Abstract: Disclosed are screening assays for identifying compounds which modulate the activity of, or signaling via, B7-4, or PD-1, especially which modulate the binding of B7-4 or PD-1 to a target molecule Further disclosed are a vaccine and also other compositions which contain agents that modulate signaling via PD-1.

Abstract: The invention identifies PD-1 as a receptor for B7-4. B7-4 can inhibit immune cell activation upon binding to an inhibitory receptor on an immune cell. Accordingly, the invention provides agents for modulating PD-1, B7-4, and the interaction between B7-4 and PD-1 in order to modulate a costimulatory or an inhibitory signal in a immune cell resulting in modulation of the immune response.

Abstract: The present invention relates to, inter alia, methods for inhibiting the interaction of the B-lymphocyte antigen, B7-2, with its natural ligand on the surface of an immune cell are disclosed. The methods comprise contacting the immune cell with an agent which inhibits B7-2 binding with its natural ligand, to thereby inhibit the interaction. Examples of such agents are provided, and include a soluble form of B7-2, an antibody that recognized B7-2. The method may also include contacting the immune cell with an agent that blocks the interaction of B7-1 with its natural ligand. Further, the method may include contacting the immune cell with an immunomodulating agent, for example, an antibody reactive with CD28, an antibody reactive with CTLA4, an antibody reactive with a cytokine, a CTLA4Ig fusion protein, a CD28Ig fusion protein, and an immunosuppressive drug. Both in vivo and in vitro applications of the method are disclosed.

Abstract: Nucleic acids encoding novel CTLA4/CD28 ligands which costimulate T cell activation are disclosed. In one embodiment, the nucleic acid has a sequence which encodes a B lymphocyte antigen, B7-2. Preferably, the nucleic acid is a DNA molecule comprising at least a portion of a nucleotide sequence shown in FIG. 8, SEQ ID NO:1 or FIG. 14, SEQ ID NO:23. The nucleic acid sequences of the invention can be integrated into various expression vectors, which in turn direct the synthesis of the corresponding proteins or peptides in a variety of hosts, particularly eukaryotic cells, such as mammalian and insect cell culture. Also disclosed are host cells transformed to produce proteins or peptides encoded by the nucleic acid sequences of the invention and isolated proteins and peptides which comprise at least a portion of a novel B lymphocyte antigen. Proteins and peptides described herein can be administered to subjects to enhance or suppress T cell-mediated immune responses.

Abstract: The invention identifies PD-1 as a receptor for B7-4. B7-4 can inhibit immune cell activation upon binding to an inhibitory receptor on an immune cell. Accordingly, the invention provides agents for modulating PD-1, B7-4, and the interaction between B7-4 and PD-1 in order to modulate a costimulatory or an inhibitory signal in a immune cell resulting in modulation of the immune response.

Abstract: Isolated ligands which bind a molecule expressed on the surface of T cells and induce antigen specific apoptosis in activated T cells are disclosed. Preferably, the T cell surface molecule is CTLA4 and the ligand is a monoclonal anti-CTLA4 antibody that binds to an epitope of CTLA4 distinct from the binding sites of B7-1 and B7-2. Upon binding of the antibody to CTLA4 on an activated T cell, in the presence of an antigenic signal, antigen specific apoptosis is induced. The invention also describes a novel natural CTLA4 ligand, distinct from B7-1 and B7-2, which mediates induction of apoptosis. Pharmaceutical compositions of anti-CTLA4 antibodies or other isolated CTLA4 ligands which can be administered to subjects to induce T cell apoptosis, thereby clonally deleting antigen specific T cells, such as alloreactive T cells in transplantation situations or autoreactive T cells in autoimmune disorders, are also disclosed.

Abstract: Novel structural forms of T cell costimulatory molecules are described. These structural forms comprise a novel structural domain or have a structural domain deleted or added. The structural forms correspond to naturally-occurring alternatively spliced forms of T cell costimulatory molecules or variants thereof which can be produced by standard recombinant DNA techniques. In one embodiment, the T cell costimulatory molecule of the invention contains a novel cytoplasmic domain. In another embodiment, the T cell costimulatory molecule of the invention contains a novel signal peptide domain or has an immunoglobulin variable region-like domain deleted. The novel structural forms of T cell costimulatory molecules can be used to identify agents which stimulate the expression of alternative forms of costimulatory molecules and to identify components of the signal transduction pathway which results in costimulation of T cells.

