Immortalization of dendritic cells with V-MYC oncogene

Details Immortalization of dendritic cells with V-MYC oncogene Immortalization of dendritic cells with V-MYC oncogene

1995-11-29

1999-01-05

Chambers, Jasemine C.

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

4353201, 435 6, 4351723, 435354, 435366, C12N 500, C12N 1500

Patent

active

058561803

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP94/01720, filed May 26, 1994.
The present invention refers to immortalized dendritic cells, to a process for their production from primary cultures and to their use for the activation, in vivo or in an vitro, of T lymphocytes in antigen specific way.
The antigen specific immune response is the result of interactions between T, B lymphocytes and antigen presenting cells (APCs). The type of immune response elicited by the antigen (cell-mediated cytotoxic or humoral responses) and the generation of immune memory are influenced by the interaction between these cells and their products, by the site where these interactions occur and by the nature of the antigen itself. It is believed that activation and suppression of the immune system are also the results of the above mentioned variables which, if not regulated, can lead to autoimmune diseases and tolerance induction.
Dendritic cells (DC), first described by Steinman and Cohn in 1973 (J. Exp. Med. 137:1142, 1973), are a population of widely distributed leukocytes that play a key role in the immune system (Steinman R. M. 1991, Annu. Rev. Immunol. 9:271-296; Romani N. et al., 1992, Spinger Semin. Immunopathol. 13:265) given that they are: i. highly specialized in antigen presentation, ii. the principal activators of resting T cells in vitro (Inaba M. D. et al., 1984, J. Exp. Med. 160:858; Croft M. et al., 1992, J. Exp. Med. 176:1431), iii. the major source of immunogenic epitopes for specific T cell clones following administration of antigen in vivo (Inaba K. et al., 1990, J. Exp. Med. 172:631; Crowley M. et al., 1990, J. Exp. Med. 172:383) and iiii. the most potent initiators of primary T cell-mediated responses in vivo (Lechler R. I. et al., 1982, J. Exp. Med. 155:31).
Several studies have suggested that DC provide naive T cells with all the necessary signals required for activation and proliferation (Steinman R. M. and Romani N., above cited). These signals are generated by the interaction of complexes of major histocompatibility complex (MHC) molecules and antigenic peptides with the T cell receptor (Davis M. et al., 1988, Nature 334:395), and by the engagement of co-stimulatory molecules, including binding of B7/BB1 molecules on antigen presenting cells (APC) to CD28 receptor on the T cell surface (Young J. W. et al., 1992, J. Clin. Invest. 90:229; Nabavi N. et al., 1992, Nature 360:266). The first signal alone elicits effector functions only in activated T cells and is unable to stimulate naive or resting T cells, which in the absence of co-stimulatory signals can enter a period of unresponsiveness (Inaba K. et al., 1985, Science 229:475; Mueller D. L. et al., 1989, J. Immunol. 142:2617; Tan P. et al., 1993, J. Exp. Med. 177:165). The expression of the co-stimulatory molecule B7/BB1 on DC populations has been recently reported and shown to be critical in DC-driven primary T cell responses (Larsen C. P. et al., 1992, J. Exp. Med. 176:1; Symington F. W. et al., 1993, J. Immunol. 150:1286; Liu Y. et al, 1992, Eur. J. Immunol. 22:2855).
Understanding the mechanisms underlying the potent stimulatory capacities of DC could explain how T cells are primed, and how the immune response is initiated. With this knowledge one might try to manipulate immune responses at very early stages and provide a way for inducing immunity or tolerance. However, an important limitation in the study of DC biology has been the small numbers of cells available from any tissue, given that no stable cell lines that are clearly similar to DC have been obtained so far.
Three different tissues have been used as major sources of DC: mouse spleen, the epidermis, where DC are known as Langerhans cells, and human blood. In each case DC constitute a tiny fraction of the starting tissue, representing about 1% of crude spleen (Steinman R. M. et al., 1979, J. Exp. Med. 149:1) or epidermal (Schuler G. et al., 1985, J. Exp. Med. 161:526; Romani N. et al., 1989, J. Invest. Dermatol. 93:600) cell suspensions and 0.1-1% of peripheral blood mononuclear cells (Freudentha

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