Dendritic cell vaccines and the ontogeny of dendritic cells

Jean Claude Gluckman, Bruno Canque

Institut National de la Recherche Scientifique EPI-0013, and laboratoire d'Immunologie Cellulaire et Immunopathologie de l'Ecole Pratique des Hautes Etudes, Institut Universitaire d'Hématologie, hôpital Saint-Louis, Paris, France

Dendritic cells (DC) are major multifunctional players of the immune system. Therefore, their use has been proposed as "nature's adjuvants" in anti-tumor DC vaccine protocols. Nevertheless, as regards their ontogeny, DC still represent an almost complete blackbox. Indeed, there exist distinct DC populations of diverse origins, which develop from hematopoietic progenitors either immature or already committed to the lymphoid or the myeloid lineages and, in the latter case, even from terminally differentiated macrophages. One may envision that, with respect to their functions, DC originating from lymphoid progenitors are rather dedicated to the adaptative immune system, along which they have phylogenetically co-evolved, whereas myeloid DC would be more involved as an interface between the innate and adaptative immune systems. However, any DC can ultimately present antigens in either an immunogenic or tolerogenic fashion, and end-up secreting the same cytokines, according to whether they are more or less, or not activated toward maturation, and depending on the microenvironment under which they have encountered antigen. Hence, DC either induce the appropriate immune response to pathogens for example, or can thwart autoimmune reactivity. Thus, besides default programming, which should be necessary to face the challenges of their usual setting, each type of DC can also display functions that are similar, in an instructive mode, in order to elicit the immune responses deemed necessary for unexpected stimuli. Such DC system provides enough flexibility and sufficient redundancy to insure that an essential function of the immune system, i.e. transmitting information from its innate to adaptative arms and effect the latter's responses, should occur under optimal conditions. This leads to the hypothesis that DC do not represent nor belong to a particular hematopoietic lineage, but that a recently evolved "lineage-independent developmental program" controls their differentiation: once switched on, either constitutively or upon a "danger signal", this program elicits rapid transformation of a wide array of leukocytes into "professional antigen-presenting cells". Working on the basis of such a unified theory of DC diversity should be useful for learning how to adequately manipulate the immune system for the development of cellular immunotherapy of cancer based on DC vaccines.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Immunotherapy.