Methods of inhibiting T cell proliferation or IL-2 accumulation with CTLA4- specific antibodies

DETAILED DESCRIPTION This invention is based, at least in part, on the discovery of novel ligands which bind a T cell surface molecule and induce antigen specific apoptosis in an activated T cell.
Preferably, the ligand is an antibody, or antibody fragment, which binds the T cell surface molecule CTLA4, in particular human CTLA4.
Anti-CTLA4 antibodies which bind an epitope on CTLA4 that is distinct from the epitope(s) recognized by the known CTLA4 ligands B7-1 and B7-2 are particularly preferred for use in inducing antigen specific T cell apoptosis.
The antibodies can be polyclonal or monoclonal antibodies, or fragments thereof.
Chimeric and humanized monoclonal antibodies, and fragments thereof, are encompassed by the invention.
In another embodiment, the ligand is a soluble recombinant form of a novel CTLA4 ligand distinct from B7-1 and B7-2 that can induce T cell apoptosis.
Alternatively, the ligand can be a modified form of B7-1 or B7-2 that binds CTLA4 without binding CD28 (e.
g.
, the modified form of B7-1 or B7-2 binds the same epitope on CTLA4 recognized by the antibodies of the invention and induces apoptosis in a T cell).
Another embodiment of the invention pertains to ligands which bind an epitope on CTLA4 which is distinct from an epitope bound by the known B7-1 and B7-2 ligands and which induces apoptosis in a T cell.
Preferably, the CTLA4 epitope recognized by a ligand, e.
g.
, antibody, of the invention includes or encompasses an amino acid sequence: (Xaa).
sub.
n -Leu-Thr-Phe-Leu-Asp-Asp-(Xaa).
sub.
n (SEQ ID NO: 33), wherein Xaa is any amino acids and n=0-20, preferably 0-5, more preferably 0-3.
This CTLA4 epitope is found in human CTLA4 at amino acid positions 59 to 64.
Thus, typically, Xaa are additional amino acid residues found at either the amino or carboxy side, or both the amino and carboxy sides, of the epitope in the human CTLA4 amino acid sequence (SEQ ID NO: 36).
Alternatively, Xaa can be an amino acid residue which increases the solubility of the resulting peptide or enhances the immunogenicity of the resulting peptide for use as an immunogen