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

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-γ 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-γ cDNA produced IFN-γ (4 ± 1.3 ng of IFN-γ/10⁶ PBHP cells). Despite a reduction in the proliferation of IFN-γ-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-γ-transduced PBHP cells demonstrated 1) up- regulation of MHC class I and II Ag expression, 2) increased FcγRI 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- γ-transduced cells. Thus, PBHP cells transduced with IFN-γ cDNA produce not only biologically active IFN-γ, 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 antimicrobicidal, cytotoxic, and APC functions plays an important role in host defense against foreign pathogens.