Julio Aliberti, MS, PhD
is focused on defining the mechanisms underlying the induction and regulation of immune responses to intracellular pathogens, including Toxoplasma gondii and Mycobacterium tuberculosis, microbes that cause an immense burden of morbidity and mortality in the world at large. The ultimate goal of this research program is the development of novel preventive and therapeutic approaches to these pathogens.
513-636-9041
julio.aliberti@cchmc.org
Julio Aliberti, MS, PhD
Academic Information
Assistant Professor, UC Department of Pediatrics
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Education and Training
BSc: Biology, FFCL Barao de Maua, Ribeirao Preto, Brazil, 1994. MS: Immunology, FMRP / USP, Ribeirao Preto, Brazil, 1996. PhD: Immunology, FMRP / USP, Ribeirao Preto, Brazil, 1998.
Publications
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Zoller EE, Lykens JE, Terrell CE, Aliberti J, Filipovich AH, Henson PM, Jordan MB. Hemophagocytosis causes a consumptive anemia of inflammation. J Exp Med. 2011 Jun 6;208(6):1203-14. Lykens JE, Terrell CE, Zoller EE, Divanovic S, Trompette A, Karp CL, Aliberti J, Flick MJ, Jordan MB. Mice with a selective impairment of IFN-gamma signaling in macrophage lineage cells demonstrate the critical role of IFN-gamma-activated macrophages for the control of protozoan parasitic infections in vivo. J Immunol. 2010 Jan 15;184(2):877-85. Machado FS, Aliberti J. Lipoxins as an immune-escape mechanism. Adv Exp Med Biol. 2009;666:78-87. Machado FS, Aliberti J. Role of lipoxin in the modulation of immune response during infection. Int Immunopharmacol. 2008 Oct;8(10):1316-9.
Machado FS, Esper L, Dias A, Madan R, Gu Y, Hildeman D, Serhan CN, Karp CL, Aliberti J. Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6. J Exp Med. 2008 May 12;205(5):1077-86. Yamauchi LM, Aliberti J, Baruffi MD, Portela RW, Rossi MA, Gazzinelli RT, Mineo JR, Silva JS. The binding of CCL2 to the surface of Trypanosoma cruzi induces chemo-attraction and morphogenesis. Microbes Infect. 2007;9:111-8. Liu CH, Machado FS, Guo R, Nichols KE, Burks AW, Aliberti J, Zhong XP. Diacylglycerol kinase zeta regulates microbial recognition and host resistance to Toxoplasma gondii. J Exp Med. 2007;204:781-92. Liu CH, Fan YT, Dias A, Esper L, Corn RA, Bafica A, Machado FS, Aliberti J. Cutting Edge: Dendritic cells are essential for in vivo interleukin-12 production and development of resistance against Toxoplasma gondii infection in mice. J. Immunol. 2006;177:31-5. Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, Hong S, Yang R, Petasis NA, Serhan C. Stereochemical assignment, anti-inflammatory properties, and receptor for the omega-3 lipid mediator resolving E1. J. Exp. Med. 2005;201:713-22. Bafica A, Scanga C, Serhan C, Machado F, White S, Sher A, Aliberti J. Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production. J. Clin. Invest. 2005;115:1601-6.
Grants
Long-term Immunity Against Toxoplasmosis. Principal Investigator. National Institute of Allergy and Infectious Diseases. April 2008 – March 2013. #R01 AI033325. Control of immune responses by lipoxins during tuberculosis. Principal Investigator. National Institutes of Health. April 2008 – March 2013. #01AI075038.
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Claire A. Chougnet, PhD
aims to understand T cell function and dysfunction at a molecular level in human disease, with a focus on defining the molecular mechanisms that underlie T cell dysfunction in HIV/AIDS, defining the molecular mechanisms responsible for immune dysfunction in aging, and understanding the development of T cell responses in very early life.
513-636-8847
claire.chougnet@cchmc.org
Claire A. Chougnet, PhD
Academic Information
Associate Professor, UC Department of Pediatrics
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Specialties
Clinical InterestsAntigen-presenting cells; HIV research; ontogeny of immune responses Research InterestsHIV/AIDS pathogenesis; immune dysfunction in aging; ontogeny of immune system
Education and Training
DPharm:Université Paris XI, Paris, France, 1980. CES (French specialized degrees; clinical biologist): Immunology, Hematology, Bacteriology-Virology, Parasitology, 1984. PhD: Université Paris V, 1991.
Publications
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Lages CS, Lewkowich I, Sproles A, Wills-Karp M, Chougnet C. Partial restoration of T-cell function in aged mice by in vitro blockade of the PD-1/ PD-L1 pathway. Aging Cell. 2010 Oct;9(5):785-98. doi: 10.1111/j.1474-9726.2010.00611.x.
Miethke AG, Saxena V, Shivakumar P, Sabla GE, Simmons J, Chougnet CA. Post-natal paucity of regulatory T cells and control of NK cell activation in experimental biliary atresia. J Hepatol. 2010 May;52(5):718-26. Epub 2010 Mar 5.
Presicce P, Moreno-Fernandez ME, Lages CS, Orsborn KI, Chougnet CA. Association of two clones allows for optimal detection of human FOXP3. Cytometry A. 2010 Jun;77(6):571-9.
Moreno-Fernandez ME, Zapata W, Blackard JT, Franchini G, Chougnet CA. Human regulatory T cells are targets for human immunodeficiency Virus (HIV) infection, and their susceptibility differs depending on the HIV type 1 strain. J Virol. 2009 Dec;83(24):12925-33. Epub 2009 Oct 14. Shivakumar P, Sabla GE, Whitington P, Chougnet CA, Bezerra JA. Neonatal NK cells target the duct epithelium via Nkg2d and drive the tissue-specific injury in biliary atresia. J Clin Invest. 2009 Aug;119(8)2281-90. Nyakeriga AM, Fichtenbaum CJ, Goebel J, Nicolaou SA, Conforti L, Chougnet CA. Engagement of the CD4 receptor affects the redistribution of lck to the immunological synapse in primary T cells: implications for T cell activation during HIV-1 infection. J Virol. 2009 Feb;83(3):1193-200. Boasso A, Shearer GM, Chougnet C. Immune dysregulation in HIV infection: know it, fix it, prevent it? J Intern Med. 2009, 265(1):78-96. Review. Lages CS, Suffia I, Velilla P, Huang B, Warshaw G, Hildeman D, Belkaid Y, Chougnet C. Functional regulatory T cells accumulate in aged hosts and promote reactivation of chronic infectious disease reactivation. J Immunol. 2008;181(3):1835-48. Velilla PA, Shata MT, Lages CS, Ying J, Fichtenbaum CJ, Chougnet C. Effect of intrauterine HIV-1 exposure on the frequency and phenotype of uninfected newborns’ dendritic cells. Clin Immunol. 2008;126:243-50. Li S, Gowans EJ, Chougnet C, Plebanski M, Dittmer U. Natural regulatory T cells and persistent viral infection. J Virol. 2008;82:21-30. Review.
Grants
Homeostasis and function of regulatory T cells in aging. National Institutes of Health. Sep 2009 - Sep 2011. #R01 AG033057 ARRA. Dysfunction in biliary atresia. National Institutes of Health. Aug 2003 - Dec 2011. #R01 DK 065008. Late Preterm Birth, Ureaplasma Species and Childhood Lung Disease. National Institutes of Health. Aug 2009 - Jul 2013. #R01 HL097064-01.
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Senad Divanovic, PhD
investigates the molecular mechanisms underlying the regulation of innate immune signaling and inflammation in: (a) development and progression of obesity; (b) development and progression of non-alcoholic fatty liver disease; and (b) induction of preterm birth. These studies, range from reductive analysis of TLR ligand signaling and challenge to the role of IL-17 axis to diverse experimental models of obesity and infection.
