초록 ▼

Methods for modulating immune responses in a subject are provided. A preferred embodiment provides methods and compositions for reducing or inhibiting transplant rejection in a subject, preferably a human subject. Transplant rejection can be inhibited or reduced in a subject by administering an effe

Methods for modulating immune responses in a subject are provided. A preferred embodiment provides methods and compositions for reducing or inhibiting transplant rejection in a subject, preferably a human subject. Transplant rejection can be inhibited or reduced in a subject by administering an effective amount of B7-H4 polypeptide, fragments or fusions thereof to inhibit or reduce the biological activity of an immune cell or to reduce the amounts of proinflammatory molecules at a site of transplant. Th1, Th17 and Th22 cells are exemplary T cells that can be targeted for inhibition by B7-H4 polypeptides, fusion proteins or fragments thereof to inhibit or reduce inflammation.

대표청구항 ▼

1. A method for inhibiting or reducing rejection of a tissue or organ transplant in a human subject, comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprisinga dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising a B7-H4 polypeptide comprising

1. A method for inhibiting or reducing rejection of a tissue or organ transplant in a human subject, comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprisinga dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising a B7-H4 polypeptide comprising the IgV domain of SEQ ID NO:63 or SEQ ID NO:64 fused to a second polypeptide or fused to a linker peptide fused to a second polypeptide,wherein at least two of the dosage units are administered at least two days apart and within two weeks,to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce rejection of the tissue or organ transplant in the subject for at least a week post administration. 2. A method for inhibiting or reducing rejection of a tissue or organ transplant in a human subject, comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprisinga dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising a B7-H4 polypeptide comprising the IgV domain of SEQ ID NO:63 or SEQ ID NO:64 fused to a second polypeptide or fused to a linker peptide fused to a second polypeptide comprisingthe hinge, CH2 and CH3 regions of an immunoglobulin,wherein at least two of the dosage units are administered at least two days apart and within two weeks,to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce rejection of the tissue or organ transplant in the subject for at least a week post administration. 3. The method of claim 1, wherein the pharmaceutical dosage unit further comprises a second therapeutic agent. 4. The method of claim 3 wherein the second therapeutic agent is selected from the group consisting of glucocorticoid fluticasone, salmeterol; antibodies to IL-12, IL-6, IFN-γ, IL-23, IL-22, IL-21 and IL-4; vitamin D3, CTLA-4-Ig, belatacept, dexamethasone, and combinations thereof. 5. The method of claim 1 wherein the transplant is an allogeneic transplant. 6. The method of claim 1, wherein the transplant is a skin graft, a tissue transplant, an organ transplant, or a bone marrow transplant. 7. A method for treating one or more symptoms of graft versus host disease (GVHD) in a human subject, comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprisinga dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising a B7-H4 polypeptide comprising the IgV domain of SEQ ID NO:63 or SEQ ID NO:64 fused to a second polypeptide or fused to a linker peptide fused to a second polypeptide,wherein at least two of the dosage units are administered at least two days apart and within two weeks,to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce one or more symptoms of GVHD in the subject for at least a week post administration. 8. A method for treating one or more symptoms of graft versus host disease (GVHD) in a human subject, comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprisinga dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising a B7-H4 polypeptide comprising the IgV domain of SEQ ID NO:63 or SEQ ID NO:64 fused to a second polypeptide or fused to a linker peptide fused to a second polypeptide,wherein the second polypeptide comprises the hinge, CH2 and CH3 regions of an immunoglobulin,wherein at least two of the dosage units are administered at least two days apart and within two weeks,to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce one or more symptoms of GVHD in the subject for at least a week post administration. 9. A method for inhibiting or reducing rejection of a tissue or organ transplant in a human subject comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprising a dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising a B7-H4 polypeptide comprising the IgV domain of B7-H4 fused to a second polypeptide or fused to a linker peptide fused to a second polypeptide, wherein at least two of the dosage units are administered at least two days apart and within two weeks,to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce rejection of tissue or organ transplant in the subject for at least a week post administration. 10. The method of claim 2, wherein the immunoglobulin is a human IgG1. 11. A method for inhibiting or reducing rejection of a tissue or organ transplant in a human subject, comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprisinga dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising the amino acid sequence of SEQ ID NO:130wherein at least two of the dosage units are administered at least two days apart and within two weeks,to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce rejection of tissue or organ transplant in the subject for at least a week post administration. 12. The method of claim 8, wherein the immunoglobulin is a human IgG1. 13. The method of claim 8, wherein the second polypeptide comprises the hinge, CH2 and CH3 regions of an immunoglobulin. 14. The method of claim 13, wherein the immunoglobulin is a human IgG1. 15. A method for treating one or more symptoms of graft versus host disease (GVHD) in a human subject, comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprising 3 mg/kg to 25 mg/kg of a fusion protein comprising the amino acid sequence of SEQ ID NO:130wherein at least two of the dosage units are administered at least two days apart and within two weeks,to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce one or more symptoms of GVHD in the subject for at least a week post administration. 16. A method for treating one or more symptoms of graft versus host disease (GVHD) in a human subject comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprising a dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising a B7-H4 polypeptide comprising the IgV domain of B7-H4 fused to a second polypeptide or fused to a linker peptide fused to a second polypeptide, wherein at least two of the dosage units are administered at least two days apart and within two weeks,to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce one or more symptoms of graft versus host disease (GVHD) in the subject for at least a week post administration. 17. The method of claim 1, wherein at least three of the dosage units are administered at least two days apart and within two weeks. 18. The method of claim 1, wherein at least two of the dosage units are administered at least two days apart and within one week. 19. The method of claim 1, wherein at least three of the dosage units are administered at least two days apart and within one week. 20. The method of claim 9, wherein at least three of the dosage units are administered at least two days apart and within two weeks. 21. The method of claim 9, wherein at least two of the dosage units are administered at least two days apart and within one week. 22. The method of claim 9, wherein at least three of the dosage units are administered at least two days apart and within one week. 23. The method of claim 11, wherein at least three of the dosage units are administered at least two days apart and within two weeks. 24. The method of claim 11, wherein at least two of the dosage units are administered at least two days apart and within one week. 25. The method of claim 11, wherein at least three of the dosage units are administered at least two days apart and within one week. 26. The method of claim 15, wherein at least three of the dosage units are administered at least two days apart and within two weeks. 27. The method of claim 15, wherein at least two of the dosage units are administered at least two days apart and within one week. 28. The method of claim 15, wherein at least three of the dosage units are administered at least two days apart and within one week. 29. The method of claim 1, wherein the administration is effective to reduce rejection of the tissue or organ transplant in the subject for at least 10 days post administration. 30. The method of claim 1, wherein the administration is effective to reduce rejection of the tissue or organ transplant in the subject for at least two weeks post administration. 31. The method of claim 1, wherein the administration is effective to reduce rejection of the tissue or organ transplant in the subject for at least three weeks post administration. 32. The method of claim 7, wherein the administration is effective to reduce one or more symptoms of GVHD in the subject for at least 10 days post administration. 33. The method of claim 7, wherein the administration is effective to reduce one or more symptoms of GVHD in the subject for at least two weeks post administration. 34. The method of claim 7, wherein the administration is effective to reduce one or more symptoms of GVHD in the subject for at least three weeks post administration. 35. The method of claim 11, wherein the administration is effective to reduce rejection of the tissue or organ transplant in the subject for at least 10 days post administration. 36. The method of claim 11, wherein the administration is effective to reduce rejection of the tissue or organ transplant in the subject for at least two weeks post administration. 37. The method of claim 11, wherein the administration is effective to reduce rejection of the tissue or organ transplant in the subject for at least three weeks post administration. 38. The method of claim 15, wherein the administration is effective to reduce one or more symptoms of GVHD in the subject for at least 10 days post administration. 39. The method of claim 15, wherein the administration is effective to reduce one or more symptoms of GVHD in the subject for at least two weeks post administration. 40. The method of claim 15, wherein the administration is effective to reduce one or more symptoms of GVHD in the subject for at least three weeks post administration.