Process for preparing dendritic cells, cells thus produced and c

Details Process for preparing dendritic cells, cells thus produced and c Process for preparing dendritic cells, cells thus produced and c

1996-10-11

1999-02-02

Feisee, Lila

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

Animal or plant cell

424 852, 424 857, 514825, 435325, A61K 3500, A61K 3510, C12N 1585

Patent

active

058661158

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the preparation of dendritic cells, which can not only be of use in basic research but can also advantageously be used therapeutically.
EPA 92.400879.0 discloses a process for producing human dendritic cells. In this, process, CD 34.sup.+ cells are treated with tumour necrosis factor-.alpha. (TNF-.alpha.) and either interleukin-3 or GM-CSF. However, it has emerged that the desired cells cannot be obtained in the requisite yield and purity when using this process.
Dendritic cells constitute the most potent antigen-presenting cells in the organism. They are derived from bone marrow progenitor cells, circulate in small numbers in the peripheral blood and appear as so-called Langerhans' cells or terminally differentiated cells (dendritic cells) in the epidermis of the skin, the gastrointestinal mucosa, the visceral pleura or the epithelia of the urogenital tract.
Following exposure to antigen, these cells migrate from the skin into the paracortex of draining lymph nodes, where, as terminally differentiated cells, they elicit a specific T cell response. Their function as antigen-presenting cells can be demonstrated in vitro in the autologous and allogenic "mixed lymphocyte reaction" and in test systems to which soluble antigens are added.
The dendritic cells can be differentiated from monocytes/macrophages, which likewise constitute antigen-presenting cells but express other surface markers. A particular differentiating marker is the CD 14 antigen, which is not found in dendritic cells but is possessed by monocytes and macrophages. The dendritic cells are not phagocytic, in contrast to the monocytes/macrophages, which are strongly phagocytosing cells. The surface antigens in the circulating dendritic cells can be defined as follows: CD1a.sup.+, CD1c.sup.+, CD 13.sup.+, CD 33.sup.+, CD 14.sup.- CD 16.sup.-, CD 3.sup.-, CD 19.sup.- and MHC II.sup.+.
After these cells have been cultured in vitro, or following physiological stimulation with antigen, expression of the MHC II molecules increases and CD 25, B 7, CD 40 and ICAM 1 are also expressed.
The dendritic cells (abbreviated DC) are antigen-presenting cells which are able to induce activation of T cells with a high degree of efficiency. They are highly specialized and optimally equipped for their task, since dendritic cells express molecules which are required for presenting antigen (MHCI and MHCII) in large quantity. In addition to this, these cells express the constitutively co-stimulatory molecules CD80 and CD86 on their surface. These molecules are in turn essential for activating the T cells. Important adhesion molecules, which guarantee intimate contact with the target cell, are also present on the surface of the dendritic cells.
Two maturation stages can be distinguished in dendritic cells. These cells of the Langerhans' type (abbreviated LC) are distributed throughout the body in non-lymphatic organs. Their task is to take up antigen and process it. While there are no specific markers for these cells, they express the following markers: CD 1a, CD 11b, CD 33, HLA-DR and CD 80. More specific detection can be achieved by means of electron microscopy. The so-called Birbeck granules, which are only possessed by Langerhans' cells, can be detected electronmicroscopically.
In the body, the Langerhans' cells migrate, after contact with antigen, from the periphery of the body into the lymphatic organs by way of the lymphatic system. During this journey, they differentiate into mature immunostimulatory dendritic cells which no longer take up any antigen but on the other hand induce powerful T cell responses.
It is possible, therefore, to distinguish between Langerhans' cells and mature dendritic cells (abbreviated DC). Typically, these DC cells exhibit a decrease in the expression of CD 1a and an increasing expression of CD 4, CD 25 and CD 80.
The dendritic cells can be used, for example, in reinforcing an anti-infection therapy. The antigen-presenting dendritic cells are of particular importance in viral and bacterial infections, a

REFERENCES:
Osband, ME et al. 1990, Immunol. Today 11:193-195.
Brugger, W. et al. 1993. Blood, 81(10):2579-2584.
Ferrajoli, A et al. 1993. Ann. Hematol. 67(6):271-284.
Dercksen, MW. et al. 1993. Int. J. Cancer, 68(5):996-1003.
Ex Vivo Expansion of Enriched Peripheral Blood CD34+ Progenitor Cells By Stem Cell Factor, Interleukin-1Beta (IL-1 Beta), IL-6, IL-3, Interferon-Gamma, and Erythropoietin, Blood, vol. 81, No. 10, pp. 2579-2584 (1993), Brugger et al.
Human Stem Cell Factor (SCF) Promotes the Growth of Dendritic Langerhans Cells from their Primitive Porgenitors (CFU-DL) In Human Bone Marrow, Blood (Supplement 1), vol. 82, No. 10, p. 102a (1993), Saraya et al.
Growth Factors Controlling Interleukin-4 Action on Hematopoietic Progenitors, Database Medline, US National Library of Medicine (NLM), Ann Hematology pp. 277-284 (1993), Ferrajoli et al.
Ex Vivo Generation of Functionally Active Antigen Presenting Cells From Peripheral blood (CD34+ Hematopoietic Progenitor Cells in Cancer Patients, Blood (Supplement 1), vol. 84, No. 10, p. 228a )1994), Fisch, P. et al.

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