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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.
Assistant Professor, UC Department of Pediatrics
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.
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.
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.
Artem Barski, PhD Assistant Professor, Genetics and Allergy & Immunology
Assistant Professor, Genetics and Allergy & Immunology
Epigenetics; epigenomics; immunology; T cell memory
Visit the Barski Lab
Artem Barski, PhD, is interested in epigenetic and transcriptional regulation of gene expression. During his post-doctoral training in Keji Zhao lab at NIH, Dr. Barski took part in the development of ChIP-Seq, a revolutionary method that combines ChIP with the next-generation sequencing. ChIP-Seq allows genome-wide mapping of chromatin modifications and transcription factor binding sites with resolution and sensitivity far exceeding older methods. Together with his NIH colleagues Dr. Barski used this approach to map more than 40 chromatin modifications in human T cells, which fundamentally improved the understanding of epigenetic regulation of transcription. Dr. Barski has since been using ChIP-Seq and other sequencing-based genome-wide methods to understand the role of chromatin modifications in gene regulation. His most recent work includes investigation of chromatin regulation of genes transcribed by RNA Polymerase III and the discovery of gene poising in T cells.
Since his arrival to Cincinnati Children’s Hospital in 2011, Dr. Barski is utilizing ChIP-Seq, RNA-Seq and other cutting-edge approaches to understand epigenetic basis of T cell activation, memory and tolerance.
Barski A, Chepelev I, Liko D, Cuddapah S, Fleming AB, Birch J, Cui K, White RJ, Zhao K. Pol II and its associated epigenetic marks are present at Pol III-transcribed noncoding RNA genes. Nat Struct Mol Biol. 2010 May;17(5):629-34. Cuddapah S, Barski A, Zhao K. Epigenomics of T cell activation, differentiation, and memory. Curr Opin Immunol. 2010 Jun;22(3):341-7.
Cuddapah S, Barski A, Cui K, Schones DE, Wang Z, Wei G, Zhao K. Native chromatin preparation and Illumina/Solexa library construction. Cold Spring Harb Protoc. 2009 Jun;2009(6):pdb.prot5237. Barski A, Jothi R, Cuddapah S, Cui K, Roh TY, Schones DE, Zhao K. Chromatin poises miRNA- and protein-coding genes for expression. Genome Res. 2009 Oct;19(10):1742-51
Barski A, Zhao K. Genomic location analysis by ChIP-Seq. J Cell Biochem. 2009 May 1;107(1):11-8. Jothi R, Cuddapah S, Barski A, Cui K, Zhao K. Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Nucleic Acids Res. 2008 Sep;36(16):5221-31. Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, Cui K, Roh TY, Peng W, Zhang MQ, Zhao K. Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet. 2008 Jul;40(7):897-903 Schones DE, Cui K, Cuddapah S, Roh TY, Barski A, Wang Z, Wei G, Zhao K. Dynamic regulation of nucleosome positioning in the human genome. Cell. 2008 Mar 7;132(5):887-98. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K. High-resolution profiling of histone methylations in the human genome. Cell. 2007 May 18;129(4):823-37. Barski A, Frenkel B. ChIP Display: novel method for identification of genomic targets of transcription factors. Nucleic Acids Res. 2004 Jul 13;32(12):e104.
Jorge A. Bezerra, MD
Professor, UC Department of Pediatrics
Jorge A. Bezerra, MD, joined the Cincinnati Children's Hospital Medical Center Division of Gastroenterology, Hepatology and Nutrition in 1990, when he began his fellowship training in pediatric gastroenterology and nutrition and graduated in 1993.
From 1992-1994, Dr. Bezerra was a research scholar in the Division of Basic Sciences. He was appointed to the division in 1994 as an assistant professor of pediatrics.
Dr. Bezerra completed his residency in pediatrics at the University of Arizona in Tucson, Arizona.
Dr. Bezerra has an active research career with his primary interests in molecular control of liver regeneration, biliary atresia, and genetic basis of intrahepatic cholestasis.
In addition to his research work, Dr. Bezerra is an active clinician for the outpatient GI clinical service and the inpatient liver service.
MD: Federal University Rio Grande Norte, Natal, Brazil, 1984
Residency: University of Arizona, Tuscon, AZ, 1989
Fellowship: Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, 1994
Certification: Pediatrics, Pediatric Gastroenterology, Hepatology and Nutrition
Bezerra JA. Biliary atresia in Brazil: where we are and where we are going. J Pediatr (Rio J). 2010 Nov-Dec;86(6):445-7. Moyer K, Kaimal V, Pacheco C, Mourya R, Xu H, Shivakumar P, Chakraborty R, Rao M, Magee JC, Bove K, Aronow BJ, Jegga AG, Bezerra JA. Staging of biliary atresia at diagnosis by molecular profiling of the liver. Genome Med. 2010 May 13;2(5):33.
Kumar Mohanty S, Ivantes CA, Mourya R, Pacheco C, Bezerra JA. Macrophages are targeted by rotavirus in experimental biliary atresia and induce neutrophil chemotaxis via Mip2/Cxcl2. Pediatr Res. 2010 Jan 6. Shivakumar P, Sabla GE, Whitington P, Chougnet CA, Bezerra JA. Neonatal NK cells target the mouse duct epithelium via Nkg2d and drive tissue-specific injury in experimental biliary atresia. J Clin Invest. 2009 Aug;119(8):2281-90. Shanmukhappa K, Matte U, Degen JL, Bezerra JA. Plasmin-mediated proteolysis is required for hepatocyte growth factor activation during liver repair. J Biol Chem. 2009 May 8;284(19):12917-23. Erickson N, Mohanty SK, Shivakumar P, Sabla G, Chakraborty R, Bezerra JA. Temporal-spatial activation of apoptosis and epithelial injury in murine experimental biliary atresia. Hepatology. 2008 May;47(5):1567-77. Shivakumar P, Sabla G, Mohanty S, McNeal M, Ward R, Stringer K, Caldwell C, Chougnet C, Bezerra JA. Effector role of neonatal hepatic CD8+ lymphocytes in epithelial injury and autoimmunity in experimental biliary atresia. Gastroenterology. 2007 Jul;133(1):268-77. Liu C, Aronow BJ, Jegga AG, Wang N, Miethke A, Mourya R, Bezerra JA. Novel resequencing chip customized to diagnose mutations in patients with inherited syndromes of intrahepatic cholestasis. Gastroenterology. 2007 Jan;132(1):119-26. Campbell KM, Arya G, Ryckman FC, Alonso M, Tiao G, Balistreri WF, Bezerra JA. High prevalence of alpha-1-antitrypsin heterozygosity in children with chronic liver disease. J Pediatr Gastroenterol Nutr. 2007 Jan;44(1):99-103. Shanmukhappa K, Sabla GE, Degen JL, Bezerra JA. Urokinase-type plasminogen activator supports liver repair independent of its cellular receptor. BMC Gastroenterol. 2006 Nov 29;6:40.
Charles C. Caldwell, PhD
focuses his research around trauma, sepsis and inflammation.
Associate Professor, Division of Pediatric Surgery
BA: University of California, San Diego, CA.
PhD: San Diego State University, San Diego, CA.
Post-doctoral Studies: Laboratory of Immunology, NIAID, NIH
Jose A. Cancelas Perez, MD, PhD Division Director of Research, Hoxworth Blood Center
Division Director of Research, Hoxworth Blood Center
Deputy Director, Hoxworth Blood Center
Director, Research Flow Cytometry Core
Leader, Stem Cell Program
Medical Director of Cellular Therapies, Hoxworth Blood Center
Hematopoietic stem cell proliferation and differentiation
Visit the Cancelas Lab.