513-636-0286
senad.divanovic@cchmc.org
Senad Divanovic, PhD
Academic Information
Assistant Professor, UC Department of Pediatrics
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Specialties
Innate immune responses; obesity; NAFLD; preterm birth
Education and Training
BA: DePauw University, Greencastle, IN, 1998. MS: Oklahoma State University, Stillwater, OK, 2000.
PhD: University of Cincinnati, Cincinnati, OH, 2005.
Post Doc: Cincinnati Children’s Hospital Medical Center, 2010
Publications
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Allen JL, Flick LM, Divanovic S, Jackson SW, Bram R, Rawlings D, Finkelman FD, Karp CL. Cutting Edge: Regulation of TLR4-driven B cell proliferation by RP105 is not B cell-autonomous. J Immunol. 2012;188:2065. Korfhagen TR, Kitzmiller J, Chen G, Sridharan A, Haitchi HM, Hegde RS, Divanovic S, Karp CL, Whitsett JA. SAM-pointed domain ETS factor mediates epithelial cell-intrinsic innate immune signaling during airway mucous metaplasia. PNAS. 2012;109:16630. Divanovic S, Sawtell NM, Trompette A, Warning JI, Dias A, Cooper AM, Yap GS, Arditi M, Shimada K, DuHadaway JB, Prendergast GC, Basaraba RJ, Mellor AL, Munn DH, Aliberti J, Karp CL. Opposing biological functions of tryptophan catabolizing enzymes during intracellular infection. J Infect Dis. 2012;205:152-61. Divanovic S, Trompette A, Jamie I. Ashworth, Marepalli B. Rao, Karp CL. Therapeutic enhancement of protective immunity during experimental Leishmania major infection. PLoS Neglected Tropical Dis. 2011;5:e1316.
Sheridan R, Lampe K, Shanmukhappa SK, Putnam P, Keddache M, Divanovic S, Bezerra J, Hoebe K. Lampe1: an ENU-germline mutation causing spontaneous hepatosteatosis identified through targeted exon-enrichment and next-generation sequencing. PLoS One. 2011;6:e21979.
Trompette A, Divanovic S, Visintin A, Blanchard C, Hegde RS, Madan R, Torne PS, Wills-Karp M, Gioannini TL, Weiss JP, Karp CL. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature. 2009;457:585-8. Divanovic S, Trompette A, Petiniot LK, Allen JL, Flick LM, Belkaid Y, Madan R, Haky JJ, Karp CL. Regulation of TLR4 signaling and the host interface with pathogens and danger: the role of RP105. J Leukocyte Biol. 2007;82:265-271.
Divanovic S, Trompette A, Atabani SF, Madan R, Golenbock DT, Visintin A, Finberg RW, Tarakhovsky A, Vogel SN, Belkaid Y, Kurt-Jones EA, Karp CL. Inhibition of TLR4/MD-2 signaling by RP105/MD-1. J Endotoxin Res. 2005;11:363-8.
Divanovic S, Trompette A, Atabani SF, Madan R, Golenbock DT, Visintin A, Finberg RW, Tarakhovsky A, Vogel SN, Belkaid Y, Kurt-Jones EA, Karp CL. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nature Immunol. 2005;6:571-8. Divanovic S, Lai ACK. Cytokine induction in human cord blood lymphocytes after pulsing with UV-inactivated influenza viruses. Immunology Lett. 2004;94:201-7.
Grants
Defining the mechanisms underlying inflammation-driven preterm birth. Principal Investigator. Cincinnati Children’s Hospital Medical Center, Perinatal Institute Pilot and Feasibility Application. Jul 2011 - Jun 2013.
IL-17 axis in pathogenesis of NASH. Principal Investigator. Cincinnati Children’s Hospital Medical Center, Trustee Grant. Jan 2012 - Dec 2013.
Better mouse models of disease: Humanizing experimental atherosclerosis. Principal Investigator. NHLBI. Apr 2012 - Mar 2014.
Endocannabinoid signaling via CB2 protects against preterm birth by modulating immune responses. Co-Investigator. March of Dimes, Prematurity Research Initiative Grant. Mar 2012 - Feb 2015.
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H. Leighton Grimes, PhD
Director, Cancer Pathology Program of the Division of Experimental Hematology and the Division of Pathology
focuses his research on the genetic development of cancerous cells and inherited blood diseases. His lab utilizes the Growth factor independent-1 transcription factor as a molecular probe to dissect hematopoiesis and leukemia. Dr. Grimes serves as the director of the Cancer Pathology Program of the Divisions of Experimental Hematology and Pathology. Visit the Grimes Lab.
513-636-6089
lee.grimes@cchmc.org
H. Leighton Grimes, PhD
Director, Cancer Pathology Program of the Division of Experimental Hematology and the Division of Pathology
Academic Information
Associate Professor, UC Department of Pediatrics
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Specialties
Biography
Grimes Laboratory: The cloning and characterization of oncoproteins and tumor suppressors over the last 25 years has not only resulted in a greater understanding of the molecular mechanisms of transformation, but it has also provided a large set of therapeutic targets. Our lab is interested in the progression of a cell with a single genetic lesion to an invasive cancer with multiple genetic alterations. We focus on the Growth factor independence-1 (Gfi1) transcription factor, which is poorly oncogenic alone, but which potently collaborates with well known oncoproteins such as c-MYC. Gfi1 is the most frequently targeted gene in Moloney murine leukemia virus-induced tumors and induces tumor progression to cytokine-independent growth. In contrast, loss of Gfi1 in hematopoietic stem cells induces cell cycle progression and eventual bone marrow failure; implicating Gfi1 as a tumor suppressor in such cells. Gfi1 null mice have no mature neutrophils, and we have identified humans with Severe Congenital Neutropenia (SCN) and Non-Immune Chronic Idiopathic Neutropenia of Adults (NI-CINA) bearing mutations in Gfi1. Interestingly, such patients are at increased risk for the development of myelodysplastic syndromes and acute myeloid leukemia. We have recently generated the first mouse model of Severe Congenital Neutropenia through the expression of mutant Gfi1 proteins in primary murine hematopoietic cells. Moreover, we are utilizing mouse models of human cancer to assess the risk of Gfi1 mutant humans for the development of acute myeloid leukemia.
Education and Training
PhD: Immunology and Molecular Pathology, University of Florida, Gainesville, FL.
Postdoctoral Fellow: Fox Chase Cancer Center.
Publications
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Guo F, Hildeman D, Tripathi P, Velu CS, Grimes HL, Zheng Y. Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18505-10. Tripathi P, Kurtulus S, Wojciechowski S, Sholl A, Hoebe K, Morris SC, Finkelman FD, Grimes HL, Hildeman DA. STAT5 is critical to maintain effector CD8+ T cell responses. J Immunol. 2010 Aug 15;185(4):2116-24. Meyer SE, Hasenstein JR, Baktula A, Velu CS, Xu Y, Wan H, Whitsett JA, Gilks CB, Grimes HL. Kruppel-like factor 5 is not required for K-RasG12D lung tumorigenesis, but represses ABCG2 expression and is associated with better disease-specific survival. Am J Pathol. 2010 Sep;177(3):1503-13. Phelan JD, Shroyer NF, Cook T, Gebelein B, Grimes HL. Gfi1-cells and circuits: unraveling transcriptional networks of development and disease. Curr Opin Hematol. 2010 Jul;17(4):300-7. Review. Arumugam PI, Urbinati F, Velu CS, Higashimoto T, Grimes HL, Malik P. The 3' region of the chicken hypersensitive site-4 insulator has properties similar to its core and is required for full insulator activity. PLoS One. 2009 Sep 10;4(9):e6995. Guo F, Velu CS, Grimes HL, Zheng Y. Rho GTPase Cdc42 is essential for B-lymphocyte development and activation. Blood. 2009 Oct 1;114(14):2909-16. Horman SR, Velu CS, Chaubey A, Bourdeau T, Zhu J, Paul WE, Gebelein B, Grimes HL. Gfi1 integrates progenitor versus granulocytic transcriptional programming. Blood. 2009 May 28;113(22):5466-75. Velu CS, Baktula AM, Grimes HL. Gfi1 regulates miR-21 and miR-196b to control myelopoiesis. Blood. 2009 May 7;113(19):4720-8. Gu Y, Harley IT, Henderson LB, Aronow BJ, Vietor I, Huber LA, Harley JB, Kilpatrick JR, Langefeld CD, Williams AH, Jegga AG, Chen J, Wills-Karp M, Arshad SH, Ewart SL, Thio CL, Flick LM, Filippi MD, Grimes HL, Drumm ML, Cutting GR, Knowles MR, Karp CL. Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature. 2009 Apr 23;458(7241):1039-42. Li-Kroeger D, Witt LM, Grimes HL, Cook TA, Gebelein B. Hox and senseless antagonism functions as a molecular switch to regulate EGF secretion in the Drosophila PNS. Dev Cell. 2008 Aug;15(2):298-308.
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David A. Hildeman, PhD
Director, Immunobiology Graduate Program
explores the molecular factors that control the decision between tolerance and immunity within T lymphocytes. Using genetic mouse models, viruses, and MHC tetrameric reagents, the lab is focused on the molecular regulation of antigen-specific T cell responses. Dr. Hildeman is also the current Director of the Immunobiology Graduate Program.
513-636-3923
david.hildeman@cchmc.org
David A. Hildeman, PhD
Director, Immunobiology Graduate Program
Academic Information
Associate Professor, UC Department of Pediatrics
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Specialties
Clinical InterestsT cells; autoimmunity; sex differences in immune responses; apoptosis Research InterestsOur lab is primarily interested in molecular factors that control the decision between tolerance and immunity within T lymphocytes. We use staphylococcal enterotoxins, recombinant vaccinia viruses, lymphocytic choriomeningitis virus and MHC tetrameric reagents as tools to study antigen -specific T cell responses. Our interest in tolerance centers on regulation of mechanisms that control the survival and death of activated T cells in vivo, namely Bcl-2 and its antagonist Bim. We are also interested in the manipulation and regulation of antigen-specific T cell responses via novel vaccine strategies to either induce tolerance or enhance immunity. Finally, we are interested in mechanisms underlying sex-based differences in T cell responses and how these differences relate to autoimmune disease.
Education and Training
PhD: University of Wisconsin-Madison, Madison, Wisconsin, 1997.
Publications
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Chae HD, Siefring JE, Hildeman DA, Gu Y, Williams DA. RhoH regulates subcellular localization of ZAP-70 and Lck in T cell receptor signaling. PLoS One. 2010 Nov 12;5(11):e13970. Chougnet CA, Tripathi P, Lages CS, Raynor J, Sholl A, Fink P, Plas DR, Hildeman DA. A major role for Bim in regulatory T cell homeostasis. J Immunol. 2011 Jan 1;186(1):156-63. Guo F, Hildeman D, Tripathi P, Velu CS, Grimes HL, Zheng Y. Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18505-10. Kasten KR, Prakash PS, Unsinger J, Goetzman HS, England LG, Cave CM, Seitz AP, Mazuski CN, Zhou TT, Morre M, Hotchkiss RS, Hildeman DA, Caldwell CC. Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through gamma delta T-cell IL-17 production in a murine model of sepsis. Infect Immun. 2010 Nov;78(11):4714-22. Tripathi P, Kurtulus S, Wojciechowski S, Sholl A, Hoebe K, Morris SC, Finkelman FD, Grimes HL, Hildeman DA. STAT5 is critical to maintain effector CD8+ T cell responses. J Immunol. 2010 Aug 15;185(4):2116-24. Kurtulus S, Tripathi P, Opferman JT, Hildeman DA. Contracting the 'mus cells' -- does down-sizing suit us for diving into the memory pool? Immunol Rev. 2010 Jul;236:54-67. Review. Lin AA, Wojciechowski SE, Hildeman DA. Androgens suppress antigen-specific T cell responses and IFN-γ production during intracranial LCMV infection. J Neuroimmunol. 2010 Sep 14;226(1-2):8-19. Kasten KR, Tschöp J, Goetzman HS, England LG, Dattilo JR, Cave CM, Seitz AP, Hildeman DA, Caldwell CC. T-cell activation differentially mediates the host response to sepsis. Shock. 2010 Oct;34(4):377-83. Kasten KR, Tschöp J, Adediran SG, Hildeman DA, Caldwell CC. T cells are potent early mediators of the host response to sepsis. Shock. 2010 Oct;34(4):327-36. Review. Madan R, Demircik F, Surianarayanan S, Allen JL, Divanovic S, Trompette A, Yogev N, Gu Y, Khodoun M, Hildeman D, Boespflug N, Fogolin MB, Gröbe L, Greweling M, Finkelman FD, Cardin R, Mohrs M, Müller W, Waisman A, Roers A, Karp CL. Nonredundant roles for B cell-derived IL-10 in immune counter-regulation. J Immunol. 2009 Aug 15;183(4):2312-20.
Grants
Regulation of Apoptosis in Activated Primary T Cells. Principal Investigator. National Institute of Allergy and Infectious Diseases. Dec 2008 – Nov 2013. #R01 AI057753.
Homeostasis and function of regulatory T cells in aging. Co-Principal Investigator. National Institute on Aging. Sep 2009 - Aug 2011. #RO1 AG3054748.
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Kasper Hoebe, PhD
focuses on mechanistic analysis of pathways of innate immune activation and the mechanisms underlying NK cell and CD8+ T cell development and cytolytic effector function, using forward genetic approaches. His discovery of an “endogenous adjuvant” pathway mediated by NK cell killing has led to research aimed at exploiting the knowledge obtained on NK cell-driven adaptive immune responses for the generation of new, safer vaccine approaches.
513-803-1056
kasper.hoebe@cchmc.org
Kasper Hoebe, PhD
Academic Information
Assistant Professor, UC Department of Pediatrics
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Specialties
Innate-adaptive connection; mechanisms underlying NK cell and CD8+ T cell development; cytolytic effector function; safer vaccine approaches
Education and Training
BS: Biology; Ultrecht University, The Netherlands, 1994.
PhD: Immunology/ Pharmacology; Ultrecht University, The Netherlands, 2001.
Publications
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Tripathi P, Kurtulus S, Wojciechowski S, Sholl A, Hoebe K, Morris SC, Finkelman FD, Grimes HL, Hildeman DA. STAT5 is critical to maintain effector CD8+ T cell responses. J Immunol. 2010 Aug 15;185(4):2116-24. Barnes MJ, Aksoylar H, Krebs P, Bourdeau T, Arnold CN, Xia Y, Khovananth K, Engel I, Sovath S, Lampe K, Laws E, Saunders A, Butcher GW, Kronenberg M, Steinbrecher K, Hildeman D, Grimes HL, Beutler B, Hoebe K. Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice. J Immunol. 2010 Apr 1;184(7):3743-54. Krebs P, Barnes MJ, Lampe K, Whitley K, Bahjat KS, Beutler B, Janssen E, Hoebe K. NK-cell-mediated killing of target cells triggers robust antigen-specific T-cell-mediated and humoral responses. Blood. 2009 Jun 25;113(26):6593-602. Hoebe K, Beutler B. Forward genetic analysis of TLR-signaling pathways: An evaluation. Adv Drug Deliv Rev. 2008 Apr 29;60(7):824-9. Rutschmann S, Hoebe K. Dissecting innate immunity by germline mutagenesis. Immunology. 2008;123(4):459-68. Baccala R, Hoebe K, Kono DH, Beutler B, Theofilopoulos AN. TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nature Med. 2007;13(5);543–51. Brinkmann MM, Spooner E, Hoebe K, Beutler B, Ploegh HL, Kim YM. The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J Cell Biol. 2007;177(2):265-75. Crozat K, Hoebe K, Ugolini S, Hong NA, Janssen E, Rutschmann S, Mudd S, Sovath S, Vivier E, Beutler B. Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis. J Exp Med. 2007;204(4):853-63. Gavin AL, Hoebe K, Duong B, Ota T, Martin C, Beutler B, Nemazee D. Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science. 2006;314(5807):1936-8. Casrouge A, Zhang SY, Eidenschenk C, Jouanguy E, Puel A, Yang K, Alcais A, Picard C, Mahfoufi N, Nicolas N, Lorenzo L, Plancoulaine S, Senechal B, Geissmann F, Tabeta K, Hoebe K, Du X, Miller RL, Heron B, Mignot C, de Villemeur TB, Lebon P, Dulac O, Rozenberg F, Beutler B, Tardieu M, Abel L, Casanova JL. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science. 2006;314(5797): 308-12.
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Edith Janssen, PhD
focuses on mechanistic analysis and translational exploitation of the processes in dendritic cells that balance pro- and anti-inflammatory immune responses to self after cell death. Dr. Janssen aims at harnessing dendritic cells to develop effective autologous cancer vaccines. Her recent discovery (with Dr. Jonathan Katz) that dysregulation of such cells suggests a potential role for therapeutic modulation of these cells in autoimmune disease.
513-803-1055
edith.janssen@cchmc.org
Edith Janssen, PhD
Academic Information
Assistant Professor, UC Department of Pediatrics
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Education and Training
MS: Utrecht University, The Netherlands, 1995.
PhD: Utrecht University, The Netherlands, 1999.
Publications
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Hennies CM, Reboulet RA, Garcia Z, Nierkens S, Wolkers MC, Janssen EM. Selective expansion of merocytic dendritic cells and CD8DCs confers anti-tumour effect of Fms-like tyrosine kinase 3-ligand treatment in vivo. Clin Exp Immunol. 2011 Jan 14. Reboulet RA, Hennies CM, Garcia Z, Nierkens S, Janssen EM. Prolonged antigen storage endows merocytic dendritic cells with enhanced capacity to prime anti-tumor responses in tumor-bearing mice. J Immunol. 2010 Sep 15;185(6):3337-47. Katz JD, Ondr JK, Opoka RJ, Garcia Z, Janssen EM. Cutting edge: merocytic dendritic cells break T cell tolerance to beta cell antigens in nonobese diabetic mouse diabetes. J Immunol. 2010 Aug 15;185(4):1999-2003. Janssen EM, Lemmens EE, Gour N, Reboulet RA, Green DR, Schoenberger SP, Pinkoski MJ. Distinct roles of cytolytic effector molecules for antigen-restricted killing by CTL in vivo. Immunol Cell Biol. 2010 Oct;88(7):761-5. Krebs P, Barnes MJ, Lampe K, Whitley K, Bahjat KS, Beutler B, Janssen E, Hoebe K. NK-cell-mediated killing of target cells triggers robust antigen-specific T-cell-mediated and humoral responses. Blood. 2009 Jun 25;113(26):6593-602. Kim-Saijo M, Janssen EM, Sugie K. CD4 cell-secreted, posttranslationally modified cytokine GIF suppresses Th2 responses by inhibiting the initiation of IL-4 production. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19402-7. Hildeman D, Janssen E. IFN-gamma and self-absorbed CD4+ T cells: a regulatory double negative. Nat Immunol. 2008 Nov;9(11):1210-2. Benedict CA, Loewendorf A, Garcia Z, Blazar BR, Janssen EM. Dendritic cell programming by cytomegalovirus stunts naïve T cell responses via the PD-L1/PD-1 pathway. J.Immunol. 2008 180:4836-4847. Mothé B, Stewart B, Oseroff C, Bui H, Stogiera S, Garcia Z, Dow C, Rodriguez-Carreno M, Kotturi M, Pasquetto V, Botten J, Crotty S, Janssen E, Buchmeier M, SetteA . Chronic LCMV infection actively down regulates CD4+ T-cell responses directed against a broad range of epitopes. J Immunol. 2007 179:1058-1067. Benedict CA, Janssen EM. Immunesuppression, learning from the masters. ERCI. 2007 3:659-662P.
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Michael B. Jordan, MD
specializes in caring for children with histiocytic disorders, primary immune deficiencies, or who are undergoing bone marrow transplantation. His laboratory focuses on understanding effector T cell function, immune regulation, and the pathogenesis of hemophagocytic lymphohistiocytosis. He is also conducting preclinical scientific studies in addition to a translational clinical trial.
513-636-0281
michael.jordan@cchmc.org
Michael B. Jordan, MD
Academic Information
Associate Professor, UC Department of Pediatrics
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Specialties
Clinical InterestsHistiocytic disorders: HLH and LCH Research InterestsBetter understanding histiocytic disorders and developing novel therapies for them; regulation of the immune response; immunotherapy of cancer
Education and Training
MD: UT Southwestern, Dallas, TX 1993.
Residency: Children's Hospital of Dallas, 1996.
Fellowship: The Children's Hospital (Denver) 2002.
Certification: American Board of Pediatrics, 1996; Sub-board of Pediatric Heme/Onc 2002.
Publications
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Marsh RA, Vaughn G, Kim MO, Li D, Jodele S, Joshi S, Mehta PA, Davies SM, Jordan MB, Bleesing JJ, Filipovich AH. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood. 2010 Dec 23;116(26):5824-31. Mehta PA, Vinks AA, Filipovich A, Bleesing J, Jodele S, Jordan MB, Marsh R, Tarin R, Edwards S, Fearing D, Lawrence J, Davies SM. Alternate-day micafungin antifungal prophylaxis in pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic study. Biol Blood Marrow Transplant. 2010 Oct;16(10):1458-62. Marsh RA, Madden L, Kitchen BJ, Mody R, McClimon B, Jordan MB, Bleesing JJ, Zhang K, Filipovich AH. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood. 2010 Aug 19;116(7):1079-82. Marsh RA, Satake N, Biroschak J, Jacobs T, Johnson J, Jordan MB, Bleesing JJ, Filipovich AH, Zhang K. STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America. Pediatr Blood Cancer. 2010 Jul 15;55(1):134-40. Lykens JE, Terrell CE, Zoller EE, Divanovic S, Trompette A, Karp CL, Aliberti J, Flick MJ, Jordan MB. Mice with a selective impairment of IFN-gamma signaling in macrophage lineage cells demonstrate the critical role of IFN-gamma-activated macrophages for the control of protozoan parasitic infections in vivo. J Immunol. 2010 Jan 15;184(2):877-85. Lin AA, Tripathi PK, Sholl A, Jordan MB, Hildeman DA. Gamma interferon signaling in macrophage lineage cells regulates central nervous system inflammation and chemokine production. J Virol. 2009 Sep;83(17):8604-15. Marsh RA, Villanueva J, Kim MO, Zhang K, Marmer D, Risma KA, Jordan MB, Bleesing JJ, Filipovich AH. Patients with X-linked lymphoproliferative disease due to BIRC4 mutation have normal invariant natural killer T-cell populations. Clin Immunol. 2009 Jul;132(1):116-23. Marsh RA, Villanueva J, Zhang K, Snow AL, Su HC, Madden L, Mody R, Kitchen B, Marmer D, Jordan MB, Risma KA, Filipovich AH, Bleesing JJ. A rapid flow cytometric screening test for X-linked lymphoproliferative disease due to XIAP deficiency. Cytometry B Clin Cytom. 2009 Sep;76(5):334-44. Jordan MB, Filipovich AH. Hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: a journey of a thousand miles begins with a single (big) step. Bone Marrow Transplant. 2008 Oct;42(7):433-7. Wojciechowski S, Jordan MB, Zhu Y, White J, Zajac AJ, Hildeman DA. Bim mediates apoptosis of CD127(lo) effector T cells and limits T cell memory. Eur J Immunol. 2006 Jul;36(7):1694-706.
Grants
Hybrid Immunotherapy for Hemophagocytic Lymphohistiocytosis. Principal Investigator. Histiocytosis Association of America. Jan 2011 - Dec 2011.
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Christopher L. Karp, MD
Adjunct Professor
Molecular mechanisms underlying regulation and dysregulation of inflammatory responses in infectious, allergic, genetic and metabolic disease, with a focus on diseases of children.
513-636-7608
chris.karp@cchmc.org
Christopher L. Karp, MD
Adjunct Professor
Academic Information
Professor, UC Department of Pediatrics
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Specialties
Molecular mechanisms underlying regulation and dysregulation of inflammatory responses in infectious, allergic, genetic and metabolic disease, with a focus on diseases of children.
Education and Training
BA: Brandeis University, Waltham, MA, 1978.
MD: University of North Carolina School of Medicine, Chapel Hill, NC, 1986.
Internal Medicine: Rhode Island Hospital, Brown University, 1986-1987.
Internal Medicine: Georgetown University Hospital, Georgetown University, 1987-1989.
NRSA Fellow: Laboratory of Parasitic Diseases, NIAID, 1989-1992.
Fellow in Infectious Diseases: Johns Hopkins University School of Medicine, 1992-1993.
Diplomate of the National Board of Medical Examiners, 1987; Diplomate in Internal Medicine, American Board of Internal Medicine, 1989; Diplomate in Infectious Disease, American Board of Internal Medicine, 1994; Certificate of Knowledge in Tropical Medicine and Travelers' Health, ASTMH, 1995
Publications
Allen JL, Trompette A, Karp CL. Toll-like receptors. In Inflammation and Allergy Drug Design, Holgate S, Wills-Karp M, Izuhara K (Eds.). Oxford: Wiley-Blackwell, Medicine, 2011. Divanovic S, Sawtell NM, Trompette A, Warning JI, Dias A, Cooper AM, Yap GS, Arditi M, Shimada K, DuHadaway JB, Prendergast GC, Basaraba RJ, Mellor AL, Munn DH, Aliberti J, Karp CL. Opposing biological functions of tryptophan catabolizing enzymes during intracellular infection. J Infect Dis. 2011. In press.
Divanovic S, Trompette A, Ashworth JI, Rao MB, Karp CL. Therapeutic enhancement of protective immunity during experimental Leishmania major infection. PLoS Neglected Tropical Diseases. 2011. 5(9): e1316. doi:10.1371/journal.pntd.0001316
Karp CL, Mahanty S. Approach to the patient with HIV and coinfecting tropical infectious diseases. in Tropical Infectious Diseases: Principles, Pathogens, and Practice, 3RD Edition; ed. Guerrant RL, Walker DH, and Weller PF. Elsevier Churchill Livingstone, Philadelphia. 2011. 1046-1065.
Puntambekar SS, Bergmann CC, Savarin C, Karp CL, Phares TW, Parra GI, Hinton DR, Stohlman SA. Shifting hierarchies of IL-10 producing T cell populations in the CNS during acute and persistent viral encephalomyelitis. J Virol. 2011. 85:6702-13. Epub 2011 Apr 27.PMID: 21525347.
Denning TL, Norris BA, Greene B, Madan R, Karp CL, Pulendran B. Functional specializations of intestinal dendritic cell and macrophage subsets that control TH-17 and T regulatory responses is dependent on the T:APC ratio, source of mouse strain and regional localization. J Immunol. 2011. 187:733-47. PMID: 21666057.
Karp CL. Guilt by intimate association: What makes an allergen an allergen? J Allergy Clin Immunol. 2010. 125:955-60. PMCID: PMC2868504.
Karp CL. Links between innate and adaptive immunity. In Fundamentals of Inflammation; ed. Serhan CN, Ward P, Gilroy D. 2009. Cambridge University Press, New York, NY. 2010. 28-38.
Wills-Karp M, Nathan A, Page K, Karp CL. New insights into the molecular mechanisms underlying allergenicity. Mucosal Immunology. 2010. 3:104-10. PMCID: PMC2821449.
Trompette A, Divanovic S, Visintin A, Blanchard C, Hegde RS, Madan R, Thorne PS, Wills-Karp M, Gioannini TL, Weiss JP, Karp CL. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature. 2009. 457:585-588. Advanced Online Publication 12/7/08. 10.1038/nature07548. PMCID: 2843411.
Sun J, Madan R, Karp CL, Braciale TJ. Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nature Medicine. 2009. 15:277-84. Advanced Online Publication 2/22/09. 10.1038/nm.1929. PMCID:2693210.
Gu YY, Harley ITW, Henderson LB, Aronow BJ, Vietor I, Huber LA, Harley JB, Kilpatrick JR, Langefeld CD, Williams AH, Jegga AG, Chen J, Wills-Karp M, Arshad SH, Ewart SL, Thio CL, Flick LM, Filippi MD, Grimes HL, Drumm ML, Cutting GR, Knowles MR, Karp CL. Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature. 2009. 458:1039-1042. Advanced Online Publication 2/25/09. 10.1038/nature07811. PMCID: 2841516.
Madan R, Demircik F, Divanovic S, Trompette A, Allen J, Gu Y, Khoudon M, Hildeman D, Boespflug N, Fogolin MB, Lothar Gröbe, Greweling M, Finkelman F, Cardin R, Mohrs M, Muller W, Roers A, Waisman A, Karp CL. Non-Redundant Counter-Regulatory Roles for B Cell-Derived IL-10. J Immunology. 2009. 183:2312-20. PMCID: PMC2772089.
Pot C, Jin H, Awasthi A, Liu SM, Lai CY, Madan R, Sharpe AH, Karp CL, Miaw SC, Ho IC, Kuchroo VK. Cutting Edge: IL-27 Induces the Transcription Factor c-Maf, Cytokine IL-21, and the Costimulatory Receptor ICOS that Coordinately Act Together to Promote Differentiation of IL-10-Producing Tr1 Cells. J Immunology. 2009. 183:797-801. PMCID: 2768608.
Murai M, Turovskaya O, Kim G, Madan R, Karp CL, Cheroutre H, Kronenberg M. IL-10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nature Immunology. 2009. 10:1178-84. PMCID: PMC2898179.
Perona-Wright G, Mohrs K, Szaba FM, Kummer LW, Madan R, Karp CL, Johnson LL, Smiley ST, Mohrs M. Systemic but not local infections elicit immunosuppressive IL-10 by natural killer cells. Cell Host Microbe. 2009. 6: 503-512. PMCID: PMC2796259.
Tschöp MH, Hugenholtz P, and Karp CL. To the core of the gut microbiome. Nature Biotechnology. 2009. 27:344-346.
Auwaerter PG, Karp CL. Coinfection with HIV and tropical infectious diseases I: Protozoal pathogens. Clin Infect Dis. 2007. 45:1208-14.
Auwaerter PG, Karp CL. Coinfection with HIV and tropical infectious diseases II: Helminthic, fungal, bacterial and viral pathogens. Clin Infect Dis. 2007. 45: 1214-20.
Divanovic S, Trompette A, Atabani SF, Madan R, Reckling S, Golenbock DT, Visintin A, Finberg RW, Tarakhovsky A, Vogel SN, Belkaid Y, Kurt-Jones EA, Karp CL. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nature Immunol 2005 ; 6:571-8. PMCID: PMC2144914.
Wills-Karp M, Santeliz J, Karp CL. The germless theory of allergic disease: the hygiene hypothesis revisited. Nature Res Immunol 2001; 1:69-75.
Karp CL, Grupe A, Schadt E, Ewart SL, Keane-Moore M, Cuomo PJ, Köhl J, Wahl L, Kuperman D, Germer S, Aud D, Peltz G, Wills-Karp M. Identification of C5 as a susceptibility locus for experimental allergic asthma. Nature Immunol 2000; 1:221-226.
Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, DD Donaldson. Interleukin-13: Central mediator of allergic asthma. Science. 1998;282:2258-2261.
Karp CL, Wysocka M, Wahl LM, Cuomo PJ, B. Sherry, Ahearn JA, Trinchieri G, Griffin DE. Mechanism of suppression of cell-mediated immunity by measles virus. Science 1996;273:228-231.
Karp CL, El-Safi SH, Wynn TA, Satti MMH, Kordofani AM, Hashim FA, Hag-Ali M, Neva FA, Nutman TB, Sacks DL. In vivo cytokine profiles in patients with kala-azar: Marked elevation of both interleukin-10 and interferon-gamma. J Clin Invest 1993;91:1644-1648. PMCID: PMC288142
Grants
Regulation of TLR Signaling and Innate Immunity by RP105. National Institutes of Health. July 2007 - June 2012 #RO1AI075159 RDP Center component II. Cystic Fibrosis Foundation. August 2007- June 2015.
Immunobiology of IFRD1, a gene modifying CF lung disease. National Institutes of Health, August 2009- July 2013. #R01HL094576.
Allergenicity resulting from functional mimicry of the TLR complex. National Institutes of Health. March 2010-February 2015. #R01 AI088372. Novel Immune-based therapy for Leishmaniasis and TB. National Institutes of Health. July 2009 - June 2010 (NCE July 2012)
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Jonathan D. Katz, PhD
is working to understand the role that autoreactive T lymphocytes play in the Immunopathogenesis of type 1 diabetes, the most common pediatric autoimmune disease. Major focuses include defining: (a) the control of autoreactive T cells via central and peripheral tolerance; (b) the role NKT cells play in regulating autoreactive T cells; and (c) the role dendritic cells play in activating and regulating autoreactive T cells in type 1 diabetes.
513-636-5306
jonathan.katz@cchmc.org
Jonathan D. Katz, PhD
Academic Information
Professor, UC Department of Pediatrics
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Specialties
Clinical InterestsT cells; MHC, beta cell death; islet antigens Research InterestsImmunology, autoimmunity, type 1 diabetes
Biography
Jonathan D. Katz, PhD, focuses on autoimmune diabetes research. Autoimmune diabetes, also known as type 1 diabetes (T1D), is the most common pediatric autoimmune disease. Roughly 1/250 individuals develop T1D in the United States.There is currently no cure for T1D and the only treatment is daily exogenous insulin replacement therapy. Many T1D patients eventually develop secondary complications, such as hearth disease, blindness, peripheral neuropathy and renal failure. Dr. Katz's work focuses on the role that autoreactive T lymphocytes play in the disease process. His lab interested in (1) the control of autoreactive T cells via central and peripheral tolerance, (2) the role NKT cells play in regulating autoreactive T cells, and (3) the role dendritic cells play in activating and regulating autoreactive T cells in T1D. Most of his work uses the non-obese diabetic (NOD) mouse strain that spontaneously develops T1D with remarkable similar to the T1D seen in human patients. The availability of the NOD strain has allowed us to take a modern, reductionist molecular and cellular immunology approach to understanding the mechanism(s) and genetics underlying T1D susceptibility and disease progression. His lab makes extensive use of knockout, transgenic, regulated gene expression, targeted ablation, cell transfer and genomic studies the progression and regulation of T1D in the NOD mouse.
Education and Training
BS: University of California, Los Angeles, Calif., 1984.
PhD: University of California, Los Angeles, Calif., 1990.
Post-Doctoral Fellow: Université Louis Pasteur, Strasbourg, France, 1990-1995.
Publications
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Katz JD, Ondr JK, Opoka RJ, Garcia Z, Janssen EM. Cutting edge: merocytic dendritic cells break T cell tolerance to beta cell antigens in nonobese diabetic mouse diabetes. J Immunol. 2010 Aug 15;185(4):1999-2003. Pang S, Zhang L, Wang H, Yi Z, Li L, Gao L, Zhao J, Tisch R, Katz JD, Wang B. CD8(+) T cells specific for beta cells encounter their cognate antigens in the islets of NOD mice. Eur J Immunol. 2009 Oct;39(10):2716-24. Saxena V, Ondr JK, Magnusen AF, Munn DH, Katz JD. The countervailing actions of myeloid and plasmacytoid dendritic cells control autoimmune diabetes in the nonobese diabetic mouse. J Immunol. 2007 Oct 15;179(8):5041-53. Wojciechowski S, Tripathi P, Bourdeau T, Acero L, Grimes HL, Katz JD, Finkelman FD, Hildeman DA. Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis. J Exp Med. 2007 Jul 9;204(7):1665-75. Cain JA, Smith JA, Ondr JK, Wang B, Katz JD. NKT cells and IFN-gamma establish the regulatory environment for the control of diabetogenic T cells in the nonobese diabetic mouse. J Immunol. 2006 Feb 1;176(3):1645-54. Vukkadapu SS, Belli JM, Ishii K, Jegga AG, Hutton JJ, Aronow BJ, Katz JD. Dynamic interaction between T cell-mediated beta-cell damage and beta-cell repair in the run up to autoimmune diabetes of the NOD mouse. Physiol Genomics. 2005 Apr 14;21(2):201-11. Hutton JJ, Jegga AG, Kong S, Gupta A, Ebert C, Williams S, Katz JD, Aronow BJ. Microarray and comparative genomics-based identification of genes and gene regulatory regions of the mouse immune system. BMC Genomics. 2004 Oct 25;5(1):82.
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Joerg Koehl, MD
Adjunct Professor
focuses on a molecular and cellular understanding of how innate and adaptive immune responses are regulated by the complement system. Ongoing projects include studies aimed at defining the pathogenesis of immune complex disease, the role of complement in regulating allergic asthma, cross-talk between complement receptors and Toll-like receptors (TLR), and the role of the C5a receptor as a drug target in kidney transplantation.
513-636-1219
Joerg.Koehl@cchmc.org
Joerg Koehl, MD
Adjunct Professor
Academic Information
Professor, UC Department of Pediatrics
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Specialties
Clinical InterestsComplement biology; toll-like receptors; IgG Fc receptors Research InterestsMechanisms underlying the cross-talk between receptors for complement cleavage products C3a and C5a, IgG Fc receptors, and toll-like receptors
Education and Training
MD University of Mainz. Germany, 1988.
Residency Medical School Hannover, Hannover, Germany.
Certification Medical Microbiology, 1994.
Fellow in Medicine (Pulmonology) Medical School Hannover, Hannover, Germany, 1991-92.
Research Fellow in Medical Microbiology Medical School Hannover, Hannover, Germany, 1988-81.
Publications
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Zhang X, Schmudde I, Laumonnier Y, Pandey MK, Clark JR, König P, Gerard NP, Gerard C, Wills-Karp M, Köhl J. A critical role for C5L2 in the pathogenesis of experimental allergic asthma. J Immunol. 2010 Dec 1;185(11):6741-52. Zhang X, Köhl J. A complex role for complement in allergic asthma. Expert Rev Clin Immunol. 2010 Mar;6(2):269-77. Review. Weaver DJ Jr, Reis ES, Pandey MK, Köhl G, Harris N, Gerard C, Köhl J. C5a receptor-deficient dendritic cells promote induction of Treg and Th17 cells. Eur J Immunol. 2010 Mar;40(3):710-21. Zhang X, Lewkowich IP, Köhl G, Clark JR, Wills-Karp M, Köhl J. A protective role for C5a in the development of allergic asthma associated with altered levels of B7-H1 and B7-DC on plasmacytoid dendritic cells. J Immunol. 2009 Apr 15;182(8):5123-30. Khodoun M, Strait R, Orekov T, Hogan S, Karasuyama H, Herbert DR, Köhl J, Finkelman FD. Peanuts can contribute to anaphylactic shock by activating complement. J Allergy Clin Immunol. 2009 Feb;123(2):342-51. Lewis AG, Köhl G, Ma Q, Devarajan P, Köhl J. Pharmacological targeting of C5a receptors during organ preservation improves kidney graft survival. Clin Exp Immunol. 2008 Jul;153(1):117-26. Köhl J, Wills-Karp M. A dual role for complement in allergic asthma. Curr Opin Pharmacol. 2007 Jun;7(3):283-9. Köhl J. Drug evaluation: the C5a receptor antagonist PMX-53. Curr Opin Mol Ther. 2006 Dec;8(6):529-38. Review. Köhl J. Self, non-self, and danger: a complementary view. Adv Exp Med Biol. 2006;586:71-94. Review. Köhl J, Wills-Karp M. Complement regulates inhalation tolerance at the dendritic cell/T cell interface. Mol Immunol. 2007 Jan;44(1-3):44-56.
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Ian P. Lewkowich, PhD
investigates the factors that drive the development of severe allergic asthma, with a particular focus on the molecular mechanisms through which Th17 cytokines enhance IL-13 signaling, the regulation of the asthmatic response through the PD-1/PD-L axis and the mechanisms of the well-described maternal influence in inherited asthma risk.
513-636-3999
ian.lewkowich@cchmc.org
Ian P. Lewkowich, PhD
Academic Information
Assistant Professor, UC Department of Pediatrics
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Specialties
Biography
While Th2 immune responses are central to disease pathology in allergic asthma, there is a growing understanding that the Th2 paradigm is not sufficient to explain the entire spectrum of disease severity. Indeed, there is growing belief that severe disease may be driven by a different process than mild to moderate disease. Using a mouse model of allergic asthma in which one strain develops a phenotype characteristic of mild asthma (C3H/HeJ), and others develop a phenotype characteristic of severe disease (A/J), we have identified several novel mechanisms through which asthma severity is regulated. We have found that the development of severe allergic asthma is associated with a limited capacity of Tregs to limit pulmonary dendritic cell activity, enhanced capacity for antigen uptake by pulmonary myeloid dendritic cells, and the development of a mixed Th2/Th17 immune response. In contrast, C3H mice demonstrate increased Treg activity, preferential antigen uptake by pulmonary plasmacytoid dendritic cells, and an exclusively Th2-biased immune response. We are presently using the A/J versus C3H/HeJ mouse model of allergic asthma to tease out the mechanisms responsible the development of severe allergic asthma.
Education and Training
PhD: University of Manitoba, Winnipeg, Canada, 2004.
Publications
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Lewkowich IP, Fox JG Perkins C, Lewis L, Finkelman FD Smith DE, Bryce PJ, Kurt-Jones EA, Wang TC, Sivaprasad U, Hershey GK, Herbert DR. Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection. J Exp Med. 2012;209(3):607-22. Lufti R, Ledford JR, Zhou P, Lewkowich IP, Page K. Dendritic Cell-Derived Tumor Necrosis Factor α Modifies Airway Epithelial Cell Responses. J Innate Immun. 2012;4(5-6):542-52. Lewkowich IP, Lajoie S, Stoffers SL, Suzuki Y, Richgels PK, Dienger K, Sproles AA, Yagita H, Hamid Q, Wills-Karp M. PD-L2 modulates asthma severity by directly decreasing dendritic cell IL-12 production. Mucosal Immunol. 2012. Stefater JA, Lewkowich IP, Rao S, Ajima R, Mariggi G, Wills-Karp M, Pollard J, Yamaguchi T, McMahon AP, Ferrara N, Gerhardt H, Lang RA. Microglial Wnt ligands suppress retinal angiogenesis via activation of the VEGF inhibitor Flt1. Nature. 2011;474(7352):511-515. Lewkowich IP, Day SB, Ledford JR, Zhou P, Dienger K, Wills-Karp M, Page K. Protease-activated receptor 2 activation of myeloid dendritic cells regulates allergic airway inflammation. Respir Res. 2011;(12):122. Lewkowich IP1, Lajoie S1, Suzuki Y, Clark JR, Sproles AA, Dienger K, Budelsky A, and Wills-Karp M, Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol. 2010;(10):928-935. Chen G, Wan H, Luo F, Zhang L, Xu Y, Lewkowich IP, Wills-Karp M and Whitsett JA. Foxa2 programs Th2 cell-mediated innate immunity in the developing lung. J Immunol. 2010;(184):6133-6141. Lewkowich IP, Lajoie S, Dienger K, Herman NS, Sproles AA, and Wills-Karp M. Enhanced allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives airway hyperresponsiveness in asthma-susceptible mice. PLoS ONE. 2008;(3):e3879. Köhl J, Baelder R, Lewkowich IP, Pandey MK, Hawlisch H, Wang L, Best J, Herman NS, Sproles AA, Zwirner J, Whitsett JA, Gerard C, Sfyroera G, Lambris JD, and Wills-Karp M. A regulatory role for the C5a anaphylotoxin on type 2 immunity in asthma. J Clin Invest. 2006;(116):783-796. Lewkowich IP, Herman NS, Schleifer KW, Dance MP, Chen BL, Dienger KM, Sproles AA, Shah JS, Köhl J, Belkaid Y, and Wills-Karp M. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J Exp Med. 2005;(202):1549-1561.
Grants
Mechanisms of steroid resistance in severe asthma. Principal Investigator. ATS Unrestricted Research Grant. Oct 2011 - Jul 2013.
Synergistic Role of IL-17 and IL-13 in asthma susceptibility. Principal Investigator. Parker B Francis Fellowship. Jul 2010 - Jun 2013.
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Jochen Mattner, MD
investigates the role of NKT cells during microbial infection and the impact of their activation on the immune response. Following a path of research that explored the presence of Sphingomonas bacteria in liver autoimmune disorders, his laboratory is now exploring the intriguing possibility that some forms of autoimmune disease may be triggered by infection with Sphingomonas or related bacteria.
513-803-0768
Jochen.Mattner@cchmc.org
Jochen Mattner, MD
Academic Information
Assistant Professor, UC Department of Pediatrics
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Biography
Dr. Mattner's laboratory studies the role of NKT cells during microbial infection and the impact of their activation on the immune response. Recently, we could identify self and microbial glycosphingolipid (GSL) ligands that trigger NKT cell activation. This observation led to the characterization of two general modes of NKT cell activation during microbial infection. One pathway involves recognition of endogenous antigen(s) upregulated through TLR signaling by gram-negative LPS-positive bacteria like Salmonella. The other involves direct recognition of microbial GSLs, the LPS substitutes in Sphingomonas and related alphaproteobacteria suggesting that NKT cells represent a major innate recognition pathway for this class of bacteria. Based on recent compelling evidence that patients with Primary Biliary Cirrhosis (PBC) are seropositive for Sphingomonas and exhibit NKT cell redistribution to the liver, we could establish a mouse model of infection-triggered autoimmunity of the liver. As our previous work had identified microbial glycosphingolipid (GSL) ligands in the cell wall of Sphingomonas that trigger NKT cell activation (see above) and as the development of liver disease was CD1d dependent, we concluded that exposure to Sphingomonas facilitates the production of auto-antibodies against PBC antigens and the induction of auto-reactive T cells due to NKT cell help. In that context, the preferential activation of NKT cells in the liver, where NKT cells are abundant and Sphingomonas preliminarily persists, may explain the biased autoreactivity towards autoantigens exposed in the liver environment and, ultimately, the severe organ-specific manifestations of Sphingomonas infection. The major focus of the laboratory is now to explore the intriguing possibility that some forms of autoimmune PBC may be triggered by infection with Sphingomonas or related bacteria.
Education and Training
MD: University of Erlangen, Erlangen, Germany, 2001.
Postdoc Scholar: University of Chicago, Department of Pathology, 2003-2005.
Research Associate / Assistant Professor: Department of Pathology, 2006-2007.
Publications
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Mattner J. Genetic susceptibility to autoimmune liver disease. World J Hepatol. 2011 Jan 27;3(1):1-7. Mohammed JP, Mattner J. Autoimmune disease triggered by infection with alphaproteobacteria. Expert Rev Clin Immunol. 2009 Jul 1;5(4):369-379. Yin N, Long X, Goff RD, Zhou D, Cantu C 3rd, Mattner J, Mezard PS, Teyton L, Bendelac A, Savage PB. Alpha anomers of iGb3 and Gb3 stimulate cytokine production by natural killer T cells. ACS Chem Biol. 2009 Mar 20;4(3):199-208. Vas J, Mattner J, Richardson S, Ndonye R, Gaughan JP, Howell A, Monestier M. Regulatory roles for NKT cell ligands in environmentally induced autoimmunity. J Immunol. 2008 Nov 15;181(10):6779-88. Mattner J, Savage PB, Leung P, Oertelt SS, Wang V, Trivedi O, Scanlon ST, Pendem K, Teyton L, Hart J, Ridgway WM, Wicker LS, Gershwin ME, Bendelac A. Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe. 2008 May 15;3(5):304-15. Liu Y, Deng S, Bai L, Freigang S, Mattner J, Teyton L, Bendelac A, Savage PB. Synthesis of diglycosylceramides and evaluation of their iNKT cell stimulatory properties. Bioorg Med Chem Lett. 2008 May 15;18(10):3052-5. Pedra JH, Mattner J, Tao J, Kerfoot SM, Davis RJ, Flavell RA, Askenase PW, Yin Z, Fikrig E. c-Jun NH2-terminal kinase 2 inhibits gamma interferon production during Anaplasma phagocytophilum infection. Infect Immun. 2008 Jan;76(1):308-16. Long X, Deng S, Mattner J, Zang Z, Zhou D, McNary N, Goff RD, Teyton L, Bendelac A, Savage PB. Synthesis and evaluation of stimulatory properties of Sphingomonadaceae glycolipids. Nat Chem Biol. 2007 Sep;3(9):559-64. Rocha FJ, Schleicher U, Mattner J, Alber G, Bogdan C. Cytokines, signaling pathways, and effector molecules required for the control of Leishmania (Viannia) braziliensis in mice .Infect Immun. 2007 Aug;75(8):3823-32. Epub 2007 May 21. Sagiv Y, Hudspeth K, Mattner J, Schrantz N, Stern RK, Zhou D, Savage PB, Teyton L, Bendelac A. Cutting edge: impaired glycosphingolipid trafficking and NKT cell development in mice lacking Niemann-Pick type C1 protein. J Immunol. 2006 Jul 1;177(1):26-30.
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Marsha Wills-Karp, PhD
Adjunct Professor
investigates the environmental and genetic determinants of allergic asthma in humans and mouse models. Her research has revealed several novel cytokine (IL-13) and immunoregulatory (C5a) genes which are associated with susceptibility to asthma. Dr. Wills-Karp founded the division in 2000 and the graduate program in 2003. She has also served as the Associate Dean of Basic Sciences at the University of Cincinnati since 2008.
513-636-7641
wildc7@cchmc.org
Marsha Wills-Karp, PhD
Adjunct Professor
Academic Information
Professor, UC Department of Pediatrics
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Specialties
Asthma; allergy; T cell immunology; genetics of asthma; cytokines
Education and Training
BS / MS: Southwest Texas State University, San Marcos, TX, 1980, 1982. PhD: University of California, Santa Barbara, CA, 1986. Postdoctoral Fellowships: Yale University, New Haven, CT, 1986-87; Johns Hopkins University, Baltimore, MD 1987-89.
Publications
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Perkins C, Yanase N, Smulian G, Gildea L, Orekov T, Potter C, Brombacher F, Aronow B, Wills-Karp M, Finkelman FD. Selective stimulation of IL-4 receptor on smooth muscle induces airway hyperresponsiveness in mice. J Exp Med. 2011 Apr; 208(4):853-67. McCormack MC, Breysse PN, Matsui EC, Hansel NN, Peng RD, Curtin-Brosnan J, Williams DL, Wills-Karp M, Diette GD. Indoor Particulate Matter Increases Asthma Morbidity in Children with Non-Atopic and Atopic Asthma. Ann Allergy, Asthma & Immunol. 2011 Apr;106(4):308-15. Guo F, Zhang S, Tripathi P, Mattner J, Phelan J, Sproles A, Mo J, Wills-Karp M, Grimes HL, Hildeman D, Zheng Y. Distinct roles of cdc42 in thymopoiesis and effector and memory T cell differentiation. PLoS One. 2011 Mar;6(3):e18002. Baye TM, Kovacic MB, Biagini Myers JM, Martin LJ, Lindsey M, Patterson TL, He H, Ericksen MB, Gupta J, Tsoras AM, Lindsley A, Rothenberg ME, Wills-Karp M, Eissa NT, Borish L, Khurana Hershey GK. Differences in candidate gene association between European ancestry and African American asthmatic children. PLoS One. 2011 Feb;6(2):e16522. Chavez-Valdez, R, Ahlawat R, Wills-Karp M, Nathan A, Sproles A, Exell T, Cristofalo E, Gauda E. Correlation between Serum Caffeine Levels and Changes in Cytokines Profile in a Cohort of Preterm Infants. J Pediatr. 2011 Jan;158(1):57-64, 64.e1. Sivaprasad U, Askew DJ, Ericksen MB, Gibson AM, Stier MT, Brandt EB, Bass SA, Daines MO, Chakir J, Stringer KF, Wert SE, Whitsett JA, Le Cras TD, Wills-Karp M, Silverman GA, Khurana Hershey GK. A nonredundant role for mouse Serpinb3a in the induction of mucus production in asthma. J Allergy Clin Immunol. 2011 Jan;127(1):254-61, 261.e1-6.
Wills-Karp M. Allergen-specific pattern recognition receptor pathways. Curr Opin Immunol. 2010 Dec;22(6):777-82. Wills-Karp M, Kapsenberg M. Allergy and hypersensitivity. Curr Opin Immunol. 2010 Dec;22(6):775-6.
Zhang X, Schmudde I, Laumonnier Y, Pandey MK, Clark JR, König P, Gerard NP, Gerard C, Wills-Karp M, Köhl J. A critical role for C5L2 in the pathogenesis of experimental allergic asthma. J Immunol. 2010 Dec 1;185(11):6741-52. Lajoie S, Lewkowich IP, Suzuki Y, Clark JR, Sproles AA, Dienger K, Budelsky AL, Wills-Karp M. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol. 2010 Oct;11(10):928-35.
Grants
Allergen-Specific Desensitization Protocols. Principal Investigator. Contract with Allertein Pharmaceuticals. 2008 - present. Effects of IL4 and IL13 on Pulmonary Smooth Muscle in Allergic Airway Disease. Co-Principal Investigator. National Institutes of Health. Jul 2009 - Aug 2011. #RO1 HL0973360-01. Asthma Positional Candidate Genes in Mice and Humans. Principal Investigator. National Institutes of Health. Dec 2005 - Nov 2011. #RO1 HL067736-11. MoFLo XDP Cell Sorter Shared Instrument Grant. Principal Investigator. National Institutes of Health. Apr 2011 - Mar 2012. #1S10RR031653-01. Center for Childhood Asthma in the Urban Environment. Co-Principal Investigator. National Institutes of Health. Sep 2007 - Jun 2012. #1P50ES015903-01. Epithelial Regulation of Th2 Immune Responses in the Lung. Principal Investigator. National Institutes of Health. Jul 2009 - Jun 2014. #RO1 AI083315-02. Epithelial Genes in Allergic Inflammation. Co-Principal Investigator. National Institutes of Health. Jul 2011 - Jun 2016. #U19 AI070235.
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