Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1998-04-30
2001-11-06
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S141100, C424S143100, C424S144100, C424S153100, C424S173100, C424S093700, C424S093710, C424S520000, C424S577000, C530S387100, C530S388100, C530S388200, C530S388220, C530S388700, C530S388730, C530S388750, C435S332000, C435S334000, C435S343000, C435S343100, C435S343200, C435S346000
Reexamination Certificate
active
06312692
ABSTRACT:
BACKGROUND OF THE INVENTION
To induce antigen-specific T cell activation and clonal expansion, two signals provided by antigen-presenting cells (APCS) must be delivered to the surface of resting T lymphocytes (Jenkins, M. and Schwartz, R. (1987)
J. Exp. Med
. 165, 302-319; Mueller, D. L., et al. (1990)
J. Immunol
. 144, 3701-3709; Williams, I. R. and Unanue, E. R. (1990)
J. Immunol
. 145, 85-93). The first signal, which confers specificity to the immune response, is mediated via the T cell receptor (TCR) following recognition of foreign antigenic peptide presented in the context of the major histocompatibility complex (MHC). The second signal, termed costimulation, induces T cells to proliferate and become functional (Schwartz, R. H. (1990)
Science
248, 1349-1356). Costimulation is neither antigen-specific, nor MHC restricted and is thought to be provided by one or more distinct cell surface molecules expressed by APCs (Jenkins, M. K., et al. (1988)
J. Immunol
. 140, 3324-3330; Linsley, P. S., et al. (1991)
J. Exp. Med
. 173, 721-730; Gimmi, C. D., et al., (1991)
Proc. Natl. Acad. Sci. USA
. 88, 6575-6579; Young, J. W., et al. (1992)
J. Clin. Invest
. 90, 229-237; Koulova, L., et al. (1991)
J. Exp. Med
. 173, 759-762; Reiser, H., et al. (1992)
Proc. Natl. Acad. Sci. USA
. 89, 271-275; van-Seventer, G. A., et al. (1990)
J. Immunol
. 144, 4579-4586; LaSalle, J. M., et al., (1991)
J. Immunol
. 147, 774-80; Dustin, M. I., et al., (1989)
J. Exp. Med
. 169, 503; Armitage, R. J., et al. (1992)
Nature
357, 80-82; Liu, Y., et al. (1992)
J. Exp. Med
. 175, 437-445). One costimulatory pathway involved in T cell activation involves the molecule CD28 on the surface of T cells. This molecule can receive a costimulatory signal delivered by a ligand on B cells or other APCs. Ligands for CD28 include members of the B7 family of B lymphocyte activation antigens, such as B7-1 and/or B7-2 (Freedman, A. S. et al. (1987)
J. Immunol
. 137, 3260-3267; Freeman, G. J. et al. (1989)
J. Immunol
. 143, 2714-2722; Freeman, G. J. et al. (1991)
J. Exp. Med
. 174, 625-631; Freeman, G. J. et al. (1993)
Science
262, 909-911; Azuma, M. et al. (1993)
Nature
366, 76-79; Freeman, G. J. et al. (1993)
J. Exp. Med
. 178, 2185-2192). B7- 1 and B7-2 are also ligands for another molecule, CTLA4,present on the surface of activated T cells, although the role of CTLA4 in costimulation is unclear.
Delivery of an antigen-specific signal with a costimulatory signal to a T cell leads to T cell activation, which can include both T cell proliferation and cytokine secretion. In contrast, delivery of an antigen-specific signal to a T cell in the absence of a costimulatory signal is thought to induce a state of unresponsiveness or anergy in the T cell, thereby inducing antigen-specific tolerance in the T cell.
Interactions between T cells and B cells play a central role in immune responses. Induction of humoral inununity to thymus-dependent antigens requires “help” provided by T helper (hereafter Th) cells. While some help provided to B lymphocytes is mediated by soluble molecules released by Th cells (for instance lymphokines such as IL-4 and IL-5), activation of B cells also requires a contact-dependent interaction between B cells and Th cells. Hirohata et al.,
J. Immunol
., 140:3736-3744 (1988); Bartlett et al.,
J. Immunol
., 143:1745-1754 (1989). This indicates that B cell activation involves an obligatory interaction between cell surface molecules on B cells and Th cells. The molecule(s) on the T cell therefore mediates contact-dependent helper effector functions of T cells. A contact dependent interaction between molecules on B cells and T cells is further supported by the observation that isolated plasma membranes of activated T cells can provide helper functions necessary for B cell activation. Brian,
Proc. Natl. Acad. Sci. USA
, 85:564-568 (1988); Hodgkin et al.,
J. Immunol
., 145:2025-2034 (1990); Noelle et al.,
J. Immunol
., 146:1118-1124 (1991).