MD: Autonomous University of Madrid, Spain, 1989.
Residency: Hematology and Hematotherapy, University of Alcala de Henares, Madrid, Spain, 1993.
PhD: Faculty of Medicine, University of Alcala de Henares, Madrid, Spain, 1996.
Dumont LJ*, Cancelas JA*, Graminske S, Friedman KD, Vassallo RR, Whitley PH, Rugg N, Dumont DF, Herschel L, Siegal AH, Szczepiorkowski ZM, Fender L, Razatos A. In vitro and in vivo quality of leukocyte-reduced apheresis platelets stored in a new platelet additive solution. Transfusion. 2012. (*both authors contributed equally).
Prada CE, Jousma E, Rizvi TA, Wu J, Dunn RS, Mayes DA, Cancelas JA, Dombi E, Kim MO, West BL, Bollag G, Ratner N. Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol. 2013 Jan;125(1):159-68.
Dumont LJ, Cancelas J, Dumont DF, Siegel AH, Szczepiorkowski ZM, Rugg R, Pratt PG, Worsham DN, Hartman EL, Dunn SK, O’Leary M, Ransom JH, Michael RA, Macdonald VW. A randomized controlled trial evaluating recovery and survival of 6% dimethyl sulfoxide-frozen autologous platelets in healthy volunteers. Transfusion. 2013 Jan;53(1):128-37.
Taniguchi Ishikawa E, Cancelas JA. Lack of communication rusts and ages stem cells. Cell Cycle. 2012 Sep 1;11(17):3149-3150.
Geiger H, Pawar SA, Kerschen EJ, Nattamai KJ, Hernandez I, Liang HP, Fernández JA, Cancelas JA, Ryan MA, Kustikova O, Schambach A, Fu Q, Wang J, Fink LM, Petersen KU, Zhou D, Griffin JH, Baum C, Weiler H, Hauer-Jensen M. Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. Nat Med. 2012 Jul;18(7):1123-9.
Chang KH, Sanchez-Aguilera A, Shen S, Sengupta A, Madhu MN, Ficker AM, Dunn SK, Kuenzi AM, Anrett JL, Santho RA, Agirre X, Perentesis JP, Deininger MW, Zheng Y, Bustelo XR, Williams DA, Cancelas JA. Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation and survival. Blood. 2012 Jul 26;120(4):800-11.
Taniguchi Ishikawa E, Gonzalez-Nieto D, Ghiaur G, Dunn SK, Ficker AM, Murali B, Madhu M, Gutstein DE, Fishman GI, Barrio LC, Cancelas JA. Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. Proc Natl Acad Sci USA. 2012 Jun 5;109(23):9071-6.
Konstantinidis DG, Pushkaran S, Johnson JF, Cancelas JA, Manganaris S, Harris CE, Williams DA, Zheng Y, Kalfa TA. Signaling and cytoskeletal requirements in erythroblast enucleation. Blood. 2012 Jun 21;119(25):6118-27.
Gonzalez-Nieto D, Li L, Köhler A, Ghiaur G, Ishikawa E, Sengupta A, Madhu M, Arnett J, Santho R, Dunn S, Fishman G, Gutstein D, Civitelli R, Barrio L, Gunzer M, Cancelas J. Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors. Blood. 2012 May 31;119(22):5144-54.
Sengupta A, Ficker A, Dunn S, Madhu M, Cancelas JA. Bmi1 reprograms chronic myelogenous leukemia B-lymphoid progenitors to become B-ALL-initiating cells. Blood. 2012 Jan 12;119(2):494-502.
Progenitor Cell Biology Consortium Administrative Coordinating Center, NHLBI/ Subaward through Univ. Maryland. Co-Director. (Cincinnati Cell Char Core). Sep 2010 – Aug 2016. #U01 HL099997.
Rational Design of a Vav/Rac Inhibitor as a New Therapy for High-Risk B-ALL. Principal Investigator. Leukemia & Lymphoma Society of North America. Oct 2012 – Sep 2015.
Cincinnati Excellence in Molecular Hematology: Cell Analysis and Sorting Core, NIH/NIDDK. Co-investigator. (Flow Cytometry Core Co-PI). Sep 2010 – Jun 2015. #P30DK090971-01.
Rac GTPase Inhibition in Chronic Myelogenous Leukemia. Principal Investigator. National Institutes of Health. Apr 2009 – Feb 2014. #R01 HL 087159.
Improving Hematopoietic Stem Cell Mobilization by the EGFR inhibitor Erlotinib. Co-Principal Investigator with Hartmut Geiger. NIH/NHLBI. Feb 2011 – Jan 2013. #R43HL108403-01.
Connexin-43 in Bone Marrow Failure After Cancer-Related Chemotherapy. Principal Investigator. Heimlich Institute. Apr 2010 – Mar 2013.
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.
Associate Professor, UC Department of Pediatrics
Antigen-presenting cells; HIV research; ontogeny of immune responses
HIV/AIDS pathogenesis; immune dysfunction in aging; ontogeny of immune system
DPharm:Université Paris XI, Paris, France, 1980.
CES (French specialized degrees; clinical biologist): Immunology, Hematology, Bacteriology-Virology, Parasitology, 1984.
PhD: Université Paris V, 1991.
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.
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.
Jay L. Degen, PhD
Molecular genetics of plasminogen activation in development, hemostasis, and tumor progression; molecular genetics and biological role of plasminogen activation in development, hemostasis, wound repair, and disease
Jay L. Degen, PhD, is studying the regulation and biological roles of urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), the two mammalian enzymes that convert plasminogen to the active serine protease, plasmin.
The PA/plasmin system of proteases is of particular interest because of its apparent dual function in the lysis of vascular fibrin clots (fibrinolysis) and the degradation of extracellular matrix in tissue remodeling and cell migration events.
Over the last few years, Dr. Degen's lab has generated and characterized gene-targeted mouse lines with deficits in the factors that are the foundation of the coagulation and fibrinolytic cascades, including fibrinogen-, plasminogen-, plasminogen activator-, and plasminogen activator receptor-deficient mouse lines.
These unique experimental animals are being intensively analyzed with regard to a wide range of phenotypic properties, including hemostasis, wound healing, angiogenesis and tumor biology.
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.
Innate immune responses; obesity; NAFLD; preterm birth
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
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.
Marie-Dominique Filippi, PhD
I am particularly interested in dissecting the molecular mechanism of hematopoietic cell migration, including neutrophils and hematopoietic stem cells in physiological settings. Migration is a critical function of hematopoietic cell in which actin cytoskeleton reorganization plays a central role. Because hematopoietic cells are utilized for the therapy of multiple blood diseases and neutrophils are responsible for maintaining an immunocompetence status, understanding the molecular mechanism of normal hematopoietic cell functions is of potential therapeutic importance. The small RHO GTPase family, members of the Ras superfamily, including Rac, RHO and CDC42, play key roles in regulating many of these functions. During my post-doc in the laboratory of Dr David Williams, we have demonstrated that two highly related proteins, Rac1 and Rac2, of the small Rho GTPase family, have distinct functions in the control of hematopoietic cell functions. In particular in neutrophils, we have shown that both Rac1 and Rac2 regulate cell migration but with distinct mechanism (Gu and Filippi et al, Science 2003) both in vitro and in vivo. In addition to this work, we have dissected the sequence/determinant specificity of Rac2 versus Rac1 functions in neutrophils and demonstrated that Rac2 controls its functions, at least in part, by distinct subcellular distributions of these GTPases (Tao et al, Blood 2002, Filippi et al, Nat Immunol 2004), highlighting one important mechanism controlling cellular functions. My laboratory, in collaboration Dr. Yi Zheng, is now focused on determining the role of CDC42 and RhoA in neutrophil migration and in determining specifically the role of RhoA in hematopoietic stem cell migration and proliferation using gene targeted knock out mice for CDC42 and RhoA and their respective regulator CDC42GAP and 190RhoGAP. These studies will use in vitro and in vivo assays of cell migration as well as immunofluorescence microscopy to study cytoskeleton rearrangement associated with cell migration. The long term goal of these studies is to identify new molecular targets of potential therapeutic importance.
Visit the Filippi Lab.
Mulloy JC, Cancelas JA, Filippi MD, Kalfa TA, Guo F, Zheng Y. Rho GTPases in hematopoiesis and hemopathies. Blood. 2010 Feb 4;115(5):936-47. Szczur K, Zheng Y, Filippi MD. The small Rho GTPase Cdc42 regulates neutrophil polarity via CD11b integrin signaling. Blood. 2009 Nov 12;114(20):4527-37. Xu H, Eleswarapu S, Geiger H, Szczur K, Daria D, Zheng Y, Settleman J, Srour EF, Williams DA, Filippi MD. Loss of the Rho GTPase activating protein p190-B enhances hematopoietic stem cell engraftment potential. Blood. 2009 Oct 22;114(17):3557-66.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.
Monk KR, Wu J, Williams JP, Finney BA, Fitzgerald ME, Filippi MD, Ratner N. Mast cells can contribute to axon-glial dissociation and fibrosis in peripheral nerve. Neuron Glia Biol. 2007 Aug;3(3):233-44.
Daria D, Filippi MD, Knudsen ES, Faccio R, Li Z, Kalfa T, Geiger H. The retinoblastoma tumor suppressor is a critical intrinsic regulator for hematopoietic stem and progenitor cells under stress. Blood. 2008 Feb 15;111(4):1894-902. Uchida K, Beck DC, Yamamoto T, Berclaz PY, Abe S, Staudt MK, Carey BC, Filippi MD, Wert SE, Denson LA, Puchalski JT, Hauck DM, Trapnell BC. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N Engl J Med. 2007 Feb 8;356(6):567-79.Filippi MD, Szczur K, Harris CE, Berclaz PY. Rho GTPase Rac1 is critical for neutrophil migration into the lung. Blood. 2007 Feb 1;109(3):1257-64. Szczur K, Xu H, Atkinson S, Zheng Y, Filippi MD. Rho GTPase CDC42 regulates directionality and random movement via distinct MAPK pathways in neutrophils. Blood. 2006 Dec 15;108(13):4205-13.Wang L, Yang L, Filippi MD, Williams DA, Zheng Y. Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment. Blood. 2006 Jan 1;107(1):98-105.
Fred Finkelman, MD
is interested in the use of in vivo mouse models to study both basic immunology and disease pathogenesis. More specifically, he is trying to understand how cytokines and other immune mechanisms control intestinal worms infections; allergic, asthmatic, and anaphylactic diseases; as well as T cell memory.
Rheumatology; cytokine control of immune-mediated disorders and host protection against parasites, cytokine regulation of allergic disorders, cytokine regulation of lymphopoiesis; regulation of cytokine responses and mechanisms of lymphocyte activation and tolerance; anaphylaxis; transfusion-related acute lung injury
Khodoun MV, Strait R, Armstrong L, Yanase N, Finkelman FD. Identification of markers that distinguish IgE- from IgG-mediated anaphylaxis. Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12413-8.
Strait RT, Mahler A, Hogan S, Khodoun M, Shibuya A, Finkelman FD. Ingested allergens must be absorbed systemically to induce systemic anaphylaxis. J Allergy Clin Immunol. 2011 Apr;127(4):982-9.e1.
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 11;208(4):853-67.
Brandt EB, Munitz A, Orekov T, Mingler MK, McBride M, Finkelman FD, Rothenberg ME. Targeting IL-4/IL-13 signaling to alleviate oral allergen-induced diarrhea. J Allergy Clin Immunol. 2009 Jan;123(1):53-8.
Herbert Herbert DR, Orekov T, Roloson A, Ilies M, Perkins C, O'Brien W, Cederbaum S, Christianson DW, Zimmermann N, Rothenberg ME, Finkelman FD. Arginase I suppresses IL-12/IL-23p40-driven intestinal inflammation during acute schistosomiasis. J Immunol. 2010 Jun 1;184(11):6438-46.
DR, Yang JQ, Hogan SP, Groschwitz K, Khodoun M, Munitz A, Orekov T, Perkins C, Wang Q, Brombacher F, Urban JF Jr, Rothenberg ME, Finkelman FD. Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J Exp Med. 2009 Dec 21;206(13):2947-57.
Morris SC, Heidorn SM, Herbert DR, Perkins C, Hildeman DA, Khodoun MV, Finkelman FD. Endogenously produced IL-4 nonredundantly stimulates CD8+ T cell proliferation. J Immunol. 2009 Feb 1;182(3):1429-38. 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.Forbes EE, Groschwitz K, Abonia JP, Brandt EB, Cohen E, Blanchard C, Ahrens R, Seidu L, McKenzie A, Strait R, Finkelman FD, Foster PS, Matthaei KI, Rothenberg ME, Hogan SP. IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. J Exp Med. 2008 Apr 14;205(4):897-913. Phelan JD, Orekov T, Finkelman FD. Cutting edge: mechanism of enhancement of in vivo cytokine effects by anti-cytokine monoclonal antibodies. J Immunol. 2008 Jan 1;180(1):44-8.
Pathogenesis and prevention of anaphylaxis induced by ingested antigens. Veterans Association. National Institutes of Health. Apr 2008 - Mar 2012.
IgG isotype regulation of antibody-mediated disorders. Principal Investigator. National Institutes of Health. Oc 2009 - Aug 2012.
Alternative macrophage activation limits immunopathology. Co-principal Investigator. National Institutes of Health. Dec 2007 - Nov 2012.
Multidisciplinary clinical research center in Cincinnati Project 2 - Improved understanding of the biology and use of TNF inhibition in JIA. Co-principal Investigator. National Institutes of Health. Apr 2008 - Mar 2013.
Regulation of CD8+ T cell homeostasis by IL-4. Principal Investigator. National Institutes of Health. Oct 2008 - Dec 2013.
IL-13 associated eosinophil lung responses. Co-principal Investigator. National Institutes of Health. Jul 2009 - Jun 2014.
Matthew J. Flick, PhD
is working to understand how hemostatic factors in the blood that are responsible for clotting also drive inflammation in the context of infection and diseases such as arthritis and fatty liver disease.
Research Interests and Focus:
1. Activation of the coagulation system, including the central coagulation protease thrombin, is a prominent feature of both human rheumatoid arthritis and experimental inflammatory arthritis. The long-term goal of Dr. Flick's research program is to determine how thrombin drives inflammatory joint disease. The proposed work will fill significant gaps in the understanding of the interplay between the thrombin- fibrinogen axis and arthritic disease, and may provide the proof-of-principle for the use of novel "customized" thrombin mutants with selected substrate specificity to treat arthritis.
