VISTA-Ig for treatment of autoimmune, allergic and inflammatory disorders
The present invention relates to a fusion proteins comprising regulatory T cell protein, VISTA (V-domain Immunoglobulin Suppressor of T cell Activation (PD-L3) and an immunoglobulin protein (Ig). The invention also provides the use of VISTA polypeptides, multimeric VISTA polypeptides, VISTA-conjugates (e.g., VISTA-Ig), and VISTA antagonists for the treatment of autoimmune disease, allergy, and inflammatory conditions.
1. A method of treating inflammation resulting from multiple sclerosis in a subject in need thereof comprising administering an effective amount of an immunosuppressive polypeptide comprising a multimeric V-region Immunoglobulin-containing Suppressor of T cell Activation (“VISTA”) polypeptide, wherein the multimeric VISTA polypeptide comprises at least 2 copies of a VISTA polypeptide comprising residues 32-190 or 16-194 of SEQ ID NO:2 or SEQ ID NO:4 which are each attached to an Ig constant region.
2. The method of claim 1 , wherein the Ig constant region is an IgG1 constant region.
3. The method of claim 1 , wherein said VISTA polypeptide comprises the amino acid sequence of SEQ ID NO: 5.
4. The method of claim 1 , wherein said VISTA polypeptide is attached to the N-terminus of an oligomerization domain.
5. The method of claim 4 , wherein the oligomerization domain is selected from GCN4, COMP, SNARE, CMP, MAT, LLR containing 1 NLRC, NOD2 nucleotide-binding NLRC2, LRR containing 1 NLRC NOD2 nucleotide-binding NLRC2, and PSORAS1.
6. The method of claim 1 wherein the Ig constant region comprises mutations in the CH2-CH3 domain which prevent FcR binding.
7. The method of claim 1 wherein the Ig constant region comprises a human Fc polypeptide.
8. The method of claim 1 wherein the multiple sclerosis comprises spino-optical multiple sclerosis.
9. The method of claim 1 which further includes administering another compound which downregulates cell-mediated immunity in the treated subject.