Vaccination Strategies for Enhanced Immunity

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Vaccination can be considered as a therapeutic modality that actively engages the immune system of the patient. It encompasses numerous principles derived from drug targeting research. Modification of the responses of the immune system may be an effective approach to improve the disease status of patients with a variety of diseases. Either prevention of au-

toimmune diseases or allergic responses, or enhancement of immune responses against infectious agents and tumour growth can be induced by these strategies [95,96]. Vaccination strategies can be divided into gene-, peptide-, protein- and cell-based strategies.

Antigen presenting cells (APC), particularly dendritic cells (DC), play a central role in the induction of the desired immune response [97]. For successful (antitumour) vaccination therapy, either an in vitro or an in vivo approach can be followed. In the in vitro approach, DCs from an animal or a patient are isolated and manipulated by transfection with DNA or RNA encoding (tumour) antigens or pro-inflammatory factors, or by loading the cells with proteins or peptides. After transfer back into the animal or patient, the cells can evoke antigen-specific immune responses [98]. Similarly, in vitro transfected tumour cells encoding a combination of genes involved in regulation of immune responses (e.g. MHC class II, a co-stimulatory molecule and a superantigen [96]) may serve as a vaccine.

The major drawback in the use of isolated DCs is the time-consuming isolation and culture methods required to obtain the cell type of interest. Therefore, in vivo vaccination strategies employing DCs have been developed. For this purpose, fusion proteins of e.g. tumour antigens and molecules that are specifically recognized by DCs are under investigation. The DC targeting molecules consist of e.g. DC-specific chemokines, mannose, the Fc moiety of immunoglobulin, cytotoxic T lymphocyte-associated antigen (CTLA-4) molecule [99-103]. They enable efficient uptake of the fusion protein by the DCs, induction of DC migratory capacity into the lympoid organs and maturation into a dedicated APC. As an example, studies by Biragyn et al. showed that active targeting of a tumour antigen into a receptor-mediated uptake route in APCs by the fusion of the antigen to APC-specific chemokines, elicited superior protection against a large tumour challenge in mice [99].

For a more detailed discussion of vaccines and vaccination strategies, the reader is referred to Volume 170 of Immunological Reviews (1999), in which various aspects of this area of research are discussed in greater detail.

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