2. The pervasive gram-positive bacteria Staphylococcus aureus is a common pathogen that is the causative agent for a wide spectrum of diseases including skin infections, pneumonia, bacteremia, toxic-shock syndrome and sepsis. Notably, this pathogen has evolved and maintained a number of proteins that directly engage the host hemostatic system, including factors that directly interact with the host coagulation factor fibrinogen. The long-term goal of his research program is to understand how bacterial derived proteins interact with host factors to promote bacterial virulence in the context of blood-born infections. This work will provide novel insight into the molecular pathways by which S. aureus invades and disseminates within host tissues and may shed light into novel strategies for eliminating this potentially devastating infectious agent.
3. Obesity is a worldwide epidemic linked to numerous disease sequelae, including non-alcoholic fatty liver disease (NAFLD). This spectrum disorder can progress from the simple accumulation of triglycerides within hepatocytes (i.e., steatosis), to inflammatory steatohepatitis, to organ failure secondary to irreversible liver fibrosis and cirrhosis. Dysregulation of the coagulation system has been documented in both patients with fatty liver disease and animal models of NAFLD, but any contribution to disease progression has remained largely undefined. Using a murine model of high fat diet (HFD)-induced NAFLD, they are testing the hypothesis that thrombin activity and fibrin deposition drive local inflammatory events promoting the progression of steatosis and steatohepatitis. Comparative studies of wild-type mice with genetically imposed deficiencies or functional alterations in prothrombin, fibrinogen and other associated coagulation factor components suggests that the thrombin-fibrinogen axis influences NAFLD pathogenesis by controlling local inflammatory processes that drive steatosis and by an unanticipated and unknown mechanism tying fibrin(ogen) to HFD-induced weight gain/obesity. Their research has far-reaching implications not only for the treatment and prevention of fatty liver disease, but also for all the downstream sequelae of obesity and even the development of diet-mediated weight gain itself.
BS: Xavier University, Cincinnati, OH.
PhD: Purdue University, West Lafayette, IN.
Post-doctoral Fellow: Cincinnati Children’s Hospital and Medical Center, Division of Developmental Biology, Cincinnati, OH.
Flick MJ, Du X, Prasad JM, Raghu H, Palumbo JS, Smeds E, Höök M, Degen JL. Genetic elimination of the binding motif on fibrinogen for the S. aureus virulence factor ClfA improves host survival in septicemia. Blood. 2013 Jan 8.
Sullivan BP, Kassel KM, Jone A, Flick MJ, Luyendyk JP. Fibrin(ogen)-independent role of plasminogen activators in acetaminophen-induced liver injury. American Journal of Pathology. 2012;180(6):2321-2329.
Qi X, Flick MJ, Frederick M, Chu Z, Mason R, DeLay M, Thornton S. Saposin C Coupled Lipid Nanovesicles Specifically Target Arthritic Mouse Joints for Optical Imaging of Disease Severity. PLoSOne. 2012;7(3):e33966.
Vidal B, Ardite E, Suelves M, Ruiz-Bonilla V, Janué A, Flick MJ, Degen JL, Serrano AL, Muñoz-Cánoves P. Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αMβ2 leukocyte integrin receptor. Human Molecular Genetics. 2012;21(9):1989-2004.
Horowitz NA, Blevins EA, Miller WM, Perry AR, Talmage KE, Mullins ES, Flick MJ, Queiroz KC, Shi K, Spek CA, Conway EM, Monia BP, Weiler H, Degen JL, Palumbo JS. Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain. Blood. 2011 Jul 25.
Raghu H, Flick MJ. Targeting the Coagulation Factor Fibrinogen for Arthritis Therapy. Curr Pharm Biotechnol. 2011 Mar 14.
Flick MJ, Chauhan AK, Frederick M, Talmage KE, Kombrinck KW, Miller W, Mullins ES, Palumbo JS, Zheng X, Esmon NL, Esmon CT, Thornton S, Becker A, Pelc LA, Di Cera E, Wagner DD, Degen JL. The development of inflammatory joint disease is attenuated in mice expressing the anticoagulant prothrombin mutant W215A/E217A. Blood. 2011 Jun 9;117(23):6326-37.
Steinbrecher KA, Horowitz NA, Blevins EA, Barney KA, Shaw MA, Harmel-Laws E, Finkelman FD, Flick MJ, Pinkerton MD, Talmage KE, Kombrinck KW, Witte DP, Palumbo JS. Colitis-associated cancer is dependent on the interplay between the hemostatic and inflammatory systems and supported by integrin alpha(M)beta(2) engagement of fibrinogen. Cancer Res. 2010 Apr 1;70(7):2634-43.
Mullins ES, Kombrinck KW, Talmage KE, Shaw MA, Witte DP, Ullman JM, Degen SJ, Sun W, Flick MJ, Degen JL. Genetic elimination of prothrombin in adult mice is not compatible with survival and results in spontaneous hemorrhagic events in both heart and brain. Blood. 2009 Jan 15;113(3):696-704.
Mechanisms linking the hemostatic protease thrombin to arthritic disease. Principal Investigator. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Jul 2009 - Jun 2014. #R01 AR056990.
Thrombin-mediated proteolysis in neuroinflammatory disease. Co-investigator. National Heart, Lung, and Blood Institute. Jul 2009 - Jun 2014. #R01 HL096126.
Coagulation factors and the pathogenesis of non-alcoholic fatty liver disease. Principle Investigator. Cincinnati Children’s Hospital Digestive Health Center (DHC) Pilot and Feasibility Grant. Jun 2012 - May 2013. P30 DK078392.
NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases Research. Director. Cincinnati Rheumatic Diseases Core Center. Aug 2011 - Jun 2016. 2P30 AR47363.
Hemostatic factors and sickle cell disease. Co-investigator. NIH. Dec 2011 - Nov 2016. R01 HLI12603.
Analysis of Staphylococcus Host Interactions. Co-investigator. NIH. Sep 2010 - Aug 2015. R01 AI020662.
H. Leighton Grimes, PhD Director, Cancer Pathology Program of the Division of Experimental Hematology and the Division of Pathology
Director, Cancer Pathology Program of the Division of Experimental Hematology and the Division of Pathology
Co-Leader, Program in Hematologic Malignancies of Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute
Transcriptional control of hematopoiesis and cancer.
Visit the Grimes Lab.
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.
Phelan JD, Saba AI, Olsson A, Zeng H, Kosan C, Messer MS, Hildeman D, Aronow B, Möröy T, Grimes HL. Growth factor independent-1 maintains Notch1-dependent transcriptional programming of lymphoid precursors. PLoS Genetics. 2013. In press.
Khandanpour C*, Phelan JD*, Vassen L, Schutte J, Chen R, Horman SR, Gaudreau MC, Krongold J, Zhu J, Paul WE, Duhrsen U, Gottgens B, Grimes HL# Moroy T#. Growth factor independence 1 (Gfi1) antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia. Cancer Cell. 2013 Feb 11;23(2):200-14. * equal first author, # shared corresponding author.
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.
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.
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.
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.
Zarebski1 A, Velu CS, Baktula AM, Bourdeau T, Horman SR, Basu S, Bertolone SJ, Horwitz M, Hildeman DA, Trent JO, Grimes HL. The Human Severe Congenital Neutropenia-Associated Gfi1N382S Mutant Blocks Murine Granulopoiesis Through CSF1. Immunity. 2008 Mar;28(3):370-80.
Person RE, Li FQ, Duan Z, Benson KF, Wechsler J, Papadaki HA, Eliopoulos G, Kaufman C, Bertolone SJ, Nakamoto B, Papayannopoulou T, Grimes HL, Horwitz M. Gfi1 Proto-Oncogene Mutation Causes Human Neutropenia and Targets Neutrophil Elastase. Nature Genetics. 2003 March 1;30: 295 - 300.
John B. Harley, MD, PhD Director, Rheumatology
is a rheumatologist and biochemist with special clinical and research interests in the genetic etiology of inflammatory diseases. His experimental focus is the many genetic effects and environmental causes of systemic lupus erythematosus (SLE) and related inflammatory diseases. Through this work, nearly 50 genes are known and Epstein Barr virus has been identified to trigger the systemic autoimmunity of lupus. Dr. Harley also builds infrastructure with which to do high throughput genotyping, expression analysis, and epigenetics, which he makes available to his colleagues from around the world. In recent experiments, Dr. Harley organized the logistics of managing >18,000 subjects at >30,000 genetic markers, 3200 subjects at 1.2 million markers, and 10,000 subjects at 196,000 markers. Dr. Harley is committed to all of the steps between association detection through replication and toward identifying the possible functional genetic variants and to pursuing their biology.
Cobb BL, Fei Y, Jonsson R, Bolstad AI, Brun JG, Rischmueller M, Lester SE, Witte T, Illei G, Brennan M, Bowman S, Moser KL, Harley JB, Sawalha AH. Genetic association between methyl-CpG binding protein 2 (MECP2) and primary Sjögren’s syndrome. Ann Rheum Dis. 2010; 69(9): 1731-2.Kim-Howard X, Maiti AK, Anaya J-M, Bruner GR, Brown E, Merrill JT, Edberg JC, Petri MA, Reveille JD, Ramsey-Goldman R, Alarcon GS, Vyse TJ, Gilkeson G, Kimberly RP, James JA, Guthridge JM, Harley JB, Nath SK. ITGAM coding variant (rs1143679) influences the risk of renal disease, discoid rash, and immunologic manifestations in lupus patients with European ancestry. Ann Rheum Dis. 2010.Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J, Berdasco M, Fraga MF, O'Hanlon TP, Rider LG, Jacinto FV, Lopez-Longo FJ, Dopazo J, Forn M, Peinado MA, Carreno L, Sawalha AH, Harley JB, Siebert R, Esteller M, Miller FW, Ballestar E. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res. 2010; 20(2):170-179. Harley JB, James JA. Everyone comes from somewhere: systemic lupus erythematosus and Epstein-Barr virus, induction of host interferon (INF) and humoral anti-EBNA1 immunity. Arthritis Rheum. 2010.\Bronson PG, Komorowski LK, Ramsay PP, May SL, Noble J, Lane JA, Thomson G, Claas FH, Seldin MF, Kelly JA, Harley JB, Moser KL, Gaffney PM, Behrens T, Criswell LA, Barcellos LF. Analysis of maternal-offspring HLA compatibility, parent-of-origin and noninherited effects for HLA-DRB1 in systemic lupus erythematosus. Arthritis Rheum. 2010.Heinlen LD, McClain MT, Ritterhouse LL, Bruner BF, Edgerton CC, Keith MP, James JA, Harley JB. 60kD Ro and nRNP A frequently initiate human lupus autoimmunity. PLoS ONE. 2010 5(3):e9599.
Sammalisto S, Hiekkalinna T, Schwander K, Kardia S, Weder AB, Rodriquez BL, Doria A, Kelly JA, Bruner GR, Harley JB, Redline S, Larkin EK, Patel SR, Ewan AJ, Weber JL, Perola M, Peltonen L. Genome-wide linkage screen for stature and body mass index in 3.032 families: evidence for sex-and population-specific genetic effects. Eur J Hum Genet. 2009 Jan 1;17(2):258-266.
Poole BD, Templeton AK, Guthridge JM, Brown EJ, Harley JB, James JA. Aberrant Epstein-Barr viral infection in systemic lupus erythematosus. Autoimmun Rev. 2009 Feb;8(4):337-42. Poole BD, Schneider RI, Guthridge JM, Velte CA, Reichlin M, Harley JB, James JA. Early targets of nuclear RNP humoral autoimmunity in human systemic lupus erythematosus. Arthritis Rheum. 2009 Feb 26; 60(3):848-859. Han S, Kim-Howard X, Deshmukh H, Kamatani Y, Viswanathan P, Guthridge JM, Thomas K, Kaufman KM, Ojwang J, Rojas-Villarraga A, Baca V, Orozco L, Rhodes B, Choi CB, Gregersen PK, Merrill JT, James JA, Gaffney PM, Moser KL, Jacob CO, Kimberly RP, Harley JB, Bae SC, Anaya JM, Alarcon-Riquelme ME, Matsuda K, Vyse TJ, Nath SK. Evaluation of imputation-based association in and around the Integrin-α-M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE). Hum Mol Genet. 2009 Mar 15;18(6):1171-80.
Molecular & Immunologic Analysis of the Pathobiology of Human Anthrax. Co-Principal Investigator. National Institute of Allergy and Infectious Diseases. Sep 2009 - Aug 2014. #AI062629-06.Genomics of Lupus. Principal Investigator. Aug 2009 - Jul 2014. #1 P01 AI083194-01.Oklahoma Autoimmunity Center of Excellence Project 2. Co-investigator. National Institute of Allergy and Infectious Diseases. May 2009 - Apr 2014. #1 U19 AI082714-01.
Genome-Wide Association Study in African-Americans with Systemic Lupus Erythematosus. Principal Investigator. Department of Defense. Sep 2010- Aug 2013. #PR094002.Genomics of Lupus Associations in the Hispanic 12q24 Linkage. Principal Investigator. National Institutes of Health. Jun 2008 - Mar 2013. #5 P01 AR049084-07.Lupus Association with Signal Transducer and Activator of Transcription 4. Principal Investigator. US Department of Veterans Affairs. Apr 2008 - Mar 2012.
Genetic Linkage in Lupus. Principal Investigator. National Institute of Allergy and Infectious Diseases. Feb 2010 - Jan 2012. #3 R37 AI024717-21S1.
Andrew Herr, PhD
Biophysical and crystallographic studies of cellular adhesion and receptor signaling
Gurjit Khurana Hershey, MD, PhD Director, Division of Asthma Research
is the principal investigator of a federally funded Asthma and Allergic Diseases Cooperative Research Center which supports, in part, the asthma and allergy-based Greater Cincinnati Pediatric Clinic Repository. She also focuses on elucidating the genetic and environmental factors that contribute to the development of asthma and eczema.
Visit the Khurana Hershey Lab
Director, Division of Asthma Research
Co-Director, Office of Pediatric Clinical Fellowships
Asthma; allergic rhinitis; food allergy; urticaria
Genetics of allergy and asthma; cytokines; signaling pathways
Gurjit Khurana Hershey, MD, PhD, received a BS degree from the University of Iowa, and MD and PhD degrees from Washington University School of Medicine. After completing pediatric residency and an allergy/immunology Fellowship at St. Louis Children’s Hospital, Dr. Khurana Hershey joined the faculty at Cincinnati Children’s Hospital Medical Center. She now directs the Division of Asthma Research at Cincinnati Children’s Hospital Medical Center and is the director of the Medical Scientist Training Program at the University of Cincinnati College of Medicine.
In addition to her clinical duties, Dr. Khurana Hershey directs an NIH-funded research program focused on the genetics and genomics of allergic inflammation with a focus on cytokines and signal transduction. Her research has been continuously funded for over fifteen years. She is the principal investigator of an NIH-funded Asthma and Allergic Diseases Cooperative Research Center (AADCRC), and is also the PI of the Inner City Asthma Consortium, an NIH funded subcontract. She is the PI of the UC T32 MSTP training grant. In addition to her research contributions, she is an outstanding clinician and teacher/mentor. Several of her trainees now hold academic faculty positions. She is the recipient of the 2013 Cincinnati Children’s Educational Achievement Award.
Dr. Khurana Hershey is a fellow of the American Pediatric Society and the American Academy of Allergy, Asthma and Immunology. She serves on the Executive Council of the American Academy of Asthma, Allergy and Immunology Program Committee, is the Chair of the Grant Review Committee and appointed Vice Chair of the Basic and Immunology Interest Section. She is a member of the Editorial Board of the Journal of Allergy and Clinical Immunology. She was recently named One of the Five Leading Women in Healthcare in the Greater Cincinnati Metropolitan Area, and Outstanding Woman at Cincinnati Children’s Hospital Medical Center.
BS: University of Iowa, Iowa City, IA, 1985.PhD: Washington University School of Medicine, St. Louis, MO, 1990.
MD: Washington University School of Medicine, St. Louis, MO, 1992. Residency: St. Louis Children's Hospital, St. Louis, MO, 1992-1995. Fellowship: St. Louis Children's Hospital, St. Louis, MO, 1995-1997.
Board Certification: American Board of Pediatrics, 2009 - Present.
Board Certification: American Board of Allergy and Immunology, 2008 - Present.
Brandt EB, Gibson AM, Bass S, Khurana Hershey GK. Exacerbation of Allergen-Induced Eczema in TLR4- and TRIF-Deficient Mice. J Immunol. 2013 Oct 1;191(7):3519-25.
Brandt EB, Kovacic MB, Lee GB, Gibson AM, Acciani TH, Le Cras TD, Budelsky AL, Khurana Hershey, GK. Diesel exhaust particle induction of IL17A contributes to severe asthma. J Allergy Clin Immunol. Sep. 2013. Epub ahead of print.
Mintz-Cole RA, Brandt EB, Bass SA, Gibson AM, Reponen T, Khurana Hershey GK. Surface availability of beta-glucans is critical determinant of host immune response to Cladosporium cladosporioides. J Allergy Clin Immunol. 2013 Jul;132(1):159-69.
Mintz-Cole RA, Gibson AM, Bass SA, Budelsky AL, Reponen T, Khurana Hershey GK. Dectin-1 and IL-17A Suppress Murine Asthma induced by Aspergillus Versicolor but not Cladosporium Cladosporioides due to Differences in β-glucan Surface Exposure. J Immunol. 2012 Oct 1;189(7):3609-17.
Kovacic MB, Myers JM, Wang N, Martin L, Lindsey M, Ericksen MB, He H, Patterson TL, Baye TM, Torgerson D, Roth, LA, Gupta J, Sivaprasad U, Gibson AM, Tsoras AM, Hu D, Eng C, Chapela R, Rodriguez-Santana JR, Rodríguez-Cintrón W, Avila PC, Beckman K, Seibold MA, Gignoux C, Musaad SM, Chen W, Burchard EG, Hershey GK. Identification of KIF3A as a novel candidate gene for childhood asthma using RNA expression and population allelic frequencies differences. PLoS One. 2011;6(8):e23714.
Sivaprasad U, Askew DJ, Ericksen MB, Gibson AM, Stier MT, Bass SA, Daines MO, Chakir J, Stringer KF, Wert SE, Whitsett JA, Le Cras TD, Wills-Karp M, Silverman GA, Khurana Hershey GK. A Non-redundant Role for Serpinb3a in the Induction of Mucous Production in Asthma. J Allergy Clin Immunol. 2011 Jan;127(1):254-61.
Baye TM, Martin LJ, Hershey GK. Application of Genetic/Genomic Approaches to Allergic Disorders. J Allergy Clin Immunol. 2010 Sep;126(3):425-36;quiz 437-8.
Chen W, Sivaprasad U, Tabata Y, Gibson AM, Stier MT, Finkelman FD, Hershey GK. IL-13 Receptor Alpha 2 Membrane and Soluble Isoforms Differ in Human and Mouse. J Immunol. 2009 Dec 15;183(12):7870-6.
Schroer KT, Biagini JM, Ryan PH, LeMasters GK, Bernstein DI, Villareal M, Lockey JE, Reponen T, Grinshpun S, Khurana Hershey GK. Associations Between multiple environmental exposures and Glutathione S-transferase P1 on Persistent Wheezing in a Birth Cohort. J Pediatr. 2009 Mar;154(3)401-8.
Daines MO, Chen W, Tabata Y, Walker BA, Gibson AM, Masino JA, Warrier MR, Daines CL, Wenzel SE, Hershey GK. Allergen-dependent solubilization of interleukin-13 receptor alpha-2 reveals a novel mechanism to regulate allergy. J Allergy Clin Immunol. 2007 Feb:119(2): 375-83.
David A. Hildeman, PhD Director, Immunobiology Graduate Program
Director, Immunobiology Graduate Program
T cells; autoimmunity; sex differences in immune responses; apoptosis
Our 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.
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.
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.
Innate-adaptive connection; mechanisms underlying NK cell and CD8+ T cell development; cytolytic effector function; safer vaccine approaches
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.
Simon P. Hogan, PhD Director of Research, Division of Allergy and Immunology
Director of Research, Division of Allergy and Immunology
Director of Admissions, Immunobiology Graduate Program
Food allergies and anaphylaxis; inflammatory bowel diseases (IBD); innate immunity; gastrointestinal immunity and function; cystic fibrosis (CF)
Visit the Hogan Lab.
Waddell A, Ahrens R, Tsai YT, Sherrill JD, Denson LA, Steinbrecher KA, Hogan SP. Intestinal CCL11 and eosinophilic inflammation is regulated by myeloid cell-specific RelA/p65 in mice. J Immunol. 2013 May 1;190(9):4773-85.
Ahrens R, Osterfeld H, Wu D, Arumugam M, Groschwitz K, Strait RA, Finkelman FD, Hogan SP. Intestinal mast cell levels influence severity of oral antigen-induced anaphylaxis. Am J Pathol. 2012 Apr;180(4):1535-46.
Beichler A, Ahrens R, Steinbrecher K, Rothenberg ME, Munitz A, Denson L, Hogan SP. Colonic eosinophilic inflammation in experimental colitis is mediated by Ly6C+ CCR2+ inflammatory monocyte-derived CCL11. J Immunol. 2011 May 15;186(10):5993-6003.
Arumugam M, Ahrens R, Osterfeld H, Kottyan LC, Shang X, Maclennan JA, Zimmermann N, Zheng Y, Finkelman FD, Hogan SP. Increased susceptibility of 129SvEvBrd mice to IgE-Mast cell mediated anaphylaxis. BMC Immunol. 2011 Feb 3;12:14.
Wu D, Ahrens R, Osterfeld H, Noah TK, Groschwitz K, Foster PS, Steinbrecher KA, Rothenberg ME, Shroyer NF, Matthaei KI, Finkelman FD, Hogan SP. Interleukin-13 (IL-13)/IL-13 receptor alpha1 (IL-13Ralpha1) signaling regulates intestinal epithelial cystic fibrosis transmembrane conductance regulator channel-dependent Cl- secretion. Journal of Biological Chemistry. 2011;286(15), 13357-13369.
Osterfeld H, Ahrens R, Strait R, Rothenberg ME, Finkelman FD, Renauld JC, Hogan SP. Divergent roles for the IL9/IL9R-pathway in systemic antigen- and oral antigen-induced anaphylaxis. J Allergy Clin Immunol. 2010;125: 469-476.
Munitz A, Cole ET, Waddell A, Groschwitz K, Ahrens R, Steinbrecher K, Willson T, Han X, Denson L, Rothenberg ME, Hogan SP. Paired immunoglobulin-like receptor B (PIR-B) negatively regulates macrophage activation in experimental colitis. Gastroenterology. 2010;139(2), 530-541.
Groschwitz K, Ahrens R, Osterfeld H, Gurish MF, Abrink M, Finkelman F, Pejler G, Hogan SP. Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(52), 22381-22386.
Ahrens R, Waddell A, Seidu L, Blanchard, C, Carey R, Forbes E, Lampinen M, Willson T, Cohen E, Stringer K, Ballard E, Munitz A, Xu H, Lee N, Lee JJ, Rothenberg ME, Denson L, Hogan SP. Intestinal macrophage/epithelial cell-derived CCL11/eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis. The Journal of Immunology. 2008;181(10), 7390-7399.
Forbes EE, Groschwitz K, Abonia JP, Brandt EB, Cohen E, Blanchard C, Ahrens R, Seidu L, McKenzie A, Strait R, Finkelman FD, Foster PS, Matthaei KI, Rothenberg ME, Hogan SP. IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. The Journal of Experimental Medicine. 2008;205(4), 897-913.
MiR-375 regulation of CFTR expression and Cl- secretory function. Principal Investigator. Cystic Fibrosis Foundation. Jul 2012-Jun 2014.
Eosinophil:M2 Macrophage:CCL11 Axis in Experimental Colitis and Pediatric Corticosteroid Resistant UC. Principal Investigator. National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK). Apr 2012-Mar 2016.
Epithelial Genes in Allergic Inflammation. Project 2 – Collaborating Investigator. National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAIDS). Sep 2006-Aug 2016.
Interleukin-9 in Experimental Intestinal Anaphylaxis. Principal Investigator. National Institutes of Health/ National Institute of Allergy and Infectious Diseases/ National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIAIDS/NIDDK). Dec 2007-Nov 2013.
Margaret K. Hostetter, MD Director, Infectious Diseases
studies the pathogenesis of bloodstream infections caused by the yeast Candida albicans. Her work has highlighted the role of C. albicans in biofilms, activation of human T cells, and evasion of innate immune mechanisms. Her clinical research is focused on the medical evaluation of internationally adopted children.
Director, Infectious Diseases
Bacterial and fungal infections; medical evaluation of internationally adopted children
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.
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, Sette A . 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.
Michael B. Jordan, MD
Histiocytic disorders: HLH and LCH
Better understanding histiocytic disorders and developing novel therapies for them; regulation of the immune response; immunotherapy of cancer
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.
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.
Theodosia A. Kalfa, MD, PhD
focuses on the study of intracellular signals in erythropoiesis and mature red blood cells, specifically the signals conducted by Rho GTPases regulating terminal erythroid maturation and enucleation. Her lab also studies the role of Rac GTPases in generation of reactive oxygen species (ROS) within red blood cells from patients and animal models with sickle-cell disease along with the signaling mechanisms and consequences of increased ROS in sickle cells.
Visit the Kalfa Lab.
Signaling in erythrocytes; erythropoiesis; Sickle Cell disease; reactive oxygen species
George A, Pushkaran S, Konstantinidis DG, Koochaki S, Malik P, Mohandas N, Zheng Y, Joiner CH, Kalfa TA. Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease. Blood. Epub ahead of print. 2013.
Konstantinidis DG, Pushkaran S, Johnson JF, Cancelas JA, Manganaris S, Harris CE, Williams DA, Zheng Y, Kalfa TA. Signaling and cytoskeletal requirements in erythroblast enucleation. Blood. 2012 Jun 21;119(25):6118-27.
Hammill AM, Risinger MA, Joiner CH, Keddache M, Kalfa TA. Compound heterozygosity for two novel mutations in the erythrocyte protein 4.2 gene causing spherocytosis in a Caucasian patient. Br J Haematol. 2011 Jan 31.
Kalfa TA. Anchoring at an island to relieve stress. Blood. 2011 Jan 20;117(3):748-9.
Mizukawa B, George A, Pushkaran S, Weckbach L, Kalinyak K, Heubi JE, Kalfa TA. Cooperating G6PD mutations associated with severe neonatal hyperbilirubinemia and cholestasis. Pediatr Blood Cancer. 2010 Oct 14.
Konstantinidis DG, George A, Kalfa TA. Rac GTPases in erythroid biology. Transfus Clin Biol. 2010 Sep;17(3):126-30.
Kalfa TA, Pushkaran S, Zhang X, Johnson JF, Pan D, Daria D, Geiger H, Cancelas JA, Williams DA, Zheng Y. Rac1 and Rac2 GTPases are necessary for early erythropoietic expansion in the bone marrow but not in the spleen. Haematologica. 2010 Jan;95(1):27-35.
Mulloy JC, Cancelas JA, Filippi MD, Kalfa TA, Guo F, Zheng Y. Rho GTPases in hematopoiesis and hemopathies. Blood. 2010 Feb 4;115(5):936-47.
Wang D, Zhang W, Kalfa TA, Grabowski G, Davies S, Malik P, Pan D. Reprogramming erythroid cells for lysosomal enzyme production leads to visceral and CNS cross-correction in mice with Hurler syndrome. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19958-63.
Daria D, Filippi MD, Knudsen ES, Faccio R, Li Z, Kalfa T, Geiger H. The retinoblastoma tumor suppressor is a critical intrinsic regulator for hematopoietic stem and progenitor cells under stress. Blood. 2008 Feb 15;111(4):1894-902.
Genetic Manipulation of Red Cell Volume Regulation. National Heart, Lung, and Blood Institute. Apr 2008 - Mar 2013. #U54 HL070871.
Rho GTPases in Terminal Erythroid Maturation. Principal Investigator. NIH/NHLBI. Sep 2012 - Jun 2016. #1R01HL116352.
TCD with Transfusions Changing to Hydroxyurea. Co-investigator. NIH/Baylor. Aug 2009 - Jul 2014. #R01HL095647.
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.
T cells; MHC, beta cell death; islet antigens
Immunology, autoimmunity, type 1 diabetes
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.
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.
Ashish R. Kumar, MD, PhD
Childhood cancer and blood disorders; immune deficiency
Leukemia biology; cancer biology
Visit the Kumar Lab.
Dr. Kumar received his medical degree from L.T.M. Medical College, Mumbai, India, his PhD in Anatomy and Cell Biology from the University of Iowa, Pediatric residency training at the Mayo Clinic and fellowship in Pediatric Hematology / Oncology / BMT at the University of Minnesota. He was appointed to the faculty of the University of Minnesota in the Department of Pediatrics where he was a member of the programs in Pediatric Leukemia and Global Pediatrics. As a faculty of the Masonic Cancer Center, he was also part of the Genetic Mechanisms of Cancer research program. Dr. Kumar’s laboratory is engaged in researching the biology of infant leukemia. Discoveries made in his laboratory have significantly enhanced the current understanding of leukemia.
Kumar AR, Yao Q, Li Q, Sam TA, Kersey JH. t(4;11) leukemias display addiction to MLL-AF4 but not to AF4-MLL. Leuk Res. 2011 Mar;35(3):305-9.
Kumar AR, Sarver AL, Wu B, Kersey JH. Meis1 maintains stemness signature in MLL-AF9 leukemia. Blood. 2010 Apr 29;115(17):3642-3.
Burke MJ, Cao Q, Trotz B, Weigel B, Kumar A, Smith A, Verneris MR. Allogeneic hematopoietic cell transplantation (allogeneic HCT) for treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Pediatr Blood Cancer. 2009 Dec 15;53(7):1289-94.Kumar AR, Li Q, Hudson WA, Chen W, Yao Q, Sam TN, Wu B, Lund EA, Kowal BJ and Kersey JH. A role for MEIS1 in MLL-fusion gene leukemia. Blood. 2009 Feb 19; 113(8):1756-8. Chen W*, Kumar AR*, Hudson WA, Li Q, Wu B, Staggs RA, Lund EA, Sam TN and Kersey JH. Malignant transformation initiated by Mll-AF9: Gene dosage and critical target cells. Cancer Cell. 2008 May; 13: 432-440. *Co-first authors. Kris Ann P. Schultz, MD, Joseph P. Neglia, MD, MPH, Angela R. Smith, MD, Hans D. Ochs, MD, Dr. med., Troy R. Torgerson, MD, PhD, and Ashish Kumar, MD, PhD. Familial Hemophagocytic Lymphohistiocytosis in Two Brothers With X-Linked Agammaglobulinemia. Pediatric Blood and Cancer 2008; 51:293–295. White JG, Kumar AR, Hogan MJ. Gray Platelet Syndrome in a Somalian Family. Platelets. 2006 Dec; 17:519-527. Mehta PA, Davies SM, Kumar A, Devidas M, Lee S, Zamzow T, Elliott J, Villanueva J, Pullen J, Zewge Y, and Filipovich A; Children’s Oncology Group. Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Leukemia. 2006 Sep; 20; 1539-1541. Chen W, Li Q, Hudson WA, Kumar A, Kirchhof N, Kersey JH. A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematological malignancy. Blood. 2006 Jul 15; 108:669-677.
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.
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.
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.
Punam Malik, MD Director, Comprehensive Sickle Cell Program
works to correct the gene responsible for sickle cell anemia. One of our lab’s major projects uses gene therapy to treat sickle cell disease. His lab is also interested in gene therapy for other diseases. He has developed various methods for delivering corrective genes to cells, improving methods for gene therapy in general.
Director, Comprehensive Sickle Cell Program
Director, Translational Trials Development and Support Laboratory
Program Leader, Molecular and Gene Therapy Program
Arumugam P, Malik P. Genetic therapy for beta-thalassemia: from the bench to the bedside. Hematology Am Soc Hematol Educ Program. 2010;2010:445-50.
Perumbeti A, Malik P. Therapy for beta-globinopathies: a brief review and determinants for successful and safe correction. Ann N Y Acad Sci. 2010 Aug;1202:36-44. Review.
Perumbeti A, Malik P. Genetic correction of sickle cell anemia and beta-thalassemia: progress and new perspective. Scientific World Journal. 2010 Apr 13;10:644-54. Review.
Sundaram N, Tailor A, Mendelsohn L, Wansapura J, Wang X, Higashimoto T, Pauciulo MW, Gottliebson W, Kalra VK, Nichols WC, Kato GJ, Malik P. High levels of placenta growth factor in sickle cell disease promote pulmonary hypertension. Blood. 2010 Jul 8;116(1):109-12.
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.
Arumugam PI, Higashimoto T, Urbinati F, Modlich U, Nestheide S, Xia P, Fox C, Corsinotti A, Baum C, Malik P. Genotoxic potential of lineage-specific lentivirus vectors carrying the beta-globin locus control region. Mol Ther. 2009 Nov;17(11):1929-37.
Perumbeti A, Higashimoto T, Urbinati F, Franco R, Meiselman HJ, Witte D, Malik P. A novel human gamma-globin gene vector for genetic correction of sickle cell anemia in a humanized sickle mouse model: critical determinants for successful correction. Blood. 2009 Aug 6;114(6):1174-85.
Urbinati F, Arumugam P, Higashimoto T, Perumbeti A, Mitts K, Xia P, Malik P. Mechanism of reduction in titers from lentivirus vectors carrying large inserts in the 3'LTR. Mol Ther. 2009 Sep;17(9):1527-36.
Williams JP, Wu J, Johansson G, Rizvi TA, Miller SC, Geiger H, Malik P, Li W, Mukouyama YS, Cancelas JA, Ratner N. Nf1 mutation expands an EGFR-dependent peripheral nerve progenitor that confers neurofibroma tumorigenic potential. Cell Stem Cell. 2008 Dec 4;3(6):658-69.
Alexander G. Miethke, MD
is interested in susceptibility factors for neonatal liver injury, including biliary atresia. He focuses on the interaction between the maturing adaptive immune system and hepatic immune responses to infectious insults during the early neonatal period.
Pediatric liver disease including biliary atresia, inherited liver diseases, autoimmune hepatitis, and primary sclerosing cholangitis; gastrointestinal problems in children with bone marrow failure syndromes
Immune mediated liver injury, specifically the role of regulatory T cells in biliary atresia and primary sclerosing cholangitis; genetic basis for intrahepatic cholestasis in children; acute liver failure in infants with mitochondrial disorders
MD: Humboldt-University, Berlin, Germany, 2000.Residency: Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 2002-2004.Fellowship: Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 2005-2007.
Advanced Fellowship: Pediatric Transplant Hepatology, University of Cincinnati and Cincinnati Children's Hospital Medical Center, 2009.Certification: Pediatrics, 2005; Pediatric Gastroenterology 2009; Pediatric Transplant Hepatology, 2010.
Evason K, Bove KE, Finegold MJ, Knisely AS, Rhee S, Rosenthal P, Miethke AG, Karpen SJ, Ferrell LD, Kim GE. Morphologic findings in progressive familial intrahepatic cholestasis 2 (PFIC2): correlation with genetic and immunohistochemical studies. Am J Surg Pathol. 2011;35:687-96.
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.
Liu C, Aronow BJ, Jegga AG, Wang N, Miethke A, Mourya R, Bezerra JA. Novel resequencing chip customized to diagnose mutations in patients with inherited syndromes of intrahepatic cholestasis. Gastroenterology. 2007 Jan;132(1):119-26.
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Sean R. Moore, MS, MD
is interested in the vicious cycle of childhood diarrhea and malnutrition in developing countries, with a current focus on the mechanisms of a promising glutamine-based oral rehydration and nutrition therapy. Dr. Moore studies the signaling pathways by which alanyl-glutamine promotes gut homeostasis and also collaborates with colleagues on the epidemiology and impact of early childhood diarrhea and undernutrition in impoverished settings.
General gastroenterology; inflammatory bowel diseases
Diarrheal diseases; glutamine; global health