Abstract
Dendritic cells (DC) are increasingly prepared in vitro for use in immunotherapy trials. Mature DC express high levels of surface molecules needed for T cell activation and are superior at antigen-presentation than immature DC. Bacillus Calmette-Guerin (BCG) is one of several products known to induce DC maturation, and interferon (IFN)-γ has been shown to enhance the activity of DC stimulated with certain maturation factors. In this study, we investigated the use of IFN-γ in combination with the powerful maturation agent, BCG. The treatment of immature DC with IFN-γ plus BCG led to the upregulation of CD54, CD80, and CD86 in comparison with BCG treatment alone. In MLR or recall immune responses, the addition of IFN-γ at the time of BCG-treatment did not increase the number of antigen-specific T cells but enhanced the development of IFN-γ-producing Th1 cells. In primary immune responses, on the other hand, BCG and IFN-γ co-treated DC stimulated higher proportions of specific T cells as well as IFN-γ secretion by these T cells. Thus the use of IFN-γ during BCG-induced DC maturation differentially affects the nature of recall versus naïve antigen-specific T-cell responses. IFN-γ co-treatment with BCG was found to induce IL-12 and, in some instances, inhibit IL-10 secretion by DC. These findings greatly enhance the potential of BCG-matured dendritic cells for use in cancer immunotherapy.
Highlights
Dendritic cells (DC), the professional antigen presenting cells of the immune system, are increasingly prepared in vitro for use in the experimental immunotherapy of cancer
We had previously found that DC respond to killed Bacillus Calmette-Guerin (BCG) mycobacteria with increased expression of MHC class I and class II molecules, CD54, CD80 and CD86, and CD83
These phenotypic consequences of maturation induced by BCG have been described by others, and are similar to those obtained using other maturation factors such as LPS or monocyte-conditioned media
Summary
Dendritic cells (DC), the professional antigen presenting cells of the immune system, are increasingly prepared in vitro for use in the experimental immunotherapy of cancer. Various protocols for the culture of these cells have been established with the specific purpose of human clinical use, and various advantages ascribed to each [1,2,3,4,5,6]. Maturation of DC is the process that converts immature DC, which are phenotypically similar to skin Langerhans cells, to mature antigen presenting cells that migrate to lymph nodes. This process results in the loss of the powerful antigen uptake capacity that characterizes immature DC and in the upregulation of co-stimulatory molecule expression and of various cytokines [9,10].
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