Abstract: Tumor cells modified to express one or more T cell costimulatory molecules are disclosed. Preferred costimulatory molecules are B7-2 and B7-3. The tumor cells of the invention can be modified by transfection with nucleic acid encoding B7-2 and/or B7-3, by using an agent which induces or increases expression of B7-2 and/or B7-3 on the tumor cell or by coupling B7-2 and/or B7-3 to the tumor cell. Tumor cells modified to express B7-2 and/or B7-3 can be further modified to express B7. Tumor cells further modified to express MHC class I and/or class II molecules or in which expression of an MHC associated protein, the invariant chain, is inhibited are also disclosed. The modified tumor cells of the invention can be used in methods for treating a patient with a tumor, preventing or inhibiting metastatic spread of a tumor or preventing or inhibiting recurrence of a tumor.

Abstract: Isolated ligands which bind a molecule expressed on the surface of T cells and induce antigen specific apoptosis in activated T cells are disclosed. Preferably, the T cell surface molecule is CTLA4 and the ligand is a monoclonal anti-CTLA4 antibody that binds to an epitope of CTLA4 distinct from the binding sites of B7-1 and B7-2. Upon binding of the antibody to CTLA4 on an activated T cell, in the presence of an antigenic signal, antigen specific apoptosis is induced. The invention also describes a novel natural CTLA4 ligand, distinct from B7-1 and B7-2, which mediates induction of apoptosis. Pharmaceutical compositions of anti-CTLA4 antibodies or other isolated CTLA4 ligands which can be administered to subjects to induce T cell apoptosis, thereby clonally deleting antigen specific. T cells, such as alloreactive T cells in transplantation situations or autoreactive T cells in autoimmune disorders, are also disclosed.

Abstract: The present invention provides compositions and methods useful for promoting or reducing T-cell trafficking to a target tissue. Also provided are compositions and methods useful for promoting or inhibiting antigen-presenting cell (APC) activation. The invention is related to discovery of functional characteristics of TIM-3, a molecule that is preferentially expressed on the surface of Th1 cells. The methods are useful for treating disorders including cancer, infectious disease, allergy, asthma, and autoimmune disease.

Abstract: Disclosed are methods for identifying an agent that modulates an immune response. One such method comprises screening for agents which inhibit the interaction between a PD-1 ligand and a PD-1 polypeptide, and determining whether the agents inhibit the interaction between a PD-1 ligand and a B7 polypeptide, to identify an agent that inhibits PD-1 ligand and PD-1 polypeptide interaction, while not inhibiting the interaction between a PD-1 ligand and a B7 polypeptide, as an agent that modulates an immune response. Another such method comprises screening for agents which inhibit the interaction between a PD-1 ligand and a B7 polypeptide, and determining whether the agents inhibit the interaction between a PD-1 ligand and a PD-1 polypeptide, to identify an agent that inhibits the PD-1 ligand and B7 polypeptide interaction, which does not inhibit the interaction between a PD-1 ligand and a PD-1 polypeptide, as an agent that modulates the immune response.

Abstract: Isolated nucleic acid molecules encoding a B cell activation antigen, B7, are provided. In one embodiment, the nucleic acid molecules are DNA sequences. The DNA sequences of the invention can be integrated into various expression vectors, which in turn can direct the synthesis of the corresponding proteins or peptides in a variety of hosts, particularly eukaryotic cells, such as mammalian and insect cell culture. Also provided are host cells transformed to produce proteins or peptides encoded by the DNA molecules of the present invention and purified proteins and peptides which comprise at least a portion of the B cell activation antigen. The proteins and peptides comprise at least a portion of the mature form of the B7 activation antigen and preferably comprise a soluble form of the B7 protein.

Abstract: Isolated nucleic acid molecules encoding a B cell activation antigen, B7, are provided. In one embodiment, the nucleic acid molecules are DNA sequences. The DNA sequences of the invention can be integrated into various expression vectors, which in turn can direct the synthesis of the corresponding proteins or peptides in a variety of hosts, particularly eukaryotic cells, such as mammalian and insect cell culture. Also provided are host cells transformed to produce proteins or peptides encoded by the DNA molecules of the present invention and purified proteins and peptides which comprise at least a portion of the B cell activation antigen. The proteins and peptides comprise at least a portion of the mature form of the B7 activation antigen and preferably comprise a soluble form of the B7 protein.

Abstract: Isolated nucleic acid molecules encoding novel CD100 molecules which stimulate a leukocyte response, such as a B cell response, including B cell aggregation, B cell differentiation, B cell survival, and/or T cell proliferationare disclosed. These novel molecules have a certain homology to semaphorins, proteins which are growth cone guidance molecules that are critical for guiding growing axons of neurons to their targets. In addition to isolated nucleic acids molecules, antisense nucleic acid molecules, recombinant expression vectors containing a nucleic acid molecule of the invention, host cells into which the expression vectors have been introduced are also described. The invention further provides isolated CD100 proteins, fusion proteins and active fragments thereof. Diagnostic and therapeutic methods utilizing compositions of the invention are also provided.

Abstract: Novel structural forms of T cell costimulatory molecules are described. These structural forms comprise a novel structural domain or have a structural domain deleted or added. The structural forms correspond to naturally-occurring alternatively spliced forms of T cell costimulatory molecules or variants thereof which can be produced by standard recombinant DNA techniques. In one embodiment, the T cell costimulatory molecule of the invention contains a novel cytoplasmic domain. In another embodiment, the T cell costimulatory molecule of the invention contains a novel signal peptide domain or has an immunoglobulin variable region-like domain deleted. The novel structural forms of T cell costimulatory molecules can be used to identify agents which stimulate the expression of alternative forms of costimulatory molecules and to identify components of the signal transduction pathway which results in costimulation of T cells.

Abstract: Disclosed is a composition for inhibiting the interactions of B7-1 and B7-2 with their natural ligands. Such compositions comprise an antibody specific for B7-2 and an antibody specific for B7-1, in a pharmaceutically acceptable carrier. The composition may be formulated for either separate or combined administration of the antibody components. The antibodies may be monoclonal antibodies, or humanized antibodies. Preferred antibodies are disclosed.

Abstract: A genetic locus and corresponding family of proteins associated with regulation of immune function and cell survival are provided. These genes encode cell surface molecules with conserved IgV and mucin domains. The locus comprising the TIM family is genetically associated with immune dysfunction, including asthma. Furthermore, the TIM gene family is located within a region of human chromosome 5 that is commonly deleted in malignancies and myelodysplastic syndrome. Polymorphisms in the gene sequences are associated with the development of airway hyperreactivity and allergic inflammation, and T cell production of IL-4 and IL-13. The proteins include the human hepatitis A cellular receptor, hHAVcr-1.

Abstract: Tumor cells modified to express a T cell costimulatory molecule are disclosed. In one embodiment, the costimulatory molecule is a CD28/CTLA4 ligand, preferably a B lymphocyte antigen B7. The tumor cells of the invention can be modified by transfection with nucleic acid encoding a T cell costimulatory molecule, by using an agent which induces or increases expression of a T cell costimulatory molecule on the tumor cell surface or by coupling a T cell costimulatory molecule to the tumor cell surface. Tumor cells further modified to express MHC class I and/or class II molecules or in which expression of an MHC associated protein, the invariant chain, is inhibited are also disclosed. The modified tumor cells of the invention can be used in methods for treating a patient with a tumor, preventing or inhibiting metastatic spread of a tumor or preventing or inhibiting recurrence of a tumor.

Abstract: Isolated nucleic acid molecules encoding novel CD100 molecules which stimulate a leukocyte response, such as a B cell response, including B cell aggregation, B cell differentiation, B cell survival, and/or T cell proliferation are disclosed. These novel molecules have a certain homology to semaphorins, proteins which are growth cone guidance molecules that are critical for guiding growing axons of neurons to their targets. In addition to isolated nucleic acids molecules, antisense nucleic acid molecules, recombinant expression vectors containing a nucleic acid molecule of the invention, host cells into which the expression vectors have been introduced are also described. The invention further provides isolated CD100 proteins, fusion proteins and active fragments thereof. Diagnostic and therapeutic methods utilizing compositions of the invention are also provided.

Abstract: Novel structural forms of T cell costimulatory molecules are described. These structural forms comprise a novel structural domain or have a structural domain deleted or added. The structural forms correspond to naturally-occurring alternatively spliced forms of T cell costimulatory molecules or variants thereof which can be produced by standard recombinant DNA techniques. In one embodiment, the T cell costimulatory molecule of the invention contains a novel cytoplasmic domain. In another embodiment, the T cell costimulatory molecule of the invention contains a novel signal peptide domain or has an immunoglobulin variable region-like domain deleted. The novel structural forms of T cell costimulatory molecules can be used to identify agents which stimulate the expression of alternative forms of costimulatory molecules and to identify components of the signal transduction pathway which results in costimulation of T cells.