Potential applications of dendritic cells

Dendritic cells (DCs) are the professional antigen-p resenting cells of the immune system. Following infection or inflammation they undergo a complex process of maturation, and migrate to lymph nodes where they present antigens to T cells. Their decisive role in inducing immunity formed the rationale for DC immunotherapy: DCs loaded with tumor antigens are injected into cancer patients to stimulate T cells to eradicate tumors. Effective immune responses and favourable clinical outcomes have indeed been observed, but only in a minority of patients. For effective immunotherapy DCs need to traffic throughout the vascular and lymphatic system to reach the T-cells located within lymph nodes. Though most immunotherapeutic agents are administered intravenously, DCs are predominantly administered intradermally. We observed that < 5% of intradermally administered mature DCs reach the draining lymph nodes amounting to inefficient homing. Despite this low number we could measure effective immune responses in some patients, but generally this may be too low. We demonstrated that DC maturation is a prerequisite to exert their immunostimulatory capacity in vivo. Immuno-monitoring revealed a remarkable difference in immune responses. In patients vaccinated with immature DC the KLH responses as well as DTH reactivity against KLH and tumor-peptides were weak and absent, respectively. In contrast, in patients vaccinated with mature DC a pronounced T cell as well a B cell response (IgG) against KLH were observed. Analysis of the response against the tumor peptides demonstrated little or no reactivity in blood. However, following intradermal administration of a delayed type hypersensitivity (DTH) challenge with gp100- and tyrosinase-peptide loaded DC essentially all patients vaccinated with mature DC showed a positive induration. Moreover, we showed the predictive value of the presence or absence of antigen-specific T cells in biopsies from DTH sites. In clinically responding patients, T cells specific for the antigen preferentially accumulated in the DTH site in accordance with the applied antigen in the DTH challenge.