Immunobiology

Faculty Members

Marsha Wills-Karp, PhD,  Professor ; Division Director; Director of Immunobiology Graduate Program; Associate Dean for Basic Science and Special Projects - UCCOM

Fred Finkelman, MD,  Professor

H. Leighton Grimes, PhD,  Associate Professor ; Director Cancer Pathology Program

David A. Hildeman, PhD,  Assistant Professor

Michael B. Jordan, MD,  Assistant Professor

Jochen Mattner, MD,  Assistant Professor

Joint Appointment Faculty Members

Eman Al-Khadra, MD,  Assistant Professor

Critical Care Medicine

Amy Nathan, MD,  Assistant Professor

Neonatology and Pulmonary Biology

Kristen Page, PhD,  Associate Professor

Critical Care Medicine

Trainees

• Pulak Tripathi, PhD,  PGY-5, 
• Adora Lin, BS,  GS-5, 
• Vanessa Saunders, BS,  GS-5, 
• Marat Khodoun, PhD,  PGY-4, 
• Ian Lewkowich, PhD,  PGY-4, 
• Erin Zoller, BS,  GS-4, 
• Chinavenmeni Velu, PhD,  PGY-3, 
• James Phelan, BS,  GS-3, 
• Meghan Rojas, BS,  GS-3, 
• Stephane Lajoie, PhD,  PGY-2, 
• Sema Kurtulus, BS,  GS-2, 
• Aditya Chaubey, PhD,  PGY-1, 
• Yuzaburo Inoue, MD/PhD,  PGY-1, 
• Theodore Johnson, MD,  PGY-1, 
• Yusuke Suzuki, PhD,  PGY-1, 
• Robert Thacker, MD,  PGY-1, 
• Mark Webb, BS,  GS-1, 

Significant Accomplishments in FY08

Identification of Novel Allergen Receptor 

Determination of Mechanisms Underlying Severe Reactions to Peanuts

Association of Novel Mutations in GFi1 with Severe Congenital Neutropenia

Significant Publications in FY08

Zarebski A, Velu CS, Baktula AM,  Bourdeau T, Horman SR,  Basu S,  Bertolone SJ, Horwitz M, Hildeman DA, Trent JO, Grimes HL.  Mutations in growth factor independent-1 associated with human neutropenia block murine granulopoiesis through colony stimulating factor-1. Immunity 2008, 28:370-380.

 

Dr. Grimes’ research team studies the Growth factor independent-1 (Gfi1) transcription factor. This year, they reported in Immunity that mutations in GFi1 are causal for Severe Congenital Neutropenia (SCN), a condition that results in recurrent bacterial and fungal infections. Specifically, they showed that the GFi1 mutation (Gfi1N382s) inhibits DNA binding and results in a dominant negative block to granulopoiesis. Moreover, this mutation selectively derepresses the monopoietic cytokine CSF1 and its receptor. Antibody absorption of Csf1 permits GFi1N382s-expressing cells to form neutrophils. Expression of Gfi1 mutants in primary stem/progenitor cells illustrates a central transcriptional program controlling neutrophil development relevant to the pathogenesis of SCN.

 

 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, 204:1665-1675.

Dr. Hildeman reported in the Journal of Experimental Medicine that the balance between the pro- and anti-apopototic molecules, Bim and Bcl-2, controls the development of T cell memory responses in the context of viral infections. Secondly, they have uncovered a novel mechanism by which T cell responses are regulated.  They have found that early activation of a unique T cell population referred to as NKT cells is critical for the optimal generation of T cell responses to viral infection.  Understanding how these molecules are regulated will allow for the development of therapies to either augment impaired immune responses or attenuate overzealous immune responses. Dr. Hildeman’s outstanding work in this area has resulted in his successful renewal of his RO1 to study these processes.

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, 3:304-315.

