Robert S. Mittler - Department of Surgery - Emory University

Citizenship: USA
AFFILIATION
Robert S. Mittler, Ph.D.
Department of Surgery and Emory Vaccine Center,
Emory University School of Medicine
Office Tel. 404-727-9425
Lab Tel. 404-712-8109
Fax No. 404-727-8199
Email: rmittler@rmy.emory.edu
1999-Present EMORY UNIVERSITY SCHOOL OF MEDICINE, Atlanta, GA
2003- Present Associate Professor, Department of Surgery, Emory Vaccine Research
Center, Member of the Winship Cancer Center, and Affiliate Scientist in
Residence, The Yerkes National Primate Research Center.
1999-2003 Assistant Professor, Department of Surgery and The Emory Vaccine
Research Center and Affiliate Scientist in Residence, The Yerkes Regional
Primate Research Center
(1984-1999) BRISTOL-MYERS SQUIBB COMPANY PHARMACEUTICAL RESEARCH
INSTITUTE, Seattle, Washington and Princeton, NJ
(1997-1998) Group Leader and Steering Committee Member
(1996-1997) Acting Director, Department of Transplantation and Autoimmunity.
(1994-1996) Senior Principal Scientist, Department of Transplantation and Auto-
immunity.
(1988-1994) Principal Scientist, Department of Cellular Immunology.
(1984-1988) Senior Research Scientist, Department of Immunology.
1990-1992 BOARD OF EDUCATION, Old Saybrook, CT
Member and Chairman
Responsibilities included formulating and overseeing implementation of
goals and practices that drive the curriculum of the school system. In
addition, the board advised and gave consent in a process that led to the
formulation and execution of the annual budget in excess of $10,000,000.
1990-1999 NEW YORK MEDICAL COLLEGE, Valhalla, NY
Adjunct Professor of Microbiology and Immunology, Department of
Microbiology and Immunology.
1988-1992 UNIVERSITY OF CONNECTICUT AT STORRS, Storrs, CT
1

Adjunct Professor of Immunology, Department of Molecular and Cell
Biology.
1980-1984 ORTHO PHARMACEUTICAL CORP., Immunobiology Division, Raritan,
New Jersey
Group Leader, Molecular Immunology Laboratory.
1978-1980 BECTON DICKINSON RESEARCH CENTER, Research Triangle Park,
NC
Principal Investigator in Immunology and Biochemistry.
1978-1980 THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL, School of
Public Health, Chapel Hill, NC
Adjunct Assistant Professor of Immunology.
1977-1978 THE SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH,
New York City, Department of Cellular Immune Reactions (Michael
Hoffmann, M.D. – P.I.).
Postdoctoral Fellow. NIH Immunobiology Training Fellowship. Isolated,
purified, and studied an LPS-inducible macrophage factor (later defined as
IL-1) that regulated B cell differentiation.
1972-1978 NASSAU COMMUNITY COLLEGE, Garden City, NY
Adjunct Assistant Professor of Biology.
Taught introductory and advanced biology courses to Biology and Allied
Health Sciences students.
1968-1972 NASSAU COMMUNITY COLLEGE, Garden City, NY
Laboratory Assistant.
Prepared materials for laboratory exercises in advanced biology and
microbiology courses. Assisted in instruction of biology and microbiology
labs.
1966-1968 Grumman Aircraft Corporation, Bethpage, Long Island, NY
Technician in the Aircraft Stress-Testing Laboratory. Tested wing stress
failure and catapult gear stress failure of Aircraft Carrier-based jet fighter
and attack aircraft.
1961-1965 United States Navy. Served Aboard the U.S.S. Cromwell DE-1014.
2

EDUCATION
HONORS
Ph.D., March 1977 - New York University School of Medicine and College of
Dentistry, New York City.
Major: Immunology Minor: Biochemistry
Thesis Title: Correlation between in vivo and in vitro assay systems of
xenogeneic transfer of delayed hypersensitivity in laboratory rodents.
MS, June 1976 - New York University School of Medicine and Dentistry, New
York City.
Major: Microbiology Minor: Biochemistry
Thesis Title: Adherence of Streptococcus salivarius to Hamster Cheek Pouch
Epithelial Cells. (MS studies completed 1974 – Foreign language requirements
were fulfilled in 1976).
BS, August 1972 - State University of New York at Stony Brook.
Major: Biology Minor: Chemistry.
New York University Graduate Fellowship
NIH Postdoctoral Training Fellowship
Sigma Xi Society
PROFESSIONAL NATIONAL ASSOCIATIONS
The American Association of Immunologist
Reviewer: Nature Biotechnology, Trends in Immunology, Blood, Journal of
Immunological Methods, Immunity, Nature Medicine, Nature Immunology,
Journal of Clinical Investigation, The Journal of Experimental Medicine, The
Journal of Leukocyte Biology, Cancer Research, Cancer Therapeutics, Cellular
Immunology, Human Immunology, Journal of Immunology, European Journal of
Immunology, American Journal of Transplantation, Infection and Immunity,
PlosOne
Associate Editor - The Journal of Immunology 2002-2006
Peer Review Committee for U.S. Army Breast Cancer Research Program 1995-
2002
Peer Review Committee for U.S. Army Prostate Cancer Research Program 1997 –
2001
Ad hoc Member NIH Experimental Immunology Study Section renamed
Transplantation, Tolerance, and Tumor Immunity - 2001 - 2005
Ad hoc Member NIH Immunobiology Study Section 2003-2004.
Ad hoc Member NIH Cancer Therapeutics Program Project Review Study
Section 2006.
Co-Chair AAI Block Symposium: "T cell development, stem cells, and cell
survival" Annual AAI meeting, Washington DC 2004.
Chair AAI Block Symposium: T cell activation, differentiation and inhibition”
Annual AAI meeting, Seattle, WA 2009.
Advisory Review Board La Jolla Institute of Allergy and Immunology
Program Project Grant 2010-2015.
3

INVITED SPEAKER:
1990 New York Medical College, Department of Microbiology and Immunology, Valhalla NY
1993 Seattle Biomedical Research Institute, Seattle, WA
1994 Robert W. Franz Cancer Research Center, Earle A Chiles Research Institute, Providence
Portland Medical Center, Portland, OR
1997 Cambridge University, Conference on Mucins and Tumor Immunology, Cambridge,
England
1999 Oregon State University, Department of Microbiology and Immunology, Corvallis, OR
2001 Leiden University Health Sciences Center, Department of Hematology and Tumor
Immunology
2001 Northwest Research Institute, Department of Immunology, Seattle, WA
2002 University of Seoul, Fourth Annual Immunology Meeting, Seoul, South Korea
2002 Ulsan University, Department of Immunology, Ulsan, South Korea
2003 Memorial Sloan-Kettering Cancer Center, New York, NY
2003 Cornell University School of Medicine, New York, NY
2003 University of Connecticut Health Sciences Center, Department of Immunology,
Farmington, CT.
2005 Crossroads between Innate and Adaptive Immunity Conference, Rhodes, Greece.
2005 H. Lee Moffitt Cancer Center, University of South Florida.
2005 American Congress Of Rheumatology – Annual Meeting, San Diego CA.
2006 Symposium for Cell and Gene Therapy, Martin Luther University Hospital, Halle-
Wittenburg, Germany.
2006 La Jolla Institute for Allergy and Immunology, San Diego CA.
2008 University of Miami School of Medicine, Miami, FL.
2008 University of Ulsan, Ulsan, South Korea
2008 The NIH Rocky Mountain National Laboratory
RESEARCH FOCUS:
Our research interests center on the CD137 (TNFRSF9 – 4-1BB) T cell costimulatory receptor,
a member of the TNFR superfamily and how it functions in regulating the immune system - with
emphasis on enhancing the induction of anti-viral and anti-tumor immunity, and the suppression
of autoimmunity. CD137 receptors are activation-induced on T cells, NK cells, NKT cells,
granulocytes, macrophages and dendritic cells. CD137 is constitutively expressed on
neutrophils, and in humans it can be expressed on neurons, astrocytes and microglia. On T
cells CD137 can serve as a costimulatory receptor, the crosslinking of which upregulates antiapoptotic
survival signals. The ligand for CD137, 4-1BBL, a member of the TNF superfamily is
weakly expressed on B cells but is upregulated upon B cell activation. Its expression is also
upregulated on other professional antigen-presenting cells (APCs) after activation or
maturation. We have found that although CD137 is expressed on activated CD4 and CD8
positive T cells, anti-CD137 mediated signaling preferentially upregulates CD8 + T cell function
and survival in vitro and in vivo. We have also found that CD137 ligands induce the eradication
of established poorly immunogenic tumors and reverse established autoimmune diseases such
as rheumatoid arthritis and systemic lupus erythematosis. Recently we have found that the
timing of anti-CD137 mAb treatment relative to a viral infection has either an
immunosuppressive effect, or an immune enhancing effect. This observation is critical to the
clinical use of anti-CD137 mAbs that are currently in Phase II clinical trials to treat melanoma
and ovarian cancer and may be used as vaccine adjuvants for treating infectious diseases. In
addition to these studies our lab is focused on the following objectives: (1) Our recent studies
have led us to the hypothesis that CD137 functions in part by maintaining the survival or
function of regulatory T cells in mammals. These T cells play a critical role in the suppression of
4

autoreactive T cells that escape thymic negative selection. We know wish to learn how CD137
regulates the function of these T cells. (2) We are also committed to studying the mechanisms
through which anti-CD137 treatment reverses SLE disease in NZB/W F1 mice; and (3) to study
the temporal interplay and physical associations between costimulatory receptors on T cells,
their cooperative/antagonistic intracellular signaling properties and gene regulation during viral
infection.
INTERNAL SERVICE AND TEACHING:
1. Member of the IMP Graduate Faculty – Instruct Ph.D. and MD/PhD graduate
students in their required courses in Immunology, Contemporary Topics in Immunology
and Immunology Colloquium.
2. Postdoctoral Medical Research Fellows trained –
1. Virginia Herndon, Ph.D.
2. Irma Grassi, Ph.D.
3. Juergen Foell, M.D.
4. Liguo Niu M.D/Ph.D.
5. Simona Strahoton, M.D.
6. Becker Hewes, M.D.
7. Benyue Zhang, M.D.
8. Christoph Hutter, Ph.D.
9. Yuanyuan Zhang, MD/Ph.D.
3. MD/Ph.D. and Ph.D. Student Thesis Committee –
Abhijit Bapat
Andrew Adams
Tom Jones
Troy Querec
Brent Koehn
David Lamar
Shana Coley
Pablo Penalosa
Luke Ubelhoer
Shumita Ganguli
Christopher Gilson
Ivana Ferrer
Kathryn Freel
Brian Norris
4. Collaborative teaching in weekly Mittler and Transplantation Research lab meetings
and in monthly Research in Progress meetings (Ahmed, Larsen-Pearson, Mittler,
Newell).
5. Served as a member of the Research Committee for the Strategic Planning Process
for the Emory Transplant Center.
6. Serve as a member of the Department of Surgery Research Committee
7. Serve as an IACUC committee member.
GRANT SUPPORT:
5

Completed:
Project Number (Principal Investigator) Dates of Approved Project: 8/1/2000 – 7/31/02
R21 AI 48471-01 (Robert S. Mittler)
Source: DAIDS/NIAID
Title of Project: The Effect of Anti-4-1BB on SIV-Specific Cellular Immunity. The goal of this
proposal is to determine whether humanized rat anti-human 4-1BB mAbs enhance development
of cell-mediated immunity in Rhesus macaques vaccinated with a DNA + MVA vaccine against
SIV. It is also a study to determine if these antibodies can induce protective anti-viral CTL
immunity in SIV infected macaques.
Role: Principal Investigator
Project Number (Principal Investigator) Dates of Approved Project: 03/01/02 – 02/29/06
1 RO1 CA 85860-01A1 (Robert .S. Mittler)
Source: NIH/NCI
Title of Project: Functional Analysis of anti-4-1BB mediated tumor immunity. The goal of this
project is to determine how best to utilize CD137 mediated signaling to achieve maximal antitumor
efficacy and to elucidate the CD137 mediated molecular and biochemical signaling
events that drive CD8 + T cells to eradicate tumors that they otherwise fail to respond to.
Project Number (Principal Investigator) Dates of Approved Project: 04/01/01–03/31/06
1RO1 AI RR49155 (Mark Feinberg)
Source: NIH/NIAIDS
Title of Project:
Cellular Immune Responses and AIDS Pathogenesis. This study is designed to test the
hypothesis that SIV pathology develops in monkeys of Asian descent because of a strong
CD8+ T cell response to the infection whereas monkeys of African descent do not develop
pathology as a consequence of infection because of an absence of a discernable CD8+ T cell
response.
Role: Co-Investigator
Project Number (Principal Investigator) Dates of Approved Project: 09/30/98 – 02/28/07
PO1 AI 044644-06 (Christian P. Larsen)
Source: NIH/NIAID
Title of Project: Transplant Tolerance: Costimulation, Cytokines & Chimerism. The objective of
this study is to understand the causes that give rise to rejection of transplanted organs and to
block them.
Role: Co-Principal Investigator
Current:
Project Number:
1RO1 AI059290-01 (Robert S. Mittler) Dates of Approved Project: 5/01/05-
1/31/10
Source: NIH/NIAIDS
Title of Project: CD137 signals in DC during antigen priming induce tolerance.
This study explores the mechanisms through which CD137 signaling regulates antigen priming
of T cells by dendritic cells.
Project Number (Principal Investigator) Dates of Approved Project: 9/1/2000-8/31/08
2000N-00065 (Robert S. Mittler)
Source: Centers for Disease Control (CDC)
6

Title of Project: Correlates of Immune Protection Following Anthrax Immunization. This study
is designed to determine immune correlates of protection in human volunteers and non-human
primates following immunization against Bacillus anthracis using AVA.
Role: Principal Investigator
Project Number (Principal Investigator) Dates of Approved Project: 04/1/02 – 03/31/07
P30 AI 42847-01 ZAI1 (James Curran)
Source: NIH/NIAID
Title of Project: Emory/Atlanta Center for AIDS Research. The goal of this project is to
establish a Center for AIDS Research to facilitate interdisciplinary AIDS Research in Atlanta.
Role: Co-Investigator
Project Number (Principal Investigator) Dates of Approved Project: 09/01/03 - 08/31/09
U19 AI 057266-01 (Rafi Ahmed)
Source: NIH/NIAID
Title of Project: Vaccine Induced Immunity in the Young and Aged. The goals of this project
are to study the human immune response to a vaccine in its entirety beginning with innate
immunity and ending with the development and maintenance of immunological memory.
Role: Co-Principal Investigator.
Pending:
Project Number (Principal Investigator)
Robert S. Mittler
Source: NIH/NIAID
Title of Project: CD137 induced T cell costimulation or tolerance.
Role: Principal Investigator
PUBLICATIONS (Peer-Reviewed):
1. Hoffmann, M.K., Oettgen, H.F., Old, L.J., Mittler, R.S. and Hammerling, U. (1978).
Induction and Immunological Properties of Tumor Necrosis Factor. J.
Reticluoendothelial Society 23:307.
2. Hoffmann, M.K., Galanos, C., Koenig, S., Mittler, R.S., Ralph, P., Oettgen, H.F. and
Hammerling, U. (1979). Macrophage Factor Controlling Differentiation of B Cells. J.
Immunol. 122:497.
3. Eisenbarth, G.S., Oie, H.K., Gazdar, A.F., Chick, W.L. and Mittler, R.S. (1980).
Production of Lymphocyte Hybridoma Antibodies Reacting with Rat Islet Cell Surface
Molecules. J. Endocrine Society.
4. Fernandez-Repollet, E., Mittler, R.S., Tiffany, S. and Schwartz, A. (1980). Detection
Prostaglandin E 2 Inhibition and Arachidonic Acid Stimulation of Macrophage
Phagocytosis with Fluorescent Microbeads. J. Amer. Fed. for Clin. Res. 28:889.
5. Nachamkin, I., Cannon, J.C. and Mittler, R.S. (1981). Monoclonal Antibodies Against
Neisseria Gonorrhoeae: Production of Antibodies Direct Against a Strain Specific Cell
Surface Antigen. Infection and Immunity. 32:641.
7

6. Nachamkin, I., Cannon, J.C. and Mittler, R.S. (1981). Monoclonal Antibodies Directed
Against A Surface Antigen of Neisseria Gonorrhoeae. Abstracts of Annual Meeting of
Amer. Soc. of Microbiologists.
7. Fernandez-Repollet, R., Mittler, R.S., Tiffany S. and Schwartz, A. (1982). In vivo
Effects of Prostagandin E 2 and Archidonic Acid on Phagocytosis of Fluorescent
Methacrylate Microbeads by Rat Peritoneal Macrophages. (1982). J of Histochemistry
and Cytochemistry. 5:466:470.
8. Estabrook, A., Berger, C.L. Mittler, R.S., LoGerfo, P., Hardy, M. and Edelson, R.L.
(1982). Antigenic Modulation of Human T-Lymphocytes by Monoclonal Antibodies.
Transplant Proceedings. 25:651.
9. Hoffmann, M.K., Polack, S., Krown, S.E. and Mittler, R.S. (1982). Deletion of Active
Human Suppressor T-lymphocytes from Peripheral Blood by Sephaex G-10 Filtration. J.
Immunol. Methods. 55:327-336.
10. Talle, M.A., Rao, P.E., Westberg, E., Allegar, N., Makowski, M., Mittler, R.S. and
Goldstein, G., (1983). Patterns of Antigenic Expression on Human Monocytes as
Defined by Monoclonal Antibodies. Cellular Immunology. 78:83.
11. Mittler, R.S., Rao, P.E., Talle, M.A., Look, R. and Goldstein, G. (1983). Membrane
Perturbation of Resting T Cells and Thymocytes Causes Display of Activation Antigens.
J. Exp. Med. 158:99.
12. Mittler, R.S., Talle, M.A., Carpenter, K.S., Rao, P.E. and Goldstein, G. (1983).
Generation and Characterization of Monoclonal Antibodies Reactive with Human Blymphocytes.
J. Immunol. 131:1754.
13. Mittler, R.S., Talle, M.A., Look, R., Sheffler, B., Rao, P.E. and Goldstein, G. (1983).
Resting and Activation Antigens of T Cells: Studies with OKT10 and OKT20 Monoclonal
Antibodies Diagnostic Immunol. 1:120.
14. Knowles, D.M., Dodson, L. D., Raab, R., Mittler, R.S., Talle, M.A., Goldstein, G. (1983).
The Application of Monoclonal Antibodies to the Characterization and Diagnosis of
Lymphoid Neoplasms: A Review of Recent Studies. Diagnostic Immunol. 1:142.
15. Talle, M.A., Rao, P.E., Allegar, N., Makowiski, M., Mittler, R.S. and Goldstein, G. (1983).
Classification of Human Lymphocytes and Monocytes with the OK Series of Monoclonal
Antibodies. Diagnostic Immunol. 1:129.
16. Knowles, D.M., Tolidjian, B., Marboe, C.C., Mittler, R.S., Talle, M.A. and Goldstein,
(1984). Distribution of Antigens Defined by OKB Monoclonal Antibodies on Benign
Malignant Lymphoid Cells and on Non-lymphoid Tissues. Blood 63:886.
17. Mittler, R.S., Rao, P., Olini, G., Westbury, L., Newman, W., Hoffmann, M. and
Goldstein, G. (1985). Activated Human B Cells Express a Functional IL-2 Receptor. J.
Immunol. 134:2393.
18. Mittler, R.S., Greenfield, R.S., Schacter, B.Z., Richard, N.F. and Hoffmann, M.K.
Antibodies to the Common Leukocyte Antigen (T200) Inhibit an Early Phase in the
Activation of Resting Human B Cells. (1987) J. Immunol. 138:3159.
8

19. Kiener, P.A. and Mittler, R.S. (1989). CD45-Protein Tyrosine Phosphatase Crosslinking
Inhibits Ti-CD3 Mediated Activation in Human T Cells. J. Immunol. 143:23.
20. Mittler, R.S. and Hoffmann, M.K. (1989). Synergism Between GP120 and GP120-
Specific Antibody In Blocking Human T Cell Activation. Science 245:1380.
21. Mittler, R.S., Goldman, S.J., Spitalny, G.L., and Burakoff, S.J. (1989). T cell Receptor-
CD4 Physical Association in a Murine T Cell Hybridoma: Induction by Antigen Receptor
Ligation. Proc. Natl. Acad. Sci. 86:8531.
22. Mecheri, S., Edidin, M., Dannecker, G., Mittler, R. S., and Hoffmann, M.K. (1989).
Immunogenic Ia-Binding Peptides Immobilize the Ia Molecule and Facilitate its
Aggregation of the B Cell Membrane. Control by the Mls-1 Gene. J. Immunol.
144:1361.
23. Mittler, R.S., Fifer, C.A., Burbach, P., Edinger, K., and Kiener, P.A. (1990). Evidence for
a New HLA Determinant that Causes T Cell Activation Without Co-Stimulation. J.
Immunol. 145:794.
24. Mittler, R.S., Rankin, B.M., and Kiener, P.A. (1991). Physical Associations Between
CD45 Occur As Late Activation Events in Antigen Receptor-Stimulated Human T Cells.
J. Immunol. 145:794.
25. Collins, T.L., Uniyal, S., Shin, J., Strominger, J.L., Mittler, R.S., and Burakoff, S.J.
(1992). p56 lck Association with CD4 is Required for the Interaction Between CD4 and
the TCR/CD3 Complex for Optimal Antigen Stimulation. J. Immunol. 148:2159.
26. Rankin, B.M., Yocum, S.A., Mittler, R.S., and Kiener, P.A. (1990). Stimulation of
Tyrosine Phosphorylation and Calcium Mobilization by Fc-gamma Receptor
Crosslinking. J. Immunol. 150:605.
27. Wang, S., Orlikowsky, T., Dudane, A., Mittler, R.S., Blum, M., Lacy, E., Riethmuller,
and Hoffmann, M.K. (1994). Deletion of T lymphocytes in Human CD4 Transgenic Mice
Induced by HIV-gp120 and gp120-specific Antibodies from AIDS Patients. Eur. J.
Immunol. 24:1553.
28. Mittler, R.S., Shieven, G.L., Dubois, P.M., Klussman, K., O’Connell, M.P., Kiener, P.A.,
and Herndon, V. (1994). CD45 Mediated Regulation of Extracellular Calcium Influx in a
CD4 Transfected Human Cell Line. J. Immunol. 153:84.
29. Schieven, G.L., Mittler, R.S., Nadler, S.G., Kirihara, J.M., Bolen, J.B., Kanner, S.B., and
Ledbetter, J.A. ZAP-70 Tyrosine Kinase, CD45 and T Cell Receptor Involvement in UV
and H 2 O 2 Induced T Cell Signal Transduction. (1994). J. Biol. Chem. 269:20718.
30. Vignali, D.A.A., Carson, R.T., Chang, B., Mittler, R.S., and Strominger, J.L. (1994).
The Two Membrane Proximal Domains of CD4 Physically and Functionally Interact with
The T Cell Receptor: C3 Complex. J. Exp. Med. 183:2097.
31. Linsley, P.S., Bradshaw, J., Greene, J., Peach, R., Bennett, K.L., and Mittler, R.S.
(1996). Intracellular Trafficking of CTLA-4 and Focal Localization Towards Sites of TCR
Engagement. Immunity. 4:535.
9

