METHODS AND COMPOSITIONS FOR THE INHIBITION OF TRANSPLANT REJECTION
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.
1 - 22 . (canceled)
23 . A method for inhibiting or reducing rejection of a tissue or organ transplant in a human subject,
comprising treating the subject according to a dosage regimen comprising intravenous administration of one or more doses 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 dosage regimen is effective to achieve a concentration of at least 1.0 μg/ml in the subject, and to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells and reduce rejection of the tissue or organ transplant in the subject for at least a week.
24 . The method of claim 23 , wherein the dosage regimen comprises at least one dose of 3 mg/kg to 20 mg/kg of the fusion protein.
25 . The method of claim 23 , wherein the dosage regimen comprises intravenous administration of doses of the fusion protein to the subject at least two days apart and within two weeks.
26 . The method of claim 23 , wherein the dosage regimen comprises intravenous administration of doses of the fusion protein to the subject at least two days apart and within one week.
27 . The method of claim 23 , wherein the dosage regimen comprises intravenous administration of two or more doses of the fusion protein to the subject at least two days apart and within one week.
28 . The method of claim 23 , wherein the dosage regimen is effective to reduce rejection of the tissue or organ transplant in the subject for at least 10 days.
29 . The method of claim 23 , wherein the dosage regimen is effective to reduce rejection of the tissue or organ transplant in the subject for at least two weeks.
30 . The method of claim 23 , wherein the dosage regimen is effective to reduce rejection of the tissue or organ transplant in the subject for at least three weeks.
31 . The method of claim 23 , wherein the second polypeptide comprises the hinge, C H 2 and C H 3 regions of an immunoglobulin.
32 . The method of claim 31 , wherein the immunoglobulin is a human IgG1.
33 . The method of claim 23 , further comprising administering the subject a second therapeutic agent.
34 . The method of claim 23 , 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.
35 . A method for inhibiting or reducing rejection of a tissue or organ transplant in a human subject,
comprising treating the subject according to a dosage regimen comprising intravenous administration of one or more doses of a fusion protein comprising the amino acid sequence of SEQ ID NO:130,
wherein the dosage regimen is effective to achieve a concentration of at least 1.0 μg/ml in the subject, and to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells and reduce rejection of the tissue or organ transplant in the subject for at least a week.
36 . The method of claim 35 , wherein the dosage regimen comprises at least one dose of 3 mg/kg to 20 mg/kg of the fusion protein.
37 . The method of claim 35 , wherein the dosage regimen comprises intravenous administration of doses of the fusion protein to the subject at least two days apart and within two weeks.
38 . The method of claim 35 , wherein the dosage regimen comprises intravenous administration of doses of the fusion protein to the subject at least two days apart and within one week.
39 . The method of claim 35 , wherein the dosage regimen comprises intravenous administration of two or more doses of the fusion protein to the subject at least two days apart and within one week.
40 . The method of claim 35 , wherein the dosage regimen is effective to reduce rejection of the tissue or organ transplant in the subject for at least 10 days.
41 . The method of claim 35 , wherein the dosage regimen is effective to reduce rejection of the tissue or organ transplant in the subject for at least two weeks.
42 . The method of claim 35 , wherein the dosage regimen is effective to reduce rejection of the tissue or organ transplant in the subject for at least three weeks.
43 . The method of claim 35 , further comprising administering the subject a second therapeutic agent.
44 . The method of claim 43 , 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.
45 . A method for treating one or more symptoms of graft versus host disease (GVHD) in a human subject,
comprising treating the subject according to a dosage regimen comprising intravenous administration of one or more doses 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 dosage regimen is effective to achieve a concentration of at least 1.0 μg/ml in the subject, and to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells and reduce one or more symptoms of GVHD in the subject for at least a week.
46 . The method of claim 45 , wherein the dosage regimen comprises at least one dose of 3 mg/kg to 20 mg/kg of the fusion protein.
47 . The method of claim 45 , wherein the dosage regimen comprises intravenous administration of doses of the fusion protein to the subject at least two days apart and within two weeks.
48 . The method of claim 45 , wherein the dosage regimen comprises intravenous administration of doses of the fusion protein to the subject at least two days apart and within one week.
49 . The method of claim 45 , wherein the dosage regimen comprises intravenous administration of two or more doses of the fusion protein to the subject at least two days apart and within one week.
50 . The method of claim 45 , wherein the dosage regimen is effective to reduce one or more symptoms of GVHD in the subject for at least 10 days.
51 . The method of claim 45 , wherein the dosage regimen is effective to reduce one or more symptoms of GVHD in the subject for at least two weeks.
52 . The method of claim 45 , wherein the dosage regimen is effective to reduce one or more symptoms of GVHD in the subject for at least three weeks.
53 . The method of claim 45 , wherein the second polypeptide comprises the hinge, C H 2 and C H 3 regions of an immunoglobulin.
54 . The method of claim 53 , wherein the immunoglobulin is a human IgG1.
55 . The method of claim 45 , further comprising administering the subject a second therapeutic agent.
56 . The method of claim 55 , 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.
57 . A method for treating one or more symptoms of graft versus host disease (GVHD) in a human subject,
comprising treating the subject according to a dosage regimen comprising intravenous administration of one or more doses of a fusion protein comprising the amino acid sequence of SEQ ID NO:130,
wherein the dosage regimen is effective to achieve a concentration of at least 1.0 μg/ml in the subject, and to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells and reduce one or more symptoms of GVHD in the subject for at least a week.
58 . The method of claim 57 , wherein the dosage regimen comprises at least one dose of 3 mg/kg to 20 mg/kg of the fusion protein.
59 . The method of claim 57 , wherein the dosage regimen comprises intravenous administration of doses of the fusion protein to the subject at least two days apart and within two weeks.
60 . The method of claim 57 , wherein the dosage regimen comprises intravenous administration of doses of the fusion protein to the subject at least two days apart and within one week.
61 . The method of claim 57 , wherein the dosage regimen comprises intravenous administration of two or more doses of the fusion protein to the subject at least two days apart and within one week.
62 . The method of claim 57 , wherein the dosage regimen is effective to reduce one or more symptoms of GVHD in the subject for at least 10 days.
63 . The method of claim 57 , wherein the dosage regimen is effective to reduce one or more symptoms of GVHD in the subject for at least two weeks.
64 . The method of claim 57 , wherein the dosage regimen is effective to reduce one or more symptoms of GVHD in the subject for at least three weeks.
65 . The method of claim 57 , further comprising administering the subject a second therapeutic agent.
66 . The method of claim 65 , 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.