Johnson, Melissa L.; Adjei, Alex A.; Opyrchal, Mateusz; Ramalingam, Suresh; Janne, Pasi A.; Dominguez, George; Gabrilovich, Dmitry; de Leon, Laura; Hasapidis, Jeannette; Diede, Scott J.; Ordentlich, Peter; Cruickshank, Scott; Meyers, Michael L.; Hellmann, Matthew D.; Kalinski, Pawel; Zureikat, Amer; Edwards, Robert; Muthuswamy, Ravi; Obermajer, Nataša; Urban, Julie; Butterfield, Lisa H.; Gooding, William; Zeh, Herbert; Bartlett, David; Zubkova, Olga; Agapova, Larissa; Kapralova, Marina; Krasovskaia, Liudmila; Ovsepyan, Armen; Lykov, Maxim; Eremeev, Artem; Bokovanov, Vladimir; Grigoryeva, Olga; Karpov, Andrey; Ruchko, Sergey; Shuster, Alexandr; Khalil, Danny N.; Campesato, Luis Felipe; Li, Yanyun; Lazorchak, Adam S.; Patterson, Troy D.; Ding, Yueyun; Sasikumar, Pottayil; Sudarshan, Naremaddepalli; Gowda, Nagaraj; Ramachandra, Raghuveer; Samiulla, Dodheri; Giri, Sanjeev; Eswarappa, Rajesh; Ramachandra, Murali; Tuck, David; Wyant, Timothy; Leshem, Jasmin; Liu, Xiu-fen; Bera, Tapan; Terabe, Masaki; Bossenmaier, Birgit; Niederfellner, Gerhard; Reiter, Yoram; Pastan, Ira; Xia, Leiming; Xia, Yang; Hu, Yangyang; Wang, Yi; Bao, Yangyi; Dai, Fu; Huang, Shiang; Hurt, Elaine; Hollingsworth, Robert E.; Lum, Lawrence G.; Chang, Alfred E.; Wicha, Max S.; Li, Qiao; Mace, Thomas; Makhijani, Neil; Talbert, Erin; Young, Gregory; Guttridge, Denis; Conwell, Darwin; Lesinski, Gregory B.; Gonzales, Rodney JM Macedo; Huffman, Austin P.; Wang, Ximi K.; Reshef, Ran; MacKinnon, Andy; Chen, Jason; Gross, Matt; Marguier, Gisele; Shwonek, Peter; Sotirovska, Natalija; Steggerda, Susanne; Parlati, Francesco; Makkouk, Amani; Bennett, Mark K.; Emberley, Ethan; Huang, Tony; Li, Weiqun; Neou, Silinda; Pan, Alison; Zhang, Jing; Zhang, Winter; Marshall, Netonia; Marron, Thomas U.; Agudo, Judith; Brown, Brian; Brody, Joshua; McQuinn, Christopher; Farren, Matthew; Komar, Hannah; Shakya, Reena; Ludwug, Thomas; Morillon, Y. Maurice; Hammond, Scott A.; Greiner, John W.; Nath, Pulak R.; Schwartz, Anthony L.; Maric, Dragan; Roberts, David D.; Naing, Aung; Papadopoulos, Kyriakos P.; Autio, Karen A.; Wong, Deborah J.; Patel, Manish; Falchook, Gerald; Pant, Shubham; Ott, Patrick A.; Whiteside, Melinda; Patnaik, Amita; Mumm, John; Janku, Filip; Chan, Ivan; Bauer, Todd; Colen, Rivka; VanVlasselaer, Peter; Brown, Gail L.; Tannir, Nizar M.; Oft, Martin; Infante, Jeffrey; Lipson, Evan; Gopal, Ajay; Neelapu, Sattva S.; Armand, Philippe; Spurgeon, Stephen; Leonard, John P.; Sanborn, Rachel E.; Melero, Ignacio; Gajewski, Thomas F.; Maurer, Matthew; Perna, Serena; Gutierrez, Andres A.; Clynes, Raphael; Mitra, Priyam; Suryawanshi, Satyendra; Gladstone, Douglas; Callahan, Margaret K.; Crooks, James; Brown, Sheila; Gauthier, Audrey; de Boisferon, Marc Hillairet; MacDonald, Andrew; Brunet, Laura Rosa; Rothwell, William T.; Bell, Peter; Wilson, James M.; Sato-Kaneko, Fumi; Yao, Shiyin; Zhang, Shannon S.; Carson, Dennis A.; Guiducci, Cristina; Coffman, Robert L.; Kitaura, Kazutaka; Matsutani, Takaji; Suzuki, Ryuji; Hayashi, Tomoko; Cohen, Ezra E. W.; Schaer, David; Li, Yanxia; Dobkin, Julie; Amatulli, Michael; Hall, Gerald; Doman, Thompson; Manro, Jason; Dorsey, Frank Charles; Sams, Lillian; Holmgaard, Rikke; Persaud, Krishnadatt; Ludwig, Dale; Surguladze, David; Kauh, John S.; Novosiadly, Ruslan; Kalos, Michael; Driscoll, Kyla; Pandha, Hardev; Ralph, Christy; Harrington, Kevin; Curti, Brendan; Akerley, Wallace; Gupta, Sumati; Melcher, Alan; Mansfield, David; Kaufman, David R.; Schmidt, Emmett; Grose, Mark; Davies, Bronwyn; Karpathy, Roberta; Shafren, Darren; Shamalov, Katerina; Cohen, Cyrille; Sharma, Naveen; Allison, James; Shekarian, Tala; Valsesia-Wittmann, Sandrine; Caux, Christophe; Marabelle, Aurelien; Slomovitz, Brian M.; Moore, Kathleen M.; Youssoufian, Hagop; Posner, Marshall; Tewary, Poonam; Brooks, Alan D.; Xu, Ya-Ming; Wijeratne, Kithsiri; Gunatilaka, Leslie A. A.; Sayers, Thomas J.; Vasilakos, John P.; Alston, Tesha; Dovedi, Simon; Elvecrog, James; Grigsby, Iwen; Herbst, Ronald; Johnson, Karen; Moeckly, Craig; Mullins, Stefanie; Siebenaler, Kristen; SternJohn, Julius; Tilahun, Ashenafi; Tomai, Mark A.; Vogel, Katharina; Vietsch, Eveline E.; Wellstein, Anton; Wythes, Martin; Crosignani, Stefano; Tumang, Joseph; Alekar, Shilpa; Bingham, Patrick; Cauwenberghs, Sandra; Chaplin, Jenny; Dalvie, Deepak; Denies, Sofie; De Maeseneire, Coraline; Feng, JunLi; Frederix, Kim; Greasley, Samantha; Guo, Jie; Hardwick, James; Kaiser, Stephen; Jessen, Katti; Kindt, Erick; Letellier, Marie-Claire; Li, Wenlin; Maegley, Karen; Marillier, Reece; Miller, Nichol; Murray, Brion; Pirson, Romain; Preillon, Julie; Rabolli, Virginie; Ray, Chad; Ryan, Kevin; Scales, Stephanie; Srirangam, Jay; Solowiej, Jim; Stewart, Al; Streiner, Nicole; Torti, Vince; Tsaparikos, Konstantinos; Zheng, Xianxian; Driessens, Gregory; Gomes, Bruno; Kraus, Manfred; Xu, Chunxiao; Zhang, Yanping; Kradjian, Giorgio; Qin, Guozhong; Qi, Jin; Xu, Xiaomei; Marelli, Bo; Yu, Huakui; Guzman, Wilson; Tighe, Rober; Salazar, Rachel; Lo, Kin-Ming; English, Jessie; Radvanyi, Laszlo; Lan, Yan; Postow, Michael; Senbabaoglu, Yasin; Gasmi, Billel; Zhong, Hong; Liu, Cailian; Hirschhorhn-Cymerman, Daniel; Zha, Yuanyuan; Malnassy, Gregory; Fulton, Noreen; Park, Jae-Hyun; Stock, Wendy; Nakamura, Yusuke; Liu, Hongtao; Ju, Xiaoming; Kosoff, Rachelle; Ramos, Kimberly; Coder, Brandon; Petit, Robert; Princiotta, Michael; Perry, Kyle; Zou, Jun; Arina, Ainhoa; Fernandez, Christian; Zheng, Wenxin; Beckett, Michael A.; Mauceri, Helena J.; Fu, Yang-Xin; Weichselbaum, Ralph R.; Lewis, Whitney; Han, Yanyan; Wu, Yeting; Yang, Chou; Huang, Jing; Wu, Dongyun; Li, Jin; Liang, Xiaoling; Zhou, Xiangjun; Hou, Jinlin; Hassan, Raffit; Jahan, Thierry; Antonia, Scott J.; Kindler, Hedy L.; Alley, Evan W.; Honarmand, Somayeh; Liu, Weiqun; Leong, Meredith L.; Whiting, Chan C.; Nair, Nitya; Enstrom, Amanda; Lemmens, Edward E.; Tsujikawa, Takahiro; Kumar, Sushil; Coussens, Lisa M.; Murphy, Aimee L.; Brockstedt, Dirk G.; Koch, Sven D.; Sebastian, Martin; Weiss, Christian; Früh, Martin; Pless, Miklos; Cathomas, Richard; Hilbe, Wolfgang; Pall, Georg; Wehler, Thomas; Alt, Jürgen; Bischoff, Helge; Geissler, Michael; Griesinger, Frank; Kollmeier, Jens; Papachristofilou, Alexandros; Doener, Fatma; Fotin-Mleczek, Mariola; Hipp, Madeleine; Hong, Henoch S.; Kallen, Karl-Josef; Klinkhardt, Ute; Stosnach, Claudia; Scheel, Birgit; Schroeder, Andreas; Seibel, Tobias; Gnad-Vogt, Ulrike; Zippelius, Alfred; Park, Ha-Ram; Ahn, Yong-Oon; Kim, Tae Min; Kim, Soyeon; Kim, Seulki; Lee, Yu Soo; Keam, Bhumsuk; Kim, Dong-Wan; Heo, Dae Seog; Pilon-Thomas, Shari; Weber, Amy; Morse, Jennifer; Kodumudi, Krithika; Liu, Hao; Mullinax, John; Sarnaik, Amod A.; Pike, Luke; Bang, Andrew; Balboni, Tracy; Taylor, Allison; Spektor, Alexander; Wilhite, Tyler; Krishnan, Monica; Cagney, Daniel; Alexander, Brian; Aizer, Ayal; Buchbinder, Elizabeth; Awad, Mark; Ghandi, Leena; Schoenfeld, Jonathan; Lessey-Morillon, Elizabeth; Ridnour, Lisa; Segal, Neil H.; Sharma, Manish; Le, Dung T.; Ferris, Robert L.; Zelenetz, Andrew D.; Levy, Ronald; Lossos, Izidore S.; Jacobson, Caron; Ramchandren, Radhakrishnan; Godwin, John; Colevas, A. Dimitrios; Meier, Roland; Krishnan, Suba; Gu, Xuemin; Neely, Jaclyn; Timmerman, John; Vanpouille-Box, Claire I.; Formenti, Silvia C.; Demaria, Sandra; Wennerberg, Erik; Mediero, Aranzazu; Cronstein, Bruce N.; Gustafson, Michael P.; DiCostanzo, AriCeli; Wheatley, Courtney; Kim, Chul-Ho; Bornschlegl, Svetlana; Gastineau, Dennis A.; Johnson, Bruce D.; Dietz, Allan B.; MacDonald, Cameron; Bucsek, Mark; Qiao, Guanxi; Hylander, Bonnie; Repasky, Elizabeth; Turbitt, William J.; Xu, Yitong; Mastro, Andrea; Rogers, Connie J.; Withers, Sita; Wang, Ziming; Khuat, Lam T.; Dunai, Cordelia; Blazar, Bruce R.; Longo, Dan; Rebhun, Robert; Grossenbacher, Steven K.; Monjazeb, Arta; Murphy, William J.; Rowlinson, Scott; Agnello, Giulia; Alters, Susan; Lowe, David; Scharping, Nicole; Menk, Ashley V.; Whetstone, Ryan; Zeng, Xue; Delgoffe, Greg M.; Santos, Patricia M.; Shi, Jian; Delgoffe, Greg; Nagasaka, Misako; Sukari, Ammar; Byrne-Steele, Miranda; Pan, Wenjing; Hou, Xiaohong; Brown, Brittany; Eisenhower, Mary; Han, Jian; Collins, Natalie; Manguso, Robert; Pope, Hans; Shrestha, Yashaswi; Boehm, Jesse; Haining, W. Nicholas; Cron, Kyle R.; Sivan, Ayelet; Aquino-Michaels, Keston; Orecchioni, Marco; Bedognetti, Davide; Hendrickx, Wouter; Fuoco, Claudia; Spada, Filomena; Sgarrella, Francesco; Cesareni, Gianni; Marincola, Francesco; Kostarelos, Kostas; Bianco, Alberto; Delogu, Lucia; Roelands, Jessica; Boughorbel, Sabri; Decock, Julie; Presnell, Scott; Wang, Ena; Marincola, Franco M.; Kuppen, Peter; Ceccarelli, Michele; Rinchai, Darawan; Chaussabel, Damien; Miller, Lance; Nguyen, Andrew; Sanborn, J. Zachary; Vaske, Charles; Rabizadeh, Shahrooz; Niazi, Kayvan; Benz, Steven; Patel, Shashank; Restifo, Nicholas; White, James; Angiuoli, Sam; Sausen, Mark; Jones, Sian; Sevdali, Maria; Simmons, John; Velculescu, Victor; Diaz, Luis; Zhang, Theresa; Sims, Jennifer S.; Barton, Sunjay M.; Kadenhe-Chiweshe, Angela; Dela Cruz, Filemon; Turk, Andrew T.; Mazzeo, Christopher F.; Kung, Andrew L.; Bruce, Jeffrey N.; Yamashiro, Darrell J.; Connolly, Eileen P.; Baird, Jason; Crittenden, Marka; Friedman, David; Xiao, Hong; Leidner, Rom; Bell, Bryan; Young, Kristina; Gough, Michael; Bian, Zhen; Kidder, Koby; Liu, Yuan; Curran, Emily; Chen, Xiufen; Corrales, Leticia P.; Kline, Justin; Aguilar, Ethan G.; Guerriero, Jennifer; Sotayo, Alaba; Ponichtera, Holly; Pourzia, Alexandra; Schad, Sara; Carrasco, Ruben; Lazo, Suzan; Bronson, Roderick; Letai, Anthony; Kornbluth, Richard S.; Gupta, Sachin; Termini, James; Guirado, Elizabeth; Stone, Geoffrey W.; Meyer, Christina; Helming, Laura; Wilson, Nicholas; Hofmeister, Robert; Neubert, Natalie J.; Tillé, Laure; Barras, David; Soneson, Charlotte; Baumgaertner, Petra; Rimoldi, Donata; Gfeller, David; Delorenzi, Mauro; Fuertes Marraco, Silvia A.; Speiser, Daniel E.; Abraham, Tara S.; Xiang, Bo; Magee, Michael S.; Waldman, Scott A.; Snook, Adam E.; Blogowski, Wojciech; Zuba-Surma, Ewa; Budkowska, Marta; Salata, Daria; Dolegowska, Barbara; Starzynska, Teresa; Chan, Leo; Somanchi, Srinivas; McCulley, Kelsey; Lee, Dean; Buettner, Nico; Shi, Feng; Myers, Paisley T.; Curbishley, Stuart; Penny, Sarah A.; Steadman, Lora; Millar, David; Speers, Ellen; Ruth, Nicola; Wong, Gabriel; Thimme, Robert; Adams, David; Cobbold, Mark; Thomas, Remy; Al-Muftah, Mariam; Wong, Michael KK; Morse, Michael; Clark, Joseph I.; Kaufman, Howard L.; Daniels, Gregory A.; Hua, Hong; Rao, Tharak; Dutcher, Janice P.; Kang, Kai; Saunthararajah, Yogen; Velcheti, Vamsidhar; Kumar, Vikas; Anwar, Firoz; Verma, Amita; Chheda, Zinal; Kohanbash, Gary; Sidney, John; Okada, Kaori; Shrivastav, Shruti; Carrera, Diego A.; Liu, Shuming; Jahan, Naznin; Mueller, Sabine; Pollack, Ian F.; Carcaboso, Angel M.; Sette, Alessandro; Hou, Yafei; Okada, Hideho; Field, Jessica J.; Zeng, Weiping; Shih, Vincent FS; Law, Che-Leung; Senter, Peter D.; Gardai, Shyra J.; Okeley, Nicole M.; Abelin, Jennifer G.; Saeed, Abu Z.; Malaker, Stacy A.; Shabanowitz, Jeffrey; Ward, Stephen T.; Hunt, Donald F.; Profusek, Pam; Wood, Laura; Shepard, Dale; Grivas, Petros; Kapp, Kerstin; Volz, Barbara; Oswald, Detlef; Wittig, Burghardt; Schmidt, Manuel; Sefrin, Julian P.; Hillringhaus, Lars; Lifke, Valeria; Lifke, Alexander; Skaletskaya, Anna; Ponte, Jose; Chittenden, Thomas; Setiady, Yulius; Sivado, Eva; Thomas, Vincent; El Alaoui, Meddy; Papot, Sébastien; Dumontet, Charles; Dyson, Mike; McCafferty, John; El Alaoui, Said; Bommareddy, Praveen K.; Zloza, Andrew; Kohlhapp, Frederick; Silk, Ann W.; Jhawar, Sachin; Paneque, Tomas; Newman, Jenna; Beltran, Pedro; Cao, Felicia; Hong, Bang-Xing; Rodriguez-Cruz, Tania; Song, Xiao-Tong; Gottschalk, Stephen; Calderon, Hugo; Illingworth, Sam; Brown, Alice; Fisher, Kerry; Seymour, Len; Champion, Brian; Eriksson, Emma; Wenthe, Jessica; Hellström, Ann-Charlotte; Paul-Wetterberg, Gabriella; Loskog, Angelica; Milenova, Ioanna; Ståhle, Magnus; Jarblad-Leja, Justyna; Ullenhag, Gustav; Dimberg, Anna; Moreno, Rafael; Alemany, Ramon; Goyal, Sharad; Silk, Ann; Mehnert, Janice; Gabrail, Nashat; Bryan, Jennifer; Medina, Daniel; Mitchell, Leah; Yagiz, Kader; Lopez, Fernando; Mendoza, Daniel; Munday, Anthony; Gruber, Harry; Jolly, Douglas; Fuhrmann, Steven; Radoja, Sasa; Tan, Wei; Pourchet, Aldo; Frey, Alan; Mohr, Ian; Mulvey, Matthew; Andtbacka, Robert H. I.; Ross, Merrick; Agarwala, Sanjiv; Grossmann, Kenneth; Taylor, Matthew; Vetto, John; Neves, Rogerio; Daud, Adil; Khong, Hung; Meek, Stephanie M.; Ungerleider, Richard; Welden, Scott; Tanaka, Maki; Williams, Matthew; Hallmeyer, Sigrun; Fox, Bernard; Feng, Zipei; Paustian, Christopher; Bifulco, Carlo; Zafar, Sadia; Hemminki, Otto; Bramante, Simona; Vassilev, Lotta; Wang, Hongjie; Lieber, Andre; Hemmi, Silvio; de Gruijl, Tanja; Kanerva, Anna; Ansari, Tameem; Sundararaman, Srividya; Roen, Diana; Lehmann, Paul; Bloom, Anja C.; Bender, Lewis H.; Walters, Ian B.; Berzofsky, Jay A.; Chapelin, Fanny; Ahrens, Eric T.; DeFalco, Jeff; Harbell, Michael; Manning-Bog, Amy; Scholz, Alexander; Zhang, Danhui; Baia, Gilson; Tan, Yann Chong; Sokolove, Jeremy; Kim, Dongkyoon; Williamson, Kevin; Chen, Xiaomu; Colrain, Jillian; Santo, Gregg Espiritu; Nguyen, Ngan; Volkmuth, Wayne; Greenberg, Norman; Robinson, William; Emerling, Daniel; Drake, Charles G.; Petrylak, Daniel P.; Antonarakis, Emmanuel S.; Kibel, Adam S.; Chang, Nancy N.; Vu, Tuyen; Campogan, Dwayne; Haynes, Heather; Trager, James B.; Sheikh, Nadeem A.; Quinn, David I.; Kirk, Peter; Addepalli, Murali; Chang, Thomas; Zhang, Ping; Konakova, Marina; Hagihara, Katsunobu; Pai, Steven; VanderVeen, Laurie; Obalapur, Palakshi; Kuo, Peiwen; Quach, Phi; Fong, Lawrence; Charych, Deborah H.; Zalevsky, Jonathan; Langowski, John L.; Kirksey, Yolanda; Nutakki, Ravi; Kolarkar, Shalini; Pena, Rhoneil; Hoch, Ute; Doberstein, Stephen K.; Cha, John; Mallon, Zach; Perez, Myra; McDaniel, Amanda; Anand, Snjezana; Uecker, Darrin; Nuccitelli, Richard; Wieckowski, Eva; Muthuswamy, Ravikumar; Ravindranathan, Roshni; Renrick, Ariana N.; Thounaojam, Menaka; Thomas, Portia; Pellom, Samuel; Shanker, Anil; Dudimah, Duafalia; Brooks, Alan; Su, Yu-Lin; Adamus, Tomasz; Zhang, Qifang; Nechaev, Sergey; Kortylewski, Marcin; Wei, Spencer; Anderson, Clark; Tang, Chad; Schoenhals, Jonathan; Tsouko, Efrosini; Heymach, John; de Groot, Patricia; Chang, Joe; Hess, Kenneth R.; Diab, Adi; Sharma, Padmanee; Hong, David; Welsh, James; Parsons, Andrea J.; Leleux, Jardin; Ascarateil, Stephane; Koziol, Marie Eve; Bai, Dina; Dai, Peihong; Wang, Weiyi; Yang, Ning; Shuman, Stewart; Deng, Liang; Dillon, Patrick; Petroni, Gina; Brenin, David; Bullock, Kim; Olson, Walter; Smolkin, Mark E.; Smith, Kelly; Nail, Carmel; Slingluff, Craig L.; Sharma, Meenu; Fa’ak, Faisal; Janssen, Louise; Khong, Hiep; Xiao, Zhilan; Hailemichael, Yared; Singh, Manisha; Vianden, Christina; Overwijk, Willem W.; Facciabene, Andrea; Stefano, Pierini; Chongyung, Fang; Rafail, Stavros; Nielsen, Michael; Vanderslice, Peter; Woodside, Darren G.; Market, Robert V.; Biediger, Ronald J.; Marathi, Upendra K.; Hollevoet, Kevin; Geukens, Nick; Declerck, Paul; Joly, Nathalie; McIntosh, Laura; Paramithiotis, Eustache; Rizell, Magnus; Sternby, Malin; Andersson, Bengt; Karlsson-Parra, Alex; Kuai, Rui; Ochyl, Lukasz; Schwendeman, Anna; Moon, James; Deng, Weiwen; Hudson, Thomas E.; Hanson, Bill; Rae, Chris S.; Burrill, Joel; Skoble, Justin; Katibah, George; deVries, Michele; Lauer, Peter; Dubensky, Thomas W.; Chen, Xin; Zhou, Li; Ren, Xiubao; Aggarwal, Charu; Mangrolia, Drishty; Cohen, Roger; Weinstein, Gregory; Morrow, Matthew; Bauml, Joshua; Kraynyak, Kim; Boyer, Jean; Yan, Jian; Lee, Jessica; Humeau, Laurent; Oyola, Sandra; Duff, Susan; Weiner, David; Yang, Zane; Bagarazzi, Mark; McNeel, Douglas G.; Eickhoff, Jens; Jeraj, Robert; Staab, Mary Jane; Straus, Jane; Rekoske, Brian; Liu, Glenn; Melssen, Marit; Grosh, William; Varhegyi, Nikole; Galeassi, Nadejda; Deacon, Donna H.; Gaughan, Elizabeth; Ghisoli, Maurizio; Barve, Minal; Mennel, Robert; Wallraven, Gladice; Manning, Luisa; Senzer, Neil; Nemunaitis, John; Ogasawara, Masahiro; Ota, Shuichi; Peace, Kaitlin M.; Hale, Diane F.; Vreeland, Timothy J.; Jackson, Doreen O.; Berry, John S.; Trappey, Alfred F.; Herbert, Garth S.; Clifton, Guy T.; Hardin, Mark O.; Toms, Anne; Qiao, Na; Litton, Jennifer; Peoples, George E.; Mittendorf, Elizabeth A.; Ghamsari, Lila; Flano, Emilio; Jacques, Judy; Liu, Biao; Havel, Jonathan; Makarov, Vladimir; Chan, Timothy A.; Flechtner, Jessica B.; Facciponte, John; Ugel, Stefano; De Sanctis, Francesco; Coukos, George; Paris, Sébastien; Pottier, Agnes; Levy, Laurent; Lu, Bo; Cappuccini, Federica; Pollock, Emily; Bryant, Richard; Hamdy, Freddie; Hill, Adrian; Redchenko, Irina; Sultan, Hussein; Kumai, Takumi; Fesenkova, Valentyna; Celis, Esteban; Fernando, Ingrid; Palena, Claudia; David, Justin M.; Gabitzsch, Elizabeth; Jones, Frank; Gulley, James L.; Herranz, Mireia Uribe; Wada, Hiroshi; Shimizu, Atsushi; Osada, Toshihiro; Fukaya, Satoshi; Sasaki, Eiji; Abolhalaj, Milad; Askmyr, David; Lundberg, Kristina; Albrekt, Ann-Sofie; Greiff, Lennart; Lindstedt, Malin; Flies, Dallas B.; Higuchi, Tomoe; Ornatowski, Wojciech; Harris, Jaryse; Adams, Sarah F.; Aguilera, Todd; Rafat, Marjan; Castellini, Laura; Shehade, Hussein; Kariolis, Mihalis; Jang, Dadi; vonEbyen, Rie; Graves, Edward; Ellies, Lesley; Rankin, Erinn; Koong, Albert; Giaccia, Amato; Ajina, Reham; Wang, Shangzi; Smith, Jill; Pierobon, Mariaelena; Jablonski, Sandra; Petricoin, Emanuel; Weiner, Louis M.; Sherry, Lorcan; Waller, John; Anderson, Mark; Bigley, Alison; Bernatchez, Chantale; Haymaker, Cara; Kluger, Harriet; Tetzlaff, Michael; Jackson, Natalie; Gergel, Ivan; Tagliaferri, Mary; Hwu, Patrick; Snzol, Mario; Hurwitz, Michael; Barberi, Theresa; Martin, Allison; Suresh, Rahul; Barakat, David; Harris-Bookman, Sarah; Drake, Charles; Friedman, Alan; Berkey, Sara; Downs-Canner, Stephanie; Edwards, Robert P.; Curiel, Tyler; Odunsi, Kunle; Bruno, Tullia C.; Moore, Brandon; Squalls, Olivia; Ebner, Peggy; Waugh, Katherine; Mitchell, John; Franklin, Wilbur; Merrick, Daniel; McCarter, Martin; Palmer, Brent; Kern, Jeffrey; Vignali, Dario; Slansky, Jill; Chan, Anissa S. H.; Qiu, Xiaohong; Fraser, Kathryn; Jonas, Adria; Ottoson, Nadine; Gordon, Keith; Kangas, Takashi O.; Leonardo, Steven; Ertelt, Kathleen; Walsh, Richard; Uhlik, Mark; Graff, Jeremy; Bose, Nandita; Gupta, Ravi; Mandloi, Nitin; Paul, Kiran; Patil, Ashwini; Sathian, Rekha; Mohan, Aparna; Manoharan, Malini; Chaudhuri, Amitabha; Chen, Yu; Lin, Jing; Ye, Yun-bin; Xu, Chun-wei; Chen, Gang; Guo, Zeng-qing; Komarov, Andrey; Chenchik, Alex; Makhanov, Michael; Frangou, Costa; Zheng, Yi; Coltharp, Carla; Unfricht, Darryn; Dilworth, Ryan; Fridman, Leticia; Liu, Linying; Rajopadhye, Milind; Miller, Peter; Concha-Benavente, Fernando; Bauman, Julie; Trivedi, Sumita; Srivastava, Raghvendra; Ohr, James; Heron, Dwight; Duvvuri, Uma; Kim, Seungwon; Topley, Heather; Mera, Toshi; Okubo, Yoshiaki; Vanamee, Eva; Foster, Rosemary; Faustman, Denise; Stack, Edward; Izaki, Daisuke; Beck, Kristen; Jia, Dan Tong; Armenta, Paul; White-Stern, Ashley; Marks, Douglas; Taback, Bret; Horst, Basil; Glickman, Laura Hix; Kanne, David B.; Gauthier, Kelsey S.; Desbien, Anthony L.; Francica, Brian; Leong, Justin L.; Sung, Leonard; Metchette, Ken; Kasibhatla, Shailaja; Pferdekamper, Anne Marie; Zheng, Lianxing; Cho, Charles; Feng, Yan; McKenna, Jeffery M.; Tallarico, John; Bender, Steven; Ndubaku, Chudi; McWhirter, Sarah M.; Gugel, Elena Gonzalez; Bell, Charles J. M.; Munk, Adiel; Muniz, Luciana; Bhardwaj, Nina; Zhao, Fei; Evans, Kathy; Xiao, Christine; Holtzhausen, Alisha; Hanks, Brent A.; Scholler, Nathalie; Yin, Catherine; Van der Meijs, Pien; Prantner, Andrew M.; Krejsa, Cecile M.; Smith, Leia; Johnson, Brian; Branstetter, Daniel; Stein, Paul L.; Jaen, Juan C.; Tan, Joanne BL; Chen, Ada; Park, Timothy; Powers, Jay P.; Sexton, Holly; Xu, Guifen; Young, Steve W.; Schindler, Ulrike; Deng, Wentao; Klinke, David John; Komar, Hannah M.; Serpa, Gregory; Elnaggar, Omar; Hart, Philip; Schmidt, Carl; Dillhoff, Mary; Jin, Ming; Ostrowski, Michael