Department Affiliation: Primary: Pharmacology and Molecular Sciences; Secondary: Oncology,
Johns Hopkins Singapore
Degree: M.D., Stanford University
Rank: Professor
Telephone Number : 410-955-8484
Fax Number: 410-955-1894
E-mail address: taugust@jhmi.edu
School of Medicine Address: 311 Biophysics Building, 725 N. Wolfe St., Baltimore, MD 21205
Genetic immunotherapy of infectious diseases and cancer by targeting DNA encoded antigen chimeras to MHC II; MHC II antigen presentation; development of DNA vaccines; immune tolerance
The research of this laboratory is directed at programs for genetic immunotherapy and studies of the mechanisms of MHC II antigen presentation and immune tolerance, and is also being conducted in laboratories of The Johns Hopkins Singapore Biomedical Centre. Current programs include studies in mice, monkeys and humans.
- A novel strategy for genetic immunotherapy by antigen targeting to helper T cells - We have developed a strategy for targeting the protein products of DNA vaccines to the major histocompatability complex (MHC) class II pathway for antigen presentation to CD4+ helper T cells. The DNA vaccine is constructed as a recombinant gene chimera, containing the antigen sequence attached to the the LAMP lysosomal membrane protein that is co-localized with MHC II of antigen presenting cells. Studies with mice and monkeys have shown that the targeted antigen induces markedly enhanced immune responses, antibody, CD4 and CD8, as compared to the nontargeted antigen. Studies are currently in progress with DNA vaccines to several viruses, HIV-1, flaviviruses, and SARS CoV are leading projects, and the BCR/Abl cancer antigen of chronic myelogenous leukemia. Other infectious disease agents and putative cancer antigens are also possible targets of this application.
- Alternative pathways for targeting of DNA encoded antigens to the MHC II pathway for antigen processing and presentation - In addition to utilizing LAMP/antigen chimeras, we are investigating the application of other systems that traffick to MHC II, including the dendritic cell receptors that capture extracellular antigens for endocytosis to the MHC II compartment. Additional LAMP molecules, including DC-LAMP, a specialized member of the LAMP family of proteins that is unique to dendritic cells and is co-expressed with MHC II, are also being investigated.
- Immune response mechanisms: These studies also encompass a variety of immune response mechanisms that individually are being analyzed: formation of immunological memory; e.g., immunodiagnosis by analysis of recall memory T- and B-cells responses, antigen-specific immunomodulation; antigen epitope identification and epitope-based vaccines.
Representative Publications:
- Ruff, A.L., Guarnieri, F.G., Staveley-O'arroll, K., Siliciano, R.F., and August, J.T. Targeting of the HIV gp160 gene product to lysosomes enhances the immune response, J. Biol. Chem., 272:8671-8678, 1997. Pub Med Reference
- Truong-Le, V.L., August, J.T., and Leong, K.W. Controlled gene delivery by DNA-gelatin nanospheres, Human Gene Therapy, 9:1709-1717, 1998. Pub Med Reference
- Qiu, J.T, Song R., Dettenhofer, M., Tian, C., August, J.T., Felber, B.K., Pavlakis, G.N., and Yu, X.F. Evaluation of novel human immunodeficiency virus type 1 Gag DNA vaccines for protein expression in mammalian cells and induction of immune responses, J. Virol., 73: 9145-9152, 1999. Pub Med Reference
- Georgantas III, R.W., Leong, K.W., and August, J.T. Antigen specific induction of peripheral T cell tolerance in vivo by co-delivery of DNA vectors encoding antigen and Fas ligand, Human Gene Therapy, 11:851-858, 2000. Pub Med Reference
- Wu, Jian-Ming, Wu, B., Guarnieri, F., August, J.T., and Drachman, D.B. Targeting antigen-specific T cells by genetically engineered antigen presenting cells. A strategy for specific immunotherapy of autoimmune disease, J. Neuroimmunology, 106:145-153, 2000. Pub Med Reference
- Furuta, K., Ikeda, M., Nakayama, Y., Nakamura, K., Tanaka, M., Hamasaki, N., Himeno, M., Hamilton, S. R., and August, J.T. Expression of lysosome-associated membrane proteins (LAMPs) in human colorectal neoplasms and inflammatory diseases, Amer. J. Pathology, 159:449-455, 2001. Pub Med Reference
- Raviprakash, K., Marques, E., Ewing D., Lu, Y., Phillips, I., Porter K.R, Kochel, T.J., August .J.T., Hayes, C.G., and Murphy, G.S. Synergistic neutralizing antibody response to a dengue virus type 2 DNA vaccine by incorporation of lysosome associated membrane protein (LAMP) sequences and use of plasmid expressing GM-CSF, Virology, 290:74-82, 2001. Pub Med Reference
- Lu, Y., Raviprakash, K., Leao, I.C., Chikhlikar, P.R., Ewing, D., Anwar, A., Chougnet, C., Murphy, G., Hayes, C.G., August, J.T., and Marques, E.T.A. Dengue 2 PreM-E/LAMP chimera targeted to the MHC class II compartment elicits long-lasting neutralizing antibodies, Vaccine, 21:2178-2189, 2003. Pub Med Reference
- Anwar, A., August, J.T., and Too, H.-P. Specific detection and quantification of the replicative form of the dengue virus by fluorescence-based PCR, submitted.
- Marques, E. T.A. Jr., Chikhlikar, P., Barros de Arruda, L., Leao, I.C., Lu, Y.,Wong, J., Chen, J-S., Byrne, B., and August, J.T. DNA encoding a HIV-1 Gag/lysosome-associated membrane protein (LAMP) chimera elicits augmented expression of Gag protein, antigen trafficking to MHC II, and enhanced Gag-specific immune responses, J. Biol. Chem., 2003, paper in press. Pub Med Reference
Other graduate programs in which Dr. August participates:
