Robert Seder, M.D.

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.

Awards / Societies

• Member, Collegium Internationale Allergologicum (1996)
• Member, American Society of Clinical Investigation (1998)

Editorial Boards

• Journal of Experimental Medicine

Keywords

Cytokines, Vaccination, Infectious Diseases, Immunotherapy

Research Group Members

Patricia Darrah, PhD, Ulrike Wille, PhD, Kathryn Foulds, PhD, Paula DeLuca, PhD, Barbara Flynn, B.A.

Selected 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.

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