Methods and compositions for immunomodulation
Provided are cells containing exogenous antigen and uses thereof.
1. A method of inducing immune tolerance in a subject having immune activation in response to an antigen that mediates an autoimmune disease, an inflammatory disease, or an allergic disease, the method comprising:
administering to the subject a pharmaceutical composition comprising a plurality of enucleated erythroid cells, the plurality of enucleated erythroid cells comprising a fusion polypeptide comprising the antigen, or an antigenic fragment thