Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Patent
1995-04-28
1999-02-16
Achutamurthy, Ponnathapura
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
4241931, 4241861, 4241881, 530811, 530815, A61K 3921, A61K 39385, A61K 3912
Patent
active
058717471
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The object of the present invention is microparticles carrying antigens on their surf ace and their use in the induction of humoral or cellular responses.
More specifically, the invention also relates to microparticles carrying a significant density of antigens on their surface.
The B cells which express immunoglobulin receptors specific for an individual antigen are highly effective for the presentation of this antigen (Rock et al. C., J. Exp. Med. (1984) 160; 1102; Hutchings et al., Eur. J. Immunol. (1987) 17:393). For example, specific B cells can present tetanus toxin to T cells at antigen concentrations 10.sup.4 times lower than those required for the presentation by nonspecific B cells or peripheral blood monocytes (Lanzavecchia, Nature (1985) 314:537).
In addition, in vivo studies with mice deficient in B cells show that these cells are required for the activation of T cells of lymphatic ganglions (Janeway et al., J Immunol. (1987) 138:2848; Kurt-Jones et al. A.K., J. Immunol. (1987) 140:3773).
Mice deficient in B cells also show reduced responses with respect to specific CD4+ and CD8+ T cells from tumors, after immunization with Freund's murine leukemia virus (Schultz et al., Science, (1990) 291).
The capacity of B cells to modify and to present the antigen with a view to recognition by CD4+ helper T cells restricted by the class II major histocompatibility complex (MHC) forms the basis of a model for the activation of the B cells by T cells (Noelle et al., The Faseb Journal (1991) 5:2770).
The recognition of the peptide-class II MHC complex by CD4+ helper T cells on the surface of the B cells leads to the formation of physically stable conjugates between the T cells and the B cells (Kupfer et al. S. J., Proc. National Acad. Sci. USA (1986) 83:6080).
This direct recognition results in the proliferation and the differentiation of B cells in response to lymphokines such as Interleukin-2, Interleukin-4 or Interleukin-5.
The induction of the antibody response against an antigen requires the presentation of the antigen by the B cells.
The majority of the studies on antigen presentation have been carried out using soluble proteins such as tetanus toxoid, lysozyme, hemocyanin (LH). However, most of the antigens to which the immune system is exposed are contained in complex particulate structures such as bacteria or parasites.
It is well known that cells which are capable of phagocytosis such as the macrophages can present bacterial antigens to T cells.
However, it is not known whether cells which do not phagocytose, such as B cells, can present complex antigens of significant size.
It has recently been shown that, in vivo, bacterial antigens must be in a soluble form in order to induce an antibody-dependent response by the T cells (Leclerc et al., J. Immunol. (1990) 144:3174; Leclerc et al., J. Immunol. (1991) 147:3545).
However, it seemed advisable to determine also that, in vivo, bacterial protein antigens are exclusively presented to the T cells by the phagocytic cells and that the B cells cannot modify antigens in particle form.
SUMMARY OF THE INVENTION
According to the present invention, the capacity of macrophages and B cells to present the same antigen, in soluble and particulate forms, has therefore been compared.
In particular, protein antigens, such as lysozyme and TNP-KLH, coupled to poly(acrolein) or polystyrene microparticles of a comparable size to that of a bacterium, have been used.
According to the invention, it has unexpectedly been shown that B cells which present TNP-KLH or lysozyme very effectively are incapable of presenting these antigens coupled to beads. However, macrophages present both forms of the antigens to T cells.
The study of antigen presentation and the induction of the cellular and/or humoral T response is of particular scientific and medical importance.
In fact, directing the response towards a purely cellular response or a purely humoral response could allow vaccination against certain pathogens, modification of certain biological dysfun
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Gengoux-Sedlik Christine
Leclerc Claude
Achutamurthy Ponnathapura
Institut Pasteur
Park Hankyel T.
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