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Research Laboratories
Cellular Immunology Laboratory
Robert Seder, M.D.
telephone office: 301-594-8483
telephone lab: 301-594-8589
fax: 301-480-2565 Address: Vaccine Research
Center, NIAID, NIH
40 Convent Drive; Building 40
Room 3512, MSC 3025
Bethesda, MD 20892-3025
Awards/Societies
Member, Collegium Internationale Allergologicum (1996); Member,
American Society of Clinical Investigation (1998)
Editorial Boards
Journal of Experimental Medicine
Group Members
Patricia Darrah, PhD, Ulrike Wille, PhD, Kathryn Foulds, PhD, Paula
DeLuca, PhD, Barbara Flynn, B.A.
Description of Research Program
The aim of the Cellular Immunology Laboratory is to rationally design
vaccines for diseases that require cellular immunity in humans.
The studies are focused into three integrated areas. 1) Understanding
the factors regulating the differentiation and maintenance of memory/effector
Th1 cells and CD8+ T cells in vivo. With regard to Th1
responses, we have previously reported that CD4+/IFN-g producing
cells are short-lived following antigenic stimulation in vivo.
We have recently shown the mechanism by which such cells are eliminated
in vivo. In this regard, IFN-g through induction of indoleamine
2,3-dioxygenase (IDO) mediates the death of such cells. Of note,
this pathway exerted a greater effect in the non-lymphoid compared
to the secondary lymphoid organs. In contrast to elimination of
IFN-g+ effector cells following activation, a heterogeneous population
of Th1 cells containing IL-2 producing cells was sustained following
antigenic stimulation in vivo. Importantly, such cells
had the capacity to develop into IFN-g producing cells. Together,
these data provide a model for maintenance of Th1 memory and efficient
control of protective but potentially deleterious CD4+/IFN-g effector
responses in non-lymphoid organs. This basic information should
have direct relevance for designing the appropriate quantitative
and qualitative type of Th1 response that will ensure both memory
and effector function.
2) Understand the cellular and molecular mechanisms by which vaccines
or adjuvants induce immunity in vivo at the level of the
antigen-presenting cell. As dendritic cells (DCs) are the most potent
cells for generating primary T cell responses, the major emphasis
will be on targeting DCs with vaccines. DCs are comprised of two
functionally distinct subsets termed myeloid (mDCs) and plasmacytoid
(pDCs) dendritic cells. mDCs are efficient at antigen presentation
and potent inducers of IL-12, while pDCs secrete IFN- a. Thus, targeting
these DC subsets should achieve optimal Th1 and CD8+ T cell responses.
One method of targeting DCs in vivo is with Toll-like receptor
(TLR) agonists or ligands acting through specific TLR expressed
in such cells. Importantly, there are substantial differences in
both the types of dendritic cell subsets and the expression of TLR
between mice and primates/humans. Thus, it is critical that vaccine
experiments using TLR agonist and ligands to target DCs be extended
from mice into non-human primates to facilitate translation into
humans.
3) Develop experimental mouse and non-human primate models for infections
requiring cellular immunity. To apply the knowledge learned from
the areas highlighted above, we use experimental mouse models of
Leishmania major and Mycobacterium tuberculosis
infection. Such diseases require Th1 responses and allow us to assess
whether memory induced by vaccination is sufficient to confer protection.
Vaccine formulations include plasmid DNA, replication defective
adenovirus and protein plus TLR ligands alone or in prime-boost
combinations. In addition, we have developed a mouse immunogenicity
model for HIV gag antigen in which we use all the current clinical
grade HIV gag vaccines as well as novel formulations. This model
allows a detailed immune analysis using intracellular cytokine staining
and a gag-specific tetramer. In addition, we have developed an in
vivo killing assay to determine whether the gag specific CD8+ T
cell responses are sufficient to mediate killing of target cells
in vivo. Such a model allows efficient modeling for application
in humans. For all these studies, a major effort has been to use
multicolor flow cytometry to phenotypic ally and functionally characterize
the immune responses following immunization and provide a more detailed
understanding of the immune correlates of protection for diseases
requiring cellular immune responses. In this regard, we believe
we have identified a new functional phenotype of Th1 cells that
correlates with protection against an intracellular infection in
mice that extends beyond measurement of the current standard of
IFN-g only. Finally, we developed non-human primate infection model
for Leishmania major to test the efficacy of our vaccines.
In addition, in collaboration with the Aeras Foundation, we will
use our expertise to help them assess immune responses in primate
models of Mycobacterium tuberculosis infection. Lastly, the SIV
challenge model will also be used for determination of vaccine efficacy
for our own studies.
Keywords
Cytokines, Vaccination, Infectious Diseases, Immunotherapy.
Recent Publications:
- Seder, R.A. and Sacks, D.L. Memory
may not need reminding. Nature Medicine, 10:507, 2004
- Seder RA, Ahmed R. Similarities
and differences in CD4+ and CD8+ effector and memory T cell generation.
Nat Immunol. 2003 Sep;4(9):835-42.
- Tritel, M., Stoddard AM., Flynn BJ., ,Darrah PA., Wu
C., Wille U., Shah JA., Huang Y, Xu L., Nabel GJ., and RA Seder.
Prime-boost
Vaccination with HIV-1 Gag Protein + CpG ODN Followed by Adenovirus
Induces Sustained and Robust Humoral and Cellular Immune Responses,
Journal of Immunology, 2003 Sep 1;171(5):2538-47.
