Dendritic cell therapy

Introduction
Dendritic cells (DC) belong to the group of antigen-presenting cells (APC). One of the first functions discovered of DC was the very important role they play in the activation of specific immune responses against pathogens. Because of this function, they are often called ?gnature?fs adjuvant?h. In recent years, through increasing understanding of the role of DC in the immune system, new areas of clinical application were discovered and conducted. One example may be the improved immune response in vaccination of nonresponders. Very recently, the possible role of DC in the biological immune response against malignancies (solid tumours) was discovered and clinically investigated. DC?fs form a complex network of APC within the organism (1).

In early stages of differentiation, in skin and mucosa, DC have been described as so-called Cells of Langerhans (CL). CL function as perceivers and incorporation of, for instance, viral and bacterial antigens (Ag), and toxins. After perception of an Ag, CL are activated by local inflammatory signals (through the production of certain cytokines, including IL-2 and Il- 6), and wander mainly through the lymphatic system, and to a certain degree through the blood flow, to the secondary lymph nodes. Here, as fully differentiated, so-called interdigitating dendritic cells (IDC), CL settle in the T-cell areas and activate T-cells antigen specific. The function of DC is the transportation of Ag from the location of infection to the secondary lymph nodes, where the specific immune response against the Ag and toxins is orchestrated. Through transportation of Ag by DC to the lymph nodes, it is made easier for T-cells to come into contact with the Ag, as non-activated T-cells circulate through the peripheral lymph system several times during a 24-hour period. After being activated by DC, T-cells change their wander pattern, and become effector cells at the location of infection. As cytotoxic T-cells, they destroy infected cells in the body, and, interestingly, also tumour cells. As T-helper cells of the TH-1 type, they stimulate macrophages in their phagocytic and bactericide activities, by producing inflammatory mediators, to eradicate intra-cellular pathogens, like tuberculosis bacteria. As TH-2 cells, they support the humoral immune response by activating the anti-body producing B-cells. APC play an important role in recruiting antigen-specific T-cells to adapt properly the immune response. Usually, T-cells by themselves do not recognize Ag. APC have to prepare the recognition of Ag. This means, that within the APC, the (specific) Ag is dissected into much smaller peptides, and bound to the major histiocompatibilty complex class I (MHC-I). Afterwards, this MHC-I is presented at the surface of the cell membrane. Only then, T-cells are able to perceive the complex between the MHC-I molecule and the Ag peptide. This leads to the activation of the resting T-cells. In the periphery of the body CL are specialized in Ag recognition and Ag processing, but still have little potential for activation of resting T-cells. After their wandering to the secondary lymph nodes, and maturation into IDC, the process is reversed. Now, the IDC have lost the ability to recognize and process the Ag almost completely. In stead, IDC, which incorporated the Ag and presented the Ag on the cell surface in its CL stage, are now able to activate resting T-cells. Thus, within the lymph node, IDC guarantee that a most accurate picture is transmitted to the T-cells about the nature and the characteristics of the infection in the periphery. The specific capability of DC to activate native T-cells can be used immune therapies, like in cancer.

The purpose of our clinical and research activities will be, to sensitise DC for tumour-specific Ag. Thus, given back to the cancer patient through an infusion (as a ?gcellular vaccine?h), in this way specifically-activated Tcells of the patient will be able to eliminate tumour cells and pathogens, including chronic viral infections, like hepatitis C, human papilloma virus (HPV) in persistent cervix dysplasia, and HIV. Recently, it was found, that pre-loaded DC with human immunodeficiency virus type 1 (HIV-1) provoked strong responses from CD8+ Tlymphocytes of late-stage HIV-1 infected individuals. These responses were enhanced under application of gamma-interferon and interleukin-2, strongly suggesting, that DC of HIV-1 positives can be engineered to evoke a stronger anti-HIV-1 CD8+ T-lymphocyte reactivity as a strategy to augment anti-retroviral therapy (10).

Production and Differentiation of Human Dendritic Cells in vitro...