Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1999-01-05
2002-04-23
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S133100, C424S134100, C424S141100, C424S143100, C424S144100, C424S153100, C424S173100, C424S184100, C424S093700, C424S093710, C424S577000, C424S192100, C514S002600, C514S008100, C514S885000, C530S387100, C530S387300, C530S388100, C530S388200, C530S388220, C530S388700, C530S388730, C530S388750, C530S350000
Reexamination Certificate
active
06375950
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 to a T cell of an antigen-specific signal with a costimulatory signal leads to T cell activation, which can include both T cell proliferation and cytokine secretion. In contrast, delivery to a T cell of an antigen-specific signal 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 immunity 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 the T cell. 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. Stamenkovic 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 tansfected 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 an antigen. The current invention is based, at least in part, on the discovery that cell-surface molecules which mediate contact-dependent helper effector functions of T cells also play a critical role in the response of T cells to alloantigens. In particular, it has been discovered that, under appropriate conditions, interference with an interaction of gp39 with a ligand on an allogeneic cell which is presenting alloantigens to the T cell can induce tolerance in the T cell. Preferably, the allogeneic cell which presents alloantigens to the T cell requires an interaction between a gp39 ligand on the cell and gp39 on the T cell to be able to provide signals necessary for activation of the T cell. Inhibiting the interaction of the gp39 ligand on the allogeneic cell with gp39 on the T cell prevents T cell activation and rather induces alloantigen-specific T cell tolerance. Induction of T cell tolerance to alloantigens as described herein can be used as a preparative regimen for tissue or organ transplantation.
Accordingly, the methods of the invention are particularly useful for inducing T cell tolerance to a donor tissue or organ in a recipient of the tissue or organ The methods involve administering to a transplant recipient: 1) an allogeneic or xenogeneic cell which expresses at least one donor antigen and which has a ligand on a cell surface which interacts with a receptor on the surface of a recipient T cell which mediates contact-dependent helper effector functions; and 2) an antagonist of the molecule on the surface of the recipient T cell which mediates contact-dependent helper effector functions. The antagonist inhibits an interaction between the molecule on the T cell and it's ligand on the allogeneic or xenogeneic cell.
In a preferred embodiment, the receptor on the surface of a recipient 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 on a T cell with a gp39 ligand on an allogeneic or xenogeneic cell. A particularly preferred gp39 antagonist is an anti-gp39 antibody. In another embodiment, the gp39 antagonist is a soluble form of a gp39 ligand, for example soluble CD40. The allogeneic or xenogeneic cell which is administered to the recipient is preferably a lymphoid cell, for example a B cell. Alternatively, the allogeneic or xenogeneic cell is a small resting B cell. The allogeneic or xenogeneic cell and the antagonist (e.g., anti-gp39 antibody) are typically administered to a recipient subject prior to transplantation of the tiss
Durie Fiona H.
Noelle Randolph J.
Gambel Phillip
Teskin Robin L.
University of Massachusetts Medical Center
LandOfFree
Methods for inducing T cell unresponsiveness to donor tissue... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods for inducing T cell unresponsiveness to donor tissue..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods for inducing T cell unresponsiveness to donor tissue... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2866598