32. Winberg, G., Grosmaire, L.S., Klussman, K., Hayden, M.S., Fell, H.P., Ledbetter, J.A.,
and Mittler, R.S. (1996). Surface Expression of CD28 Single Chain Fv for
Costimulation by Tumor Cells. Immunol. Rev. 153:209.
33. Brown, TJ, Shuford, WW, Wang, WC, Nadler, SG, Bailey, TS, Marquardt, H., and
Mittler RS. (1996). Characterization of a CD43/leukosialin-mediated pathway for
inducing apoptosis in human T-lymphoblastoid cells. J. Biol. Chem. 271:27686.
34. Gilliland, L.K., Norris, N.A., Marquardt, J., Tsu, T.T., Hayden, M.S., Neubauer, M.G.,
Yelton, D.E., Mittler, R.S., and Ledbetter, J.A. (1996). Rapid and Reliable Cloning of
Antibody Variable Regions and Generation of Recombinant Single Chain Antibody
Fragments. Tissue Antigens. 47:1.
35. Cabrian K.M., Berry, K.K., Shuford, W.W., Mittler, R.S., Rodgers, J.N., and Linsley,
P.S. (1996). Suppression of T Cell Dependent Immune Responses in Monkeys by
CTLA4-Ig. Transplantation Proceedings. 28:3261.
36. Hayden, M.S., Grosmaire, L.S., Norris, N.A., Gilliland, L.K.., Winberg, G., Tritchler, D.,
Tsu, T.T., Linsley, P.S., Mittler, R.S., Senter, P.D., Fell, H.P., and Ledbetter, J.A.
(1996). Costimulation by CD28 sFv Expressed on the Tumor Cell Surface or as a
Bispecific Molecule Targeted to the L6 Carcinoma Antigen. Tissue Antigens. 48:242.
37. Ledbetter J.A., Francisco, J.A., Siegall, C.B., Guilliland, L.K., Hollenbaugh, D., Aruffo,
A., Siadak, A.W., Mischel-Petty, N., Grosmaire, L.S., Gordon, M.L., Brown, T.J., Moran-
Davis, P., Mittler, R.S., Kiener, P.A., and Nadler, S.G. (1997). Agonistic activity of a
CD40-specific single-chain Fv constructed from the variable regions of mAb G28-5. Crit.
Rev. Immunol. 17:427.
38. Melero, I., Shuford, W.W., Newby S.A., Aruffo, A., Ledbetter, J.A., Hellstrom, K.E.,
Mittler, R.S., and Chen, L. (1997). Induction of Tumor-Specific CTL and Eradication of
Established Poorly Immunogenic Tumors by Anti-4-1 BB Monoclonal Antibodies. Nat.
Med. 3:683. (Mittler and Chen are senior coauthors).
39. Shuford, W.W., Klussman, K., Tritchler, T.S., Loo, D.T., Chalupny, N.J., Siadak, A.W.,
Brown, T.J., Emswiler, J., Raecho, J., Larson, C.P., Pearson, T.C., Ledbetter, J.A.,
Aruffo, A., and Mittler, R.S. (1997). 4-1BB Costimulatory Signals Preferentially Induce
CD8 + T Cell Proliferation and Lead to the Amplification In Vivo of Cytotoxic T Cell
Responses. J. Exp. Med. 186:47.
40. Loo, D.T., Chalupny, N.J., Bajorath, J., Shuford, W.W., Mittler, R.S., and Aruffo, A.
(1997). Analysis of 4-1BBL and Laminin Binding to Murine 4-1BB, a Member of the
Tumor Necrosis Factor Receptor Superfamily, and Comparison with Human 4-1BB. J.
Biol. Chem. 272:64489.
41. Melero, I., Bach, N., Hellstrom, K.E., Aruffo, A., Mittler, R.S., and Chen, L. (1998).
Amplification of Tumor Immunity by Gene Transfer of the Costimulatory 4-1BB Ligand:
Synergy with the CD28 Costimulatory Pathway. Eur. J. Immunol. 28:1116.
42. Orlikowsky, T., Wang, Z.-Q., Dudhane, A., Mittler, R.S., Trejo, V., Dannecker, G.E.,
Niethammer, D., and Hoffmann, M.K. (1998). Elevated Major Histocompatibility
Complex Class I Expression Protects T Cells From Antibody and Macrophage-Mediated
10

Deletion. Immunology. 95:437.
43. Melero, I., Johnston, J.V, Shufford, W.W., Mittler, R.S., and Chen, L. (1998). NK1.1 +
Cells Express 4-1BB (CDw137) Costimulatory Molecule and are Required for Tumor
Immunity Elicited by Anti-4-1BB Monoclonal Antibodies. Cell. Immunol 190:167.
44. Wang, Z.-Q., Trejo, V., Orlikowsky, T., Mittler, R.S., and Hoffmann, M.K. (1999).
MHC Class I Molecules on CD4 + T Cells Regulate Receptor-Mediated Activation
Signals. Cell. Immunol. 193:108.
45. Wang, Z.-Q., Horowitz, H., Orlikowsky, T., Han, B.-I., Trejo, V., Bapat, A.S., Mittler,
R.S., Rayanade, R.J., Yang, S.Y., and Hoffmann, M.K. (1999). Polyspecific Self-
Reactive Antibodies in HIV Infected Individuals Facilitates T Cell Deletion and Inhibit
Costimulatory Accessory Cell Function. J. Infec. Dis. 180:1072.
46. Takashashi, C., Mittler, R.S., and Vella, A.T. (1999). 4-1BB is a Bonafide CD8 T Cell
Survival Signal. J. Immunol. Cutting Edge: 162:5037.
47. Mittler, R.S., Bailey, T.S., Klussman, K., TrailSmith, M.D., and Hoffmann, M.K. (1999).
Anti-4-1BB Monoclonal Antibodies Abrogate T Cell-Dependent Humoral Responses In
Vivo Through the Induction of Helper T Cell Anergy. J. Exp. Med.190: 1535.
48. Tan, J.T., Whitmire, J.K., Murali-Krishna, K., Ahmed,R., Altman, J.D., Mittler, R.S.,
Sette, A., Pearson, T.C., and Larsen, C.P. (2000). 4-1BB Costimulation is Required for
Protective Anti-Viral Immunity After Peptide Vaccination. J. Immunol. 164:2320.
49. Tan, J.T., Ha, J., Cho, R., Tucker-Burden, C., Hendrix, R.C., Mittler, R.S., Pearson,
T.C., and Larsen, C.P. (2000). Analysis of Expression and Function of the Costimulatory
Molecule 4-1BB in Alloimmune Responses. Transplantation 70:175.
50. Chen, S-H., Pham-Nguyen, K.B., Martinet, O., Huang, Y., Yang, W., Thung, S.N.,
Chen, L., Mittler, R.S., and Woo, S.L.C. (2000). Mol. Therapy 2:39
51. Takahashi, C., Mittler, R.S., and Vella, A.T. (2001). Contrasting the Effects of 4-1BB
Engagement Between CD4 and CD8 Activated T Cell Subsets in vivo: Differential
Clonal Expansion of CD4 and CD8 T Cells to CD28 and 4-1BB Ligation. Immunol.
Let. 76:183.
52. Diehl, L.,van Mierlo, G., van der Voort, den Boer, A.T., Fransen, M., van Bostelan, L., E,
Krimpenfort, P., Melief, C., Mittler, R.S., Toes, R., and Offringa, R. (2002). In Vivo
Triggering Through 4-1BB Enables T helper-Independent Priming of Cytotoxic T
Lymphocytes in the Presence of an Intact CD28 Costimulatory Pathway. J. Immunol.
168:3755.
53. Wilcox, R.A., Chapoval, A.I., Shin, T., Otsuji, M., Gorski, K.S., Flies, D.B., Tamada, K.,
Mittler, R.S., Tsuchiya, H., Pardoll, D.M., and Chen, L. (2002) Expression of functional
CD137 receptor by dendritic cells. (2002). Cutting Edge: J. Immunol. 168:4262.
54. Laderach, D., Movassagh, M., Johnson, A., Mittler, R.S., and Galy, A. (2002). 4-1BBcostimulation
enhances human CD8 + T cell priming by augmenting the proliferation and
survival of effector CD8 + T cells. Int. Immunology 14:1155.
11

55. Wu, Z-Q, Khan, A.Q., Shen, Y., Wolcott, K.M., Dawick, W., Watts, T.H., Mittler, R.S.,
and Snapper, C.M. (2003). 4-1BB differentially regulates murine in vivo protein-and
polysaccharide-specific Ig isotype responses to Streptococcus pneumoniae. Infect. and
Immun. 71:196.
56. Foell, J., McCausland, M., Burch, J., Corrazzi, N., Yan, X-J, Suwyn, C., O’Neil, S.P.,
Hoffmann, M.K., and Mittler, R.S. (2003) CD137 mediated T cell costimulation
terminates existing autoimmune disease in SLE-prone NZB/W F1 mice. Ann of the NY
Acad. Sci. 987:230-5.
57. Foell, J.L., Strahoutin, S., O’Neill, S.P., McCausland, M.M., Suwyn, C., Chander, P.N.,
Bapat, A. S., Yan, X-J, Chiorrazzi, N., Hoffmann, M.K., and Mittler, R.S. (2003).
Engagement of CD137 costimulatory molecules corrects a critical immune dysfunction
in SLE-prone NZB x NZW F1 mice. J. Clin. Invest. 10:1505-18.
58. Myers L., Takahashi, C., Mittler, R.S., Rossi, R.J., and Vella, A.T. (2003). 4-1BB
costimulation and TLR specific adjuvants combine to optimize peripheral T cell survival,
but consequently impair recall responsiveness. Proc. Soc. Nat. Acad. Sci. (USA)
100(9):5348-53.
59. Wang, J., Guo, Z., Dong, Y., Kim, O., Hart, J., Adams, A.,. Larsen, C.P., Mittler, R.S.,
and Newell, K.A. (2003). The role of 4-1BB in allograft rejection mediated by CD8 + T
cells. Amer. J. Transpl. 3:543-51.
60. Mittler R.S., Foell J., McCausland M., Strahotin S., Niu L., Bapat A., Hewes L.B.
(2004). Anti-CD137 antibodies in the treatment of autoimmune disease and cancer.
Immunol. Res. 29:197-208.
61. Foell. J.L., Diez-Mendiondo. B.I., Diez, O.H., Holzer , U., Ruck, P., Bapat, A.S.,
Hoffmann, M.K., Mittler, R.S., and Dannecker , G.E. (2004) Engagement of the CD137
(4-1BB) costimulatory molecule inhibits and reverses the autoimmune process in
collagen-induced arthritis and establishes lasting disease resistance. Immunology
113:89. (Mittler and Dannecker are co-senior authors).
62. Lee, S.J., Myers, L., Muralimohan, G., Dai, J., Qiao, Y., Li, Z., Mittler, R.S., and Vella,
A.T. (2004). 4-1BB and OX40 dual costimulation synergistically stimulate primary
specific CD8 T cells for robust effector functions. J. Immunol. 173:3002
63. Munks MW, Mourich DV, Mittler RS, Weinberg AD, Hill AB. (2004). 4-1BB and
OX40 stimulation enhance CD8 and CD4 T-cell responses to a DNA prime, poxvirus
boost vaccine. Immunology112:559-66.
64. Cho HR, Kwon B, Yagita H, La S, Lee EA, Kim JE, Akiba H, Kim J, Suh JH, Vinay DS,
Ju SA, Kim BS, Mittler RS, Okumura K, Kwon BS. (2004). Blockade of 4-1BB
(CD137)/4-1BB ligand interactions increases allograft survival. Transpl Int. 17:351.
65. Mittler, R.S. (2004) Suppressing the self in rheumatoid arthritis. (2004). Nat. Med.
10:1047.
66. Cuadros, C., Dominguez, A.L., Lollini, P-L, Croft, M., Mittler, R.S., Borgstrom, P.
Lustgarten, J. (2005). Vaccination with dendritic cells pulsed with apoptotic tumors in
combination with anti-OX40 and anti-4-1BB monoclonal antibodies induce a T cell
12

