Adjuvant Properties of Thermal Component of Hyperthermia Enhanced Transdermal Immunization: Effect on Dendritic Cells

Abstract

Hyperthermia enhanced transdermal (HET) immunization is a novel needle free immunization strategy employing application of antigen along with mild local hyperthermia (42°C) to intact skin resulting in detectable antigen specific Ig in serum. In the present study, we investigated the adjuvant effect of thermal component of HET immunization in terms of maturation of dendritic cells and its implication on the quality of the immune outcome in terms of antibody production upon HET immunization with tetanus toxoid (TT). We have shown that in vitro hyperthermia exposure at 42°C for 30 minutes up regulates the surface expression of maturation markers on bone marrow derived DCs. This observation correlated in vivo with an increased and accelerated expression of maturation markers on DCs in the draining lymph node upon HET immunization in mice. This effect was found to be independent of the antigen delivered and depends only on the thermal component of HET immunization. In vitro hyperthermia also led to enhanced capacity to stimulate CD4+ T cells in allo MLR and promotes the secretion of IL-10 by BMDCs, suggesting a potential for Th2 skewing of T cell response. HET immunization also induced a systemic T cell response to TT, as suggested by proliferation of splenocytes from immunized animal upon in vitro stimulation by TT. Exposure to heat during primary immunization led to generation of mainly IgG class of antibodies upon boosting, similar to the use of conventional alum adjuvant, thus highlighting the adjuvant potential of heat during HET immunization. Lastly, we have shown that mice immunized by tetanus toxoid using HET route exhibited protection against challenge with a lethal dose of tetanus toxin. Thus, in addition to being a painless, needle free delivery system it also has an immune modulatory potential.

Synergism Between Propolis and Hyperthermal Intraperitoneal Chemotherapy with Cisplatin on Ehrlich Ascites Tumor in Mice

“…WSDP is known to directly activate macrophages and dendritic cells, which in turn stimulate NK cells through interleukin‐12 secretion . It is known that natural killer cells and macrophages cooperate in tumor rejection, whereas hyperthermia may have either a direct suppressive effect on tumor cells or it may act indirectly via enhanced or host immune function …”

“…[21][22][23][24][25][26][27] It is known that natural killer cells and macrophages cooperate in tumor rejection, 16,[20][21][22][23][24][25][26] whereas hyperthermia may have either a direct suppressive effect on tumor cells or it may act indirectly via enhanced or host immune function. 51,52 It has been theorized that following tumor heating, absorbed fragments of necrotic cancer cells provide the antigenic stimulus needed to enhance the host immune system that then lead to the destruction of tumor cells. 53,54 In the present study, the most pronounced effect on animal survival was achieved with the combination of WSDP and cisplatin when combined with hyperthermia; the enhancement of cytotoxicity in combination with hyperthermia and synergistic activity of WSDP and cisplatin should be considered to be the case as was suggested by Orsolić et al 2 According to other findings by Lindegaard et al, 55 the synergistic effect between hyperthermia and cisplatin is the highest during simultaneous application as was also shown in this study.…”

Stressful Presentations: Mild Cold Stress in Laboratory Mice Influences Phenotype of Dendritic Cells in Naïve and Tumor-Bearing Mice

“…DCs in ear skin subjected to thermal stress in culture show increased migration compared to control samples (75), while increased DC migration into the lymph nodes of thermally stressed mice has also been demonstrated (61). …”

Mild Hyperthermia Enhances Transport of Liposomal Gemcitabine and Improves In Vivo Therapeutic Response

“…While previous efforts have demonstrated the use of GNR-mediated photothermal therapy to improve accumulation of thermo-sensitive polymers [23] , these strategies have caused irreversible vascular damage and do not account for the transport contributions associated with MHT treatment. Other previous studies have used water-bath heating to produce MHT conditions, the rate of heating is very slow [24] and uncontrolled [25] . We applied prolonged MHT treatment (20 min) to overcome thermo-tolerance known to occur in cancer cells [26] while staying below threshold settings reported to cause permanent vessel occlusive damage that arise once temperature reaches 43°C and maintained for 240 min [27] .…”