 

Dr. Mattner, who joined the Division in January of this year, reported in Cell Host Microbe the novel finding that autoimmune liver disease is triggered by an immune response to a specific microbial infection mediated via a unique lipid ligand recognized by NKT cells. Dr. Mattner has already received a grant from the DigestiveHealthCenter here at CCHMC to continue his work in this exciting area.

 

Division Highlights

Division Collaboration

Collaboration with Allergy & Immunology

Collaborating Faculty: Kimberly Risma, PhD

Collaboration with Developmental Biology

Collaborating Faculty: Brian Gebelein, PhD

Collaboration with Molecular Immunology

Collaborating Faculty: Claire Chougnet, PhD

Collaboration with Experimental Hematology

Collaborating Faculty: Yi Zheng, PhD

Division Publications

1. Finkelman FD. Anaphylaxis: lessons from mouse models. J Allergy Clin Immunol. 2007; 120: 506-15; quiz 516-7.
2. Finkelman FD. Use of unrestrained, single-chamber barometric plethysmography to evaluate sensitivity to cholinergic stimulation in mouse models of allergic airway disease. J Allergy Clin Immunol. 2008; 121: 334-5.
3. Finkelman FD, Vercelli D. Advances in asthma, allergy mechanisms, and genetics in 2006. J Allergy Clin Immunol. 2007; 120: 544-50.
4. Finkelman FD, Wills-Karp M. Usefulness and optimization of mouse models of allergic airway disease. J Allergy Clin Immunol. 2008; 121: 603-6.
5. 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; 205: 897-913.
6. Herbert DR, Orekov T, Perkins C, Rothenberg ME, Finkelman FD. IL-4R alpha expression by bone marrow-derived cells is necessary and sufficient for host protection against acute schistosomiasis. J Immunol. 2008; 180: 4948-55.
7. Munitz A, Brandt EB, Mingler M, Finkelman FD, Rothenberg ME. Distinct roles for IL-13 and IL-4 via IL-13 receptor alpha1 and the type II IL-4 receptor in asthma pathogenesis. Proc Natl Acad Sci U S A. 2008; 105: 7240-5.
8. Phelan JD, Orekov T, Finkelman FD. Cutting edge: mechanism of enhancement of in vivo cytokine effects by anti-cytokine monoclonal antibodies. J Immunol. 2008; 180: 44-8.
9. Simons FE, Frew AJ, Ansotegui IJ, Bochner BS, Golden DB, Finkelman FD, Leung DY, Lotvall J, Marone G, Metcalfe DD, Muller U, Rosenwasser LJ, Sampson HA, Schwartz LB, van Hage M, Walls AF. Risk assessment in anaphylaxis: current and future approaches. J Allergy Clin Immunol. 2007; 120: S2-24.
10. Simons FE, Frew AJ, Ansotegui IJ, Bochner BS, Golden DB, Finkelman FD, Leung DY, Lotvall J, Marone G, Metcalfe DD, Muller U, Rosenwasser LJ, Sampson HA, Schwartz LB, van Hage M, Walls AF. Practical allergy (PRACTALL) report: risk assessment in anaphylaxis. Allergy. 2008; 63: 35-7.
11. Duan Z, Person RE, Lee HH, Huang S, Donadieu J, Badolato R, Grimes HL, Papayannopoulou T, Horwitz MS. Epigenetic regulation of protein-coding and microRNA genes by the Gfi1-interacting tumor suppressor PRDM5. Mol Cell Biol. 2007; 27: 6889-902.
12. 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; 204: 1665-75.
13. Hildeman D, Jorgensen T, Kappler J, Marrack P. Apoptosis and the homeostatic control of immune responses. Curr Opin Immunol. 2007; 19: 516-21.
14. 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; 205: 1077-86.
15. Reckling S, Divanovic S, Karp CL, Wojciechowski S, Belkaid Y, Hildeman D. Proapoptotic Bcl-2 family member Bim promotes persistent infection and limits protective immunity. Infect Immun. 2008; 76: 1179-85.
16. Zarebski A, Velu CS, Baktula AM, Bourdeau T, Horman SR, Basu S, Bertolone SJ, Horwitz M, Hildeman DA, Trent JO, Grimes HL. Mutations in growth factor independent-1 associated with human neutropenia block murine granulopoiesis through colony stimulating factor-1. Immunity. 2008; 28: 370-80.
17. 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; 18: 3052-5.
18. 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; 3: 559-64.
19. 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; 3: 304-15.
20. 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; 76: 308-16.
21. 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; 75: 3823-32.
22. Khodoun M, Lewis CC, Yang JQ, Orekov T, Potter C, Wynn T, Mentink-Kane M, Hershey GK, Wills-Karp M, Finkelman FD. Differences in expression, affinity, and function of soluble (s)IL-4Ralpha and sIL-13Ralpha2 suggest opposite effects on allergic responses. J Immunol. 2007; 179: 6429-38.
23. Page K, Lierl KM, Herman N, Wills-Karp M. Differences in susceptibility to German cockroach frass and its associated proteases in induced allergic inflammation in mice. Respir Res. 2007; 8: 91.
24. Page K, Lierl KM, Hughes VS, Zhou P, Ledford JR, Wills-Karp M. TLR2-mediated activation of neutrophils in response to German cockroach frass. J Immunol. 2008; 180: 6317-24.
25. Wills-Karp M. Complement activation pathways: a bridge between innate and adaptive immune responses in asthma. Proc Am Thorac Soc. 2007; 4: 247-51.