mediated protective immunity in Her-2/neu transgenic mice. Int. J. Cancer, In Press.
67. Myers, L., Croft, M., Kwon, B.S., Mittler, R.S., and Vella, A.T. (2005). Peptide-specific
CD8 regulatory T cells utilize IFN-g to elaborate TGFb based suppression. J.
Immunol.174:7625
68. Nishimoto H, Lee SW, Hong H, Potter KG, Maeda-Yamamoto M, Kinoshita T,
Kawakami Y, Mittler RS, Kwon BS, Ware CF, Croft M, Kawakami T. (2005).
Costimulation of mast cells by 4-1BB, a member of the tumor necrosis factor receptor
superfamily, with the high-affinity IgE receptor. Blood 106:4241
69. Fukushima, A., Yamaguchi, T., Ishida, W., Fukata, K., Mittler, R.S., Yagita, H., and
Ueno H. (2005). Engagement of 4-1BB inhibits the development of experimental allergic
Conjunctivitis in mice. J. Immunol. 175:4897.
70. Myers, L., Lee, S.W., Rossi, R.J., Lefrancois, L., Kwon, B.S., Mittler, R.S., Croft, M.
and Vella, A.T. (2005). Combined CD137 (4-1BB) and adjuvant therapy generates a
developing pool of peptide-specific CD8 memory T cells. Int. Immunol. 18:325.
71. Tobias, P., Foell, J., Werner, C., Burdach, S., Mittler, RS, and Hansen, G. (2006).
Signaling through CD137 (4-1BB) Controls T helper 2 cell-mediated allergic
Inflammation and airway hyperreactivity. J. Clin. Invest. 116:1025.
72. Uno, T., Takeda, K., Kojima, Y., Yoshizawa, H., Akiba, H., Rolonk, A., Mittler, R.S.,
Gejyo. F., Okumura, Smyth, M.J., and Yagita, H. (2006) A rational antibody-based
therapy of established cancer that combines tumor cell apoptosis and T cell activation.
Nat. Med. 12:693.
73. Wohlfert EA, Gorelik, L., Mittler, R.S., Flavell, RA, Clark, RB. (2006). Cutting
Edge: deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T
cell TGF-beta sensitivity in vitro and in vivo. J. Immunol. 176:1316.
74. McMillin, D.W., Hewes, B., Gangadharan, B., Archer, D.R., Mittler, R.S., and Spencer,
H.T. (2006). Complete regression of large solid tumors, using engineered drug-resistant
hematopoietic cells and anti-CD137 immunotherapy. Human Gene Therapy 17:798
75. Menoret A, Myers LM, Lee SJ, Mittler RS, Rossi RJ and Vella AT (2006). TGFbeta
Protein Processing and Activity through TCR Triggering of Primary CD8+ T Regulatory
Cells. J. Immunol. 177:6091.
76. Niu, L., Strahotin, S., Hewes, B., Zhang, B., Spencer, T., Archer, D., Dillehay, D., Kwon,
B.S., Chen, L., Vella, A.T., and Mittler, R.S. (2007). Cytokine-mediated disruption of
lymphocyte trafficking, hematopoiesis, and induction of lymphopenia, anemia, and
thrombocytopenia in anti-CD137 treated mice. J. Immunol. 178:4194.
77. Irie J, Wu Y, Kachapati K, Mittler RS, Ridgway WM. (2007). Modulating Protective
and Pathogenic CD4+ Subsets via CD137 in Type 1 Diabetes. Diabetes 186-96.
78. Laughlin EM, Miller JD, James E, Fillos D, Ibegbu CC, Mittler RS, Akondy R, Kwok
W,Ahmed R, Nepom G. 2007. Antigen-Specific CD4+ T Cells Recognize Epitopes of
Protective Antigen Following AVA Vaccination. Infect Immun. 75:4670.
13

79. Zhang, B., Maris, C.H., Foell, J., Whitmire, J., Niu, L., Song, J., Kwon, B.S., Vella, A.T.,
Ahmed, R., Jacob, J., and Mittler, R.S. 2007. CD137 T cell costimulation
induced suppression or enhanced immune function during acute viral infection.
J. Clin. Invest. 117:3029.
80. Lee, S.J., Rossi, R.J., Lee, S.K., Croft, M., Kwon, B.S., Mittler, R.S., Vella, A.T. 2007.
CD134 costimulation couples the CD137 pathway to induce production of supereffector
CD8 T cells that become IL-7 dependent. J. Immunol. 179:2203.
81. Moens, L., Jeurissen A., Mittler R.S., Wuyts G., Michiels G., Boon L., Ceuppens J.L.,
Bossuyt X. 2007. Distinct approaches to investigate the importance of the murine 4-1BB
4-1BBL interaction in the antibody response to Streptococcus pneumoniae. J Leukoc
Biol. 82:638.
82. Polte T, Jagemann A, Foell J, Mittler R.S., Hansen G. 2007. CD137 ligand prevents the
development of T-helper type 2 cell-mediated allergic asthma by interferon-gamma-
producing CD8(+) T cells. Clin Exp Allergy 37:1374.
83. McNamara, J.O., Kolonias, D., Pastor, F., Mittler, R.S., Chen, L., Giangrande, P.H.,
Sullenger, B., and Gilboa, E. 2008. Costimulation of CD8+ T cells and Inhibition of
tumor growth with multivalent 4-1BB binding aptamers. J. Clin. Invest. 118:376.
84. Robertson, S.J., Messer, R.J., Carmody, A.B., Mittler, R.S., Burlak, C., and Hazenkrug,
K.J. 2008. CD137-costimulation of CD8+ T cells confers resistance to suppression by
virus-induced regulatory T cells. J. Immunol. 180:5267.
85. Lee, S-W, Park, Y., So, T., Kwon, B.S., Cheroutre, H., Mittler, R.S., and Croft, M.
2008. A novel regulatory role for 4-1BB and 4-1BBL in myelopoiesis and the
development of dendritic cells. Nat. Immunol. 9:917
86. Bandyopadhyay S, Long M, Qui HZ, Hagymasi AT, Slaiby AM, Mihalyo MA, Aguila HL,
Mittler R.S., Vella AT, Adler AJ. 2008. Self-antigen prevents CD8 T cell effector
differentiation by CD134 and CD137 dual costimulation. J. Immunol. 181:7728.
87. Paiardini, M, Cervasi, B., Engram, J.C., Gordon, S.N., Klatt, N.R., Muthukumar, a., Else,
J., Mittler, R.S., Staprans, S.I., Sodora, D.L., Silvestri, G. 2009. Bone marrow-based
homeostatic proliferation of mature T-cells in non-human primates: implications for AIDS
pathogenesis.Blood 113:612.
88. Lee, S.J., Long, M., Adler, A.J., Mittler, R.S., Vella, A.T. 2009. The IKK-neutralizing
compound Bay11 kills supereffector CD8 T cells by altering caspase-dependent
activation-induced cell death. J. Leuk. Biol. 85:175
89. Sumi T, Ishida W, Mittler R.S., Yagita H, Taguchi O, Fukushima A. 2009. Regulatory T
Cells Participate in 4-1BB-Mediated Suppression of Experimental Allergic Conjunctivitis.
Int. Arch Allergy Immunol. 148:305.
90. Kim YH, Choi BK, Oh HS, Kang WJ, Mittler RS, Kwon BS. 2009. Mechanisms involved
in synergistic anticancer effects of anti-4-1BB and cyclophosphamide therapy. Mol.
Cancer Ther. 8:469.
91. Lee SW, Salek-Ardakani S, Mittler RS, Croft M. 2009. Hypercostimulation through
14

4-1BB distorts homeostasis of immune cells. J Immunol. 182:6753.
92. Schabowsky RH, Elpek KG, Madireddi S, Sharma RK, Yolcu ES, Bandura-Morgan L,
Miller R, Macleod KJ, Mittler RS, Shirwan H. 2009. A novel form of 4-1BBL has better
immunomodulatory activity than an agonistic anti-4-1BB Ab without Ab-associated
severe toxicity. Vaccine Oct. 14. [Epub ahead of print].
93. Ganguly S, Liu J, Pillai VB, Mittler, RS, Amara RR. 2010. Adjuvantive effects of anti-4-
1BB agonist Ab and 4-1BBL DNA for a HIV-1 Gag DNA vaccine: Different effects on
cellular and humoral immunity. Vaccine Nov. 25. [Epub ahead of print].
94. Zhang B, Zhang Y, Vella AT, and Mittler RS. 2010. Dendritic cells and Stat3 are
essential for CD137-induced CD8 T cell activation-induced cell death. 2010.
J. Immunol. 184:4770.
95. Skountzou I, Koutsonanos DG, Kim JH, Powers R, Satyabhama L, Masseoud F,
Weldon WC, Martin-Mdel P, Mittler RS, Compans R, Jacob J. 2010. Immunity to pre-
1950 H1N1 influenza viruses confers cross-protection against the pandemic swine-origin
(H1N1) influenza virus. J. Immunol. 185:1642.
96. Engram JC, Cervasi B, Borghans JA, Klatt NR, Gordon SN, Chahroudi A, Else, JG,
Mittler RS, Sodora DL, De Hoer RJ, Brenchley JM, Silvestri G, Paiardini M. 2010.
Lineage-specific T-cell reconstitution following in vivo CD4+ and CD8+ Lymphocyte
Depletion in nonhuman primates. Blood 116:748.
Book Chapters and Review Articles:
1. Eisenbarth, G. S., Shimzu, K., Conn, M., Mittler, R.S., and Wells, S. (1981).
Monoclonal Antibody F12A2B5: Reaction with a Plasma Membrane Antigen of
Vertebrate Neurons and Peptide Secreting Endocrine Cells. In Monoclonal Antibodies
Against Neural Antigens. Cold Spring Harbor Symposium. pp. 209-218.
2. Goldstein, G., Lifter, J. and Mittler, R. S. (1982). Immunoregulatory Changes in Human
Disease Detected by Monoclonal Antibodies to T Lymphocytes. In Monoclonal
Antibodies in Clinical Medicine. Eds. McMichael, A. and Fabre, W. Academic Press,
London. pp. 39-70.
3. Goldstein, F., Lifter, J. and Mittler, R.S. (1982). Monoclonal Antibodies to Human
Lymphocyte Surface Antigens. In Monoclonal Antibodies and T Cell Products. Ed.
Katz, D., CROC Press, Inc., Florida. pp. 71-90
4. Hoffmann,M.K., M. Chun, I.A. Hirst and R.S. Mittler (1987). The IgM Antibody
Response in Cultures of Mouse and Human Lymphoid Cells. In Proceedings of the First
International Conference on In vitro Immunization. Carl Borrebaeck, Editor. Elsevier
Publications, Cambridge, U.K.
5. Goldman, S.J., Mittler, R.S., Veillette, A., and Burakoff, S.J. (1990). The Role of CD4 in
T Cell Activation. Immunogenicity UCLA Symposium on Molecular and Cellular Biology.
Vol. 113:93-102. C, Janeway, J. Sprent and E. Sercaz, ed. Alan R. Liss, N.Y.C.,
Publisher.
15

6. Foell, J., Hewes, B., and Mittler, R.S. (2006). T cell costimulatory and inhibitory
receptors as therapeutic targets for inducing anti-tumor immunity. Molecular
Mechanisms and Therapeutic Reversal of Immune Suppression in Cancer. Curr Cancer
Drug Targets. 2007 7:55-70.
7. Foell, J., and Mittler, R.S. (2006). Co-stimulatory molecules as immunotherapeutic
targets in systemic lupus erythematosus. Springer Semin Immunopathol. 2006 28:153-
62.
8. Mittler, R.S. Niu, L., Hewes, B., and Foell, J. (2007). Regulation of T Cell-Dependent
Humoral Immunity Through CD137 (4-1BB) Mediated Signals, p55-82. CD137 pathway
in immune responses and disease. Lieping Chen, MD/PhD, Editor. Springer US
Publisher.
Patents:
1. Mittler, R.S., et. al. Methods and Compositions for Immunomodulation (April 3, 2001)
U.S. Patent Number 6,210, 669.
2. Mittler, R.S., et al. Humanized Antibodies Against human 4-1BB (May 3, 2005)
U.S. Patent Number 6,887,673.
3. Mittler, R.S., et al. Polynucleotides encoding humanized antibodies against human 4-
1BB (May 8, 2007) U.S. Patent Number 7,214,493.
16