IN-VITRO GENERATION OF HUMAN DENDRITIC CELLS AND CELL THERAPY

Dendritic cells (DC) are the most potent antigen-presenting cells: the y, only, can prime naive T lymphocytes and even elicit generation of c ytotoxic T lymphocytes to soluble antigens. Thus ex vivo antigen-pulse d DC represent a potentially powerful tool to elicit T-cell mediated r esponses against viral or tumor-associated antigens. Because isolation of DC as such from the blood is hampered by their scarcity, culture m ethods to generate them from different progenitors or precursors have been developed. Indeed, the possibility of obtaining relatively high n umbers of DC from bone marrow, cord blood or adult blood CD34(+) proge nitors, or even blood monocytes, in cultures with different combinatio ns of growth factors - mainly based on the use of GM-CSF, TNF-alpha an d IL-4 has allowed the study of their ontogeny, the characterization o f the different types of DC obtained under diverse conditions, and the assessment of whether they relate to a single pathway of differentiat ion. For example, the finding that monocytes acid even macrophages can differentiate into DC depending on the cytokines used has to be recon ciled with evidence that supports earlier branching off of the macroph age and DC lineages, and raises questions as to the identity of the la tter lineage. Also, besides DC of myeloid origin, DC arise from lympho id progenitors, and lymphoid DC display different properties than myel oid DC - at least in mice. From a practical point of view, there is a need to define the most appropriate cytokine combinations and schedule s to optimize proliferation, differentiation and maturation of DC from different sources. In addition, because the capacity of DC to capture , process and present antigens varies according to their differentiati on/maturation stage and origin, it appears necessary to define which t ype of DC to use for cell therapy in the setting of a given pathology for efficient and safe use.