- Shah JA., Darrah PA., Ambrozak, DR., Turon TN., Mendez
S., Kirman JR., and Seder RA. Dendritic
Cells are Responsible for the Capacity of CpG Oligodeoxynucleotides
to Act as an Adjuvant for Protective Vaccine ImmunityAgainst Leishmania
major in Mice. Journal of Experimental Medicine, 2003 Jul
21;198(2):281-91.
- Freidag BL, Mendez S, Cheever AW, Kenney RT, Flynn B,
Sacks DL, Seder RA. Immunological
and pathological evaluation of rhesus macaques infected with Leishmania
major. Experimental Parasitology, 2003 Mar-Apr;103(3-4):160-8.
- Kirman JR, Turon T, Hua S, Kraus C, Polo JM, Belisle
J, Morris S and Seder RA. Enhanced
Immunogenicity to Mycobacterium tuberculosis by Vaccinating with
an Alphavirus Plasmid Replicon Expressing Antigen 85. Infection
and Immunity, 2003 Jan;71(1):575-9.
- Wu C., Kirman JR, Rotte MJ, Davey DF, Davis H, Perfetto
SP, Rhee EG, Freidag BL, Hill BJ, Douek DC and Seder RA.
Distinct
Lineages of Th1 Cells have Differential Capacities for Memory
Cell Generation in vivo. Nat. Immunol 3:852-858, 2002.
- Rhee, E.G., Méndez S, Shah JA. Wu C., Kirman
JR, Turon TN, Davey DF, Davis H, Klinman DM, Coler RN, Sacks DL
and Seder RA. Vaccination
with Heat-killed Leishmania Antigen or Recombinant Leishmanial
Protein and CpG Oligodeoxynucleotides Induces Long-term Memory
CD4+ and CD8+T cell Responses and Protection Against Leishmania
major Infection. J. Exp. Med 195:1-10, 2002.
- Stobie L, Gurunathan S, Prussin C, Sacks DL, Glaichenhaus
N, Wu CY, Seder R.A. The
role of antigen and IL-12 in sustaining Th1 memory cells in vivo:
IL-12 is required to maintain memory/effector Th1 cells sufficient
to mediate protection to an infectious parasite challenge.
Proceeding National Academy of Science, 97:8427-8432, 2000.
- Seder,R.A. and Hill A. Vaccines
against intracellular infections requiring cellular immunity.
Nature, 406: 793-798, 2000.
- Gurunathan S, Stobie, L. Prussin, C, Sacks DL, Glaichenhaus
N. Iwasaki, A, Fowell, DJ, Locksley RM, Chang, JT, Wu, C. and
Seder R.A. Requirements
for the maintenance of Th 1 immunity in vivo following DNA vaccination:
A potential immunoregulatory role for CD8+ T cells. J. Immunol,
165:914-924, 2000.
- Freidag, BL, Melton, GB, Collins,F., Klinman DM, Cheever
A., Stobie L, Suen W., and Seder R.A. CpG
Oligodeoxynucleotides and Interleukin-12 Improve the Efficacy
of Mycobacterium Bovis BCG Vaccination in Mice Challenged with
M. tuberculosis. Infection and Immunity, 68:2948-2953, 2000.
- Gurunathan, S, Klinman, DM, and Seder R.A.
DNA
Vaccines: Immunology, Application and Optimization. Annual
Review of Immunology, 18:927-974, 2000.
- Seder, RA and Gurunathan, S. DNA
Vaccination: Designer Vaccines for the 21s Century. N England
Journal of Medicine, 341:277-278, 1999.
- McDyer, J.F., Dybul, M., Goletz, T.J., Kinder, A.L.,
Thomas, E.K., Berzofsky, J.A., Fauci, A.S., and Seder, R.A.
Differential
effects of CD40 ligand/trimer simulation on the ability of dendritic
cells to replicate and transmit HIV infection: Evidence for CC-chemokine-dependent
and -independent mechanisms. Journal of Immunology. 162(6):
3711-3717, 1999.
- Gurunathan, S., Prussin, C., Sacks, D.L., and Seder,
R.A. Vaccine
requirements for sustained cellular immunity to an intracellular
parasitic infection. Nature Medicine. 4: 1409-15, 1998.
- Gurunathan, S., Irvine, K.R., Wu, C.Y., Cohen, J.I.,
Thomas, E., Prussin, C., Restifo, N.P., and Seder, R.A.
CD40
ligand/trimer DNA enhances both humoral and cellular immune responses
and induces protective immunity to infectious and tumor challenge.
Journal of Immunology. 9: 4563-4572, 1998.
- Zhou, P. and Seder, R.A. CD40 ligand is not
essential for induction of type I cytokine responses or protective
immunity following primary or secondary infection with Histoplasma
capsulatum. Journal of Experimental Medicine. 87: 1-10, 1998.
- Gurunathan, S., Sacks, D.L., Brown, D.R., Reiner, S.L.,
Charest, H., Glaihenhaus, N., and Seder, R.A.
Vaccination
with DNA encoding the immunodominant LACK parasite antigen confers
protective immunity to mice infected with Leishmania major.
Journal of Experimental Medicine. 186: 1-11, 1997.
If you are interested in a Research Fellowship,
please send your CV to:
Dr. Robert A. Seder
NIH/Vaccine Research Center
40 Convent Drive
Bldg. 40, Room 4500
Bethesda, MD 20892-3005 |
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