C.; Koti, Madhuri; Au, Katrina; Peterson, Nichole; Truesdell, Peter; Reid-Schachter, Gillian; Graham, Charles; Craig, Andrew; Francis, Julie-Ann; Kotlan, Beatrix; Balatoni, Timea; Farkas, Emil; Toth, Laszlo; Ujhelyi, Mihaly; Savolt, Akos; Doleschall, Zoltan; Horvath, Szabolcs; Eles, Klara; Olasz, Judit; Csuka, Orsolya; Kasler, Miklos; Liszkay, Gabriella; Barnea, Eytan; Blakely, Collin; Flynn, Patrick; Goodman, Reid; Bueno, Raphael; Sugarbaker, David; Jablons, David; Broaddus, V. Courtney; West, Brian; Kunk, Paul R.; Obeid, Joseph M.; Winters, Kevin; Pramoonjago, Patcharin; Stelow, Edward B.; Bauer, Todd W.; Rahma, Osama E.; Lamble, Adam; Kosaka, Yoko; Huang, Fei; Saser, Kate A.; Adams, Homer; Tognon, Christina E.; Laderas, Ted; McWeeney, Shannon; Loriaux, Marc; Tyner, Jeffery W.; Druker, Brian J.; Lind, Evan F.; Liu, Zhuqing; Lu, Shanhong; Kane, Lawrence P.; Shayan, Gulidanna; Femel, Julia; Lane, Ryan; Booth, Jamie; Lund, Amanda W.; Rodriguez, Anthony; Engelhard, Victor H.; Metelli, Alessandra; Wu, Bill X.; Fugle, Caroline W.; Saleh, Rachidi; Sun, Shaoli; Wu, Jennifer; Liu, Bei; Li, Zihai; Morris, Zachary S.; Guy, Emily I.; Heinze, Clinton; Kler, Jasdeep; Gressett, Monica M.; Werner, Lauryn R.; Gillies, Stephen D.; Korman, Alan J.; Loibner, Hans; Hank, Jacquelyn A.; Rakhmilevich, Alexander L.; Harari, Paul M.; Sondel, Paul M.; Huelsmann, Erica; Broucek, Joseph; Brech, Dorothee; Straub, Tobias; Irmler, Martin; Beckers, Johannes; Buettner, Florian; Schaeffeler, Elke; Schwab, Matthias; Noessner, Elfriede; Wolfreys, Alison; Da Costa, Andre; Silva, John; Crosby, Andrea; Staelens, Ludovicus; Craggs, Graham; Cauvin, Annick; Mason, Sean; Paterson, Alison M.; Lake, Andrew C.; Armet, Caroline M.; O’Connor, Rachel W.; Hill, Jonathan A.; Normant, Emmanuel; Adam, Ammar; Biniszkiewicz, Detlev M.; Chappel, Scott C.; Palombella, Vito J.; Holland, Pamela M.; Becker, Annette; Leleti, Manmohan R.; Newcomb, Eric; Tan, Joanne B. L.; Rapisuwon, Suthee; Radfar, Arash; Gardner, Kellie; Gibney, Geoffrey; Atkins, Michael; Rennier, Keith R.; Crowder, Robert; Wang, Ping; Pachynski, Russell K.; Carrero, Rosa M. Santana; Rivas, Sarai; Beceren-Braun, Figen; Anthony, Scott; Schluns, Kimberly S.; Sawant, Deepali; Chikina, Maria; Yano, Hiroshi; Workman, Creg; Salerno, Elise; Mauldin, Ileana; Deacon, Donna; Shea, Sofia; Pinczewski, Joel; Gajewski, Thomas; Spranger, Stefani; Horton, Brendan; Suzuki, Akiko; Leland, Pamela; Joshi, Bharat H.; Puri, Raj K.; Sweis, Randy F.; Bao, Riyue; Luke, Jason; Theodoraki, Marie-Nicole; Mogundo, Frances-Mary; Won, Haejung; Moreira, Dayson; Gao, Chan; Zhao, Xingli; Duttagupta, Priyanka; Jones, Jeremy; D’Apuzzo, Massimo; Pal, Sumanta
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    Persistence of Prolonged C-peptide Production in Type 1 Diabetes as Measured With an Ultrasensitive C-peptide Assay
    (American Diabetes Association, 2012) Wang, Limei; Lovejoy, Nicholas Fraser; Faustman, Denise
    Objective: To examine persistence of C-peptide production by ultrasensitive assay years after onset of type 1 diabetes and factors associated with preserving β-cell function. Research Design and Methods: Serum C-peptide levels, a marker of insulin production and surviving β-cells, were measured in human subjects (n = 182) by ultrasensitive assay, as was β-cell functioning. Twenty-two times more sensitive than standard assays, this assay’s lower detection limit is 1.5 pmol/L. Disease duration, age at onset, age, sex, and autoantibody titers were analyzed by regression analysis to determine their relationship to C-peptide production. Another group of four patients was serially studied for up to 20 weeks to examine C-peptide levels and functioning. Results: The ultrasensitive assay detected C-peptide in 10% of individuals 31–40 years after disease onset and with percentages higher at shorter duration. Levels as low as 2.8 ± 1.1 pmol/L responded to hyperglycemia with increased C-peptide production, indicating residual β-cell functioning. Several other analyses showed that β-cells, whose C-peptide production was formerly undetectable, were capable of functioning. Multivariate analysis found disease duration (β = −2.721; P = 0.005) and level of zinc transporter 8 autoantibodies (β = 0.127; P = 0.015) significantly associated with C-peptide production. Unexpectedly, onset at >40 years of age was associated with low C-peptide production, despite short disease duration. Conclusions: The ultrasensitive assay revealed that C-peptide production persists for decades after disease onset and remains functionally responsive. These findings suggest that patients with advanced disease, whose β-cell function was thought to have long ceased, may benefit from interventions to preserve β-cell function or to prevent complications.
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    Proof-of-Concept, Randomized, Controlled Clinical Trial of Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes
    (Public Library of Science, 2012) Faustman, Denise; Wang, Limei; Okubo, Yoshiaki; Burger, Douglas E.; Ban, Liqin; Man, Guotong; Zheng, Hui; Schoenfeld, David; Pompei, Richard; Avruch, Joseph; Nathan, David
    Background: No targeted immunotherapies reverse type 1 diabetes in humans. However, in a rodent model of type 1 diabetes, Bacillus Calmette-Guerin (BCG) reverses disease by restoring insulin secretion. Specifically, it stimulates innate immunity by inducing the host to produce tumor necrosis factor (TNF), which, in turn, kills disease-causing autoimmune cells and restores pancreatic beta-cell function through regeneration. Methodology/Principal Findings Translating these findings to humans, we administered BCG, a generic vaccine, in a proof-of-principle, double-blind, placebo-controlled trial of adults with long-term type 1 diabetes (mean: 15.3 years) at one clinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n = 6) or reference subjects with (n = 57) or without (n = 16) type 1 diabetes, depending upon the outcome measure. We monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion. BCG-treated patients and one placebo-treated patient who, after enrollment, unexpectedly developed acute Epstein-Barr virus infection, a known TNF inducer, exclusively showed increases in dead insulin-autoreactive T cells and induction of Tregs. C-peptide levels (pmol/L) significantly rose transiently in two BCG-treated subjects (means: 3.49 pmol/L [95% CI 2.95–3.8], 2.57 [95% CI 1.65–3.49]) and the EBV-infected subject (3.16 [95% CI 2.54–3.69]) vs.1.65 [95% CI 1.55–3.2] in reference diabetic subjects. BCG-treated subjects each had more than 50% of their C-peptide values above the 95th percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level. Conclusions/Significance: We conclude that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes. Trial Registration ClinicalTrials.gov NCT00607230