A molecule, CD40,has been identified on the surface of immature and mature B lymphocytes which, when crosslinked by antibodies, induces B cell proliferation. Valle et al.,
Eur. J. Immunol
., 19:1463-1467 (1989); Gordon et al.,
J. Immunol
., 140:1425-1430 (1988); Gruber et al.,
J. Immunol
., 142: 4144-4152 (1989). CD40 has been molecularly cloned and characterized. Stainenkovic et al.,
EMBO J
., 8:1403-1410 (1989). A ligand for CD40,gp39 (also called CD40 ligand or CD40L) has also been molecularly cloned and characterized. Armitage et al.,
Nature
, 357:80-82 (1992); Lederman et al.,
J. Exp. Med
., 175:1091-1101 (1992); Hollenbaugh et al.,
EMBO J
., 11:4313-4319 (1992). The gp39 protein is expressed on activated, but not resting, CD4
+
Th cells. Spriggs et al.,
J. Exp. Med
., 176:1543-1550 (1992); Lane et al.,
Eur. J. Immunol
., 22:2573-2578 (1992); Roy et al.,
J. Immunol
., 151:1-14 (1993). Cells transfected with the gp39 gene and expressing the gp39 protein on their surface can trigger B cell proliferation and, together with other stimulatory signals, can induce antibody production. Armitage et al.,
Nature
, 357:80-82 (1992); Hollenbaugh et al.,
EMBO J
., 11:4313-4319 (1992).
SUMMARY OF THE INVENTION
Cell-surface molecules which mediate contact-dependent helper effector functions of T cells are important for inducing immune responses which require T cell help. For example, the interaction of gp39 on T cells with CD40 on B cells plays a central role in activating B cell responses to antigens. The current invention is based, at least in part, on the discovery that cell-surface molecules which mediate contact-dependent helper effector functions also play a critical role in the response of T cells to antigens. In particular, it has been discovered that, under appropriate conditions, interference of an interaction between gp39 on a T cell and a ligand on a cell which is presenting antigen to the T cell can induce antigen-specific T cell tolerance. Accordingly, the cell which presents antigen to the T cell requires an interaction between a gp39 ligand (e.g., CD40) on the cell and gp39 on the T cell to be able to provide signals necessary for activation of the T cell. Inhibition of the interaction between the gp39 ligand and gp39 prevents T cell activation and rather induces antigen-specific T cell tolerance.
The methods of the invention pertain to induction of antigen-specific T cell tolerance. The methods involve contacting a T cell with: 1) a cell which presents antigen to the T cell and has a ligand on the cell surface which interacts with a receptor on the surface of the T cell which mediates contact-dependent helper effector functions; and 2) an antagonist of the receptor on the surface of a T cell which mediates contact-dependent helper effector functions. The antagonist inhibits the interaction of the receptor with it's ligand. A T cell can be contacted with the cell which presents antigen and the antagonist in vitro, or alternatively, the cell and the antagonist can be administered to a subject to induce T cell tolerance in vivo.
In a preferred embodiment, the receptor on the surface of the T cell which mediates contact-dependent helper effector functions is gp39. In this embodiment, the antagonist is a molecule which inhibits the interaction of gp39 with its ligand on a cell which presents antigen to the T cell. A particularly preferred gp39 antagonist is an anti-gp39 antibody. Alternatively, the gp39 antagonist is a soluble form of a gp39 ligand, for example soluble CD40. The cell which presents antigen to a T cell is preferably a B cell. The B cell can be a small, resting B cell. To induce T cell tolerance to a soluble antigen, the B cell can be contacted with the antigen prior to contact with the T cell (e.g., prior to administration to a subject). In another embodiment, to induce T cell tolerance to alloantigens, the cell which is used to present antigen to the T cell is an allogeneic cell. The allogeneic cell can be, for example, an allogeneic B cell, allogeneic bone marrow, allogeneic spleen cells or allogeneic cells
Aruffo Alejandro
Foy Teresa M.
Ledbetter Jeffrey A.
Noelle Randolph J.
Gambel Phillip
Teskin Robin L.
Trustees of Dartmouth College
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