ANALYSIS OF DENDRITIC CELL STIMULATION UTILIZING A MULTI-FACETED NANOPOLYMER DELIVERY SYSTEM AND THE IMMUNE MODULATOR 1-METHYL TRYPTOPHAN.
Dendritic cells (DCs) play a pivotal role in immune modulation. Therefore, understanding and regulating the mechanism of DC activation is paramount for functional optimization of any immunotherapy strategy. In particular, the paradoxical ability of DCs to secrete the immune suppressive enzyme indoleamine 2, 3-dioxygenase (IDO) and the suppressive cytokine IL-10 during the course of, and in response to, stimulation is of great interest. 1-Methyl-Tryptophan (1 MT) is a known inhibitor of IDO and has thus been administered in numerousin vitroandin vivosystems to block IDO activity. However, the effect 1 MT has on DCs beyond inhibiting IDO, especially in therapeutic models, has rarely been analyzed. In the current study, we have administered 1 MT via a nanopolymer-based delivery system in conjunction with an antigen (ovalbumin, OVA) and an adjuvant (CpG motif DNA) to determine both the effects of 1 MT on DCs and the resulting efficacy of the polymer-based treatments. 1 MT delivery alone, either via the polymer-based delivery vehicle or dissolved in solution, induced no significant change in DC activation as measured by surface expression of CD80, CD86, and MHCII and several secreted products such as IL-12. These same factors were upregulated however, when 1 MT was delivered in conjunction with OVA and CpG. Although soluble delivery of these components increased the levels of expression and secretion of key proteins, a differential effect of DC stimulation was seen as a result of the polymer delivery system. The T cell suppressive IL-10 secretion was lower with the polymer-based treatments and IL-12 immune-enhancing secretion was increased when 1 MT was supplemented into the polymer system. As a result, including 1 MT in the polymers along with OVA and CpG was seen to have additional effects on DC stimulation and was able to shift DCs to a state more indicative of inducing a Th1-type response.
Department of Biomedical Engineering, Rutgers University, 599 Taylor Road Piscataway, New Jersey, USA.
Kevin P
KP
Nikitczuk
The Cancer Institute of New Jersey, Departments of Surgery and Molecular Genetics Microbiology, and Immunology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
Edmund C
EC
Lattime
Department of Biomedical Engineering, Rutgers University, 599 Taylor Road Piscataway, New Jersey, USA.
Rene S
RS
Schloss
Department of Biomedical Engineering, Rutgers University, 599 Taylor Road Piscataway, New Jersey, USA.
Martin L
ML
Yarmush
1-methyl-tryptophan; 1MT; DC; Dendritic cells; PLGA