The Journal of Immunology, Vol 156, Issue 11 4345-4353, Copyright © 1996 by American Association of Immunologists

ARTICLES

Autocrine activation of hemopoietic progenitor-derived myelo-monocytic cells by IFN-gamma gene transfer

SS Ahuja, MR Brown, TA Fleisher, SK Ahuja and HL Malech
Laboratory of Host Defenses, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.

Immunomodulatory cytokines have been used with success as adjunctive therapy in genetic disorders such as chronic granulomatous disease and infectious diseases such as leishmaniasis and leprosy. As the first step toward developing novel methods to deliver immunomodulatory cytokines, we used retrovirus-mediated somatic gene transfer techniques to produce IFN-gamma from human peripheral blood CD34+ hemopoietic progenitor (PBHP) cells. After transduction, the PBHP cells were made to differentiate toward myelo-monocytic lineages. Only the PBHP-derived myelo-monocytic cells that were transduced with the IFN-gamma cDNA produced IFN-gamma(4 +/- 1.3 ng of IFN-gamma/10(6) PBHP cells.) Despite a reduction in the proliferation of IFN-gamma-transduced PBHP cells as well as a decrease in erythroid colony formation, there was an enhancement of monocyte differentiation and activation. Monocytes differentiated from the IFN-gamma-transduced PBHP cells demonstrated 1) up-regulation of MHC class I and II Ag expression, 2) increased Fc(gamma)RI expression, and 3) enhanced superoxide production in response to both opsonized zymosan (25-fold) and phorbol ester (3- fold). Furthermore, a functional response to a monocyte-specific chemokine, monocyte chemotactic protein-1 (mobilization of intracellular Ca2+) was seen only in the IFN-gamma-transduced cells. Thus, PBHP cells transduced with IFN-gamma cDNA produce not only biologically active IFN-gamma, but also enhanced monocyte differentiation, resulting in an activated state that includes unique functions, such as responsiveness to monocyte chemotactic protein-1. These transduced activated monocytes may be specifically suited to cellular therapy requiring homing to sites of inflammation where their anti- microbicidal, cytotoxic and APC functions play an important role in host defense against foreign pathogens.

This article has been cited by other articles:

				Y. Peng, F.-c. Lin, P. H. Verardi, L. A. Jones, M. B. McChesney, and T. D. Yilma Pseudotyped Single-Cycle Simian Immunodeficiency Viruses Expressing Gamma Interferon Augment T-Cell Priming Responses In Vitro J. Virol., March 1, 2007; 81(5): 2187 - 2195. [Abstract] [Full Text] [PDF]

				S. S. Ahuja, R. L. Reddick, N. Sato, E. Montalbo, V. Kostecki, W. Zhao, M. J. Dolan, P. C. Melby, and S. K. Ahuja Dendritic Cell (DC)-Based Anti-Infective Strategies: DCs Engineered to Secrete IL-12 Are a Potent Vaccine in a Murine Model of an Intracellular Infection J. Immunol., October 1, 1999; 163(7): 3890 - 3897. [Abstract] [Full Text] [PDF]

				C. Jiang, D. M. Magee, and R. A. Cox Construction of a Single-Chain Interleukin-12-Expressing Retroviral Vector and Its Application in Cytokine Gene Therapy against Experimental Coccidioidomycosis Infect. Immun., June 1, 1999; 67(6): 2996 - 3001. [Abstract] [Full Text] [PDF]

				S. S. Ahuja, S. Mummidi, H. L. Malech, and S. K. Ahuja Human Dendritic Cell (DC)-Based Anti-Infective Therapy: Engineering DCs to Secrete Functional IFN-{gamma} and IL-12 J. Immunol., July 15, 1998; 161(2): 868 - 876. [Abstract] [Full Text] [PDF]

				S. Mummidi, S. S. Ahuja, B. L. McDaniel, and S. K. Ahuja The Human CC Chemokine Receptor 5 (CCR5) Gene. MULTIPLE TRANSCRIPTS WITH 5'-END HETEROGENEITY, DUAL PROMOTER USAGE, AND EVIDENCE FOR POLYMORPHISMS WITHIN THE REGULATORY REGIONS AND NONCODING EXONS J. Biol. Chem., December 5, 1997; 272(49): 30662 - 30671. [Abstract] [Full Text] [PDF]