Grants, Contracts, and Industry Agreements

Grimes, L

Hildeman, D

Horman, S

Jordan, M

Lewkowich, I

Mattner, J

Wills-Karp, M

Wills-Karp, M

Wills-Karp, M.

Grimes, H.L.

Hildeman, D.

Jordan, M.

Immunobiology Graduate Program

The Immunobiology Graduate Program is an inter-departmental program within the University of Cincinnati that offers PhD and MS degrees in Immunology. The Division of Immunobiology serves as the administrative home of the Graduate Program. The program is governed by the director Dr. Wills-Karp and Associate Director Dr. Christopher Karp and a Steering Committee composed of members of several departments/divisions at CCHMC and UC. Dr. Jonathan Katz is the coordinator of the Foundations in Immunology Courses.

The Immunobiology Program provides broadly based instruction in immunology, along with rigorous research training that emphasizes modern approaches to understanding the function of the immune system in health and disease. To this end, the program currently has 45 faculty members from 4 departments and 12 divisions within the College of Medicine and CCHMC. Since its inception in 2003, we have enrolled 25 outstanding students from around the country and abroad. Milestones achieved this year include the graduation of our first student and the successful completion of the written qualifier by all of the first year students. Our students have distinguished themselves already by receiving several travel and research awards (AAAI, Keystone Symposium, XXI International Complement Workshop).

The Program is supported financially by a variety of sources. This year, tuition support was provided through University Graduate Scholarships awarded by the University of Cincinnati. Student stipends were supported through a variety of sources including funds from the University of Cincinnati (UGA), NIH training grants, external grants to their advisors, and funds from Cincinnati Children's Research Foundation. The program anticipates sustained growth over the next few years with a target class size of 10 new students per year.

Immunobiology Graduate Program Students, 2007-2008

Student Honors

• Jessica Allen Supported by NIH Bioterrorism Training Grant
• Jill Fritz Supported by Cardiovascular and Pulmonary Training Grant
• Katherine Groschwitz Received ST*AR Travel Award from AAAAI, and Keystone Symposia Scholarship; "Mast Cell-Mediated Intestinal Permeability," National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Leah Kottyan Received ST*AR Travel Award from AAAAI, Outstanding Trainee Award from International Eosinophil Society meeting and P.E.O Scholar Award (PEO is a philanthropic organization that provides competitive, merit-based awards for women of the United States and Canada who are either pursuing a doctoral level degree or engaged in postgraduate study or research at an accredited college or university).
• Cortez McBerry Received Yates Scholarship Award
• Vanessa Saunders Received ST*AR Travel Award from AAAAI, Travel Award from American Thoracic Society, UC Conference Travel Award for Autumn Immunology Conference, Preparing Future Faculty Program
• Xun Zhang Received Trainee Award from the XXI International Complement Workshop

Publications (2007-08)

1. Tuner MJ, ML DeLay, S Bai, E Klenk, and RA Colbert. HLA-B27 up-regulation causes accumulation of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in transgenic rats: Implications for the pathogenesis of spondylarthritis-like disease. Arthritis Rheum. 56(1):215-223. 2007.
2. Zhang X, J Clark, G Köhl, M Wills-Karp and J Köhl. Opposing roles for C5aR- and C3aR signaling in the development of maladaptive immunity in allergic asthma. Mol Immunol. 44(16):3912. 2007.
3. Phelan JD, T Orekov, and F Finkelman. Cutting edge: Mechanism of enhancement of in vivo cytokine effects by anti-cytokine monoclonal antibodies. J Immunol. 180(1):44-8. 2008.
4. Smith JA, MJ Turner, ML DeLay, EI Klenk, DP Sowders, and RA Colbert. Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-beta induction via X-box binding protein 1. Eur J Immunol, 38(5):1194-1203. 2008.

Abstracts

1. Saunders V, I Lewkowich., N Herman, K Dienger, J Clark, P Breysse and M Wills-Karp. "Ambient Particulate Matter Exposure Results in Recruitment and Activation Myeloid Dendritic Cells in the Murine Lung." American Thoracic Society, May, 2008
2. Zoller E, J Lykens, L Filipovich and M Jordan. Systemic activation of macrophages by interferon gamma causes consumptive cytopenias and hemophagocytosis. Experimental Biology 2008, April 2008. San Diego CA.
3. Saunders VC, B Sakthivel, CC Lewis, K Dienger, P Breysse, B Aronow and M Wills-Karp. "Ambient Particulate Matter Induced Epithelial Cell Gene Changes in Susceptible versus Resistant Mouse Strains". American Academy of Allergy Asthma and Immunology March, 2008
4. Klenk EI and RA Colbert. The role of the unfolded protein response (UPR) in IL-23 regulation. 36th Annual Autumn Immunology Conference, November, 2007. Chicago IL
5. Allen JL, R Madan, DJ Rawlings, FD Finkelman and CL Karp. Regulation of TLR4 signaling by RP105 in B cells. 36th Annual Autumn Immunology Conference, November, 2007. Chicago IL
6. Saunders VC, B Sakthivel, CC Lewis, K Dienger, P Breysse, B Aronow, M Wills-Karp. "Ambient Particulate Matter Induced Epithelial Cell Gene Changes in Susceptible and Resistant Mouse Strains". 36th Annual Autumn Immunology Conference, November 2007, Chicago IL
7. Zoller E, J Lykens, L Filipovich and M Jordan. Systemic activation of macrophages by interferon gamma causes hemophagocytosis and consumptive anemias. 36th Annual Autumn Immunology Conference, November 2007. Chicago IL.
8. Lin A, S Wojciechowski, M Jordan and D Hildeman. "Sex differences in immune cell recruitment and cytokine production after intracranial LCMV infection." Organization for the Study of Sex Differences Annual Meeting, May 9-12, 2007. Washington, DC
9. Kottyan, LC, AR Collier, KA Niese, CO Radu, ON Witte, ME Rothenberg and N Zimmermann. The T-cell Death Associated Gene-8 (TDAG8) is an acid-sensing eosinophil receptor that critically regulates airway eosinophilia. International Eosinophil Conference, Snowbird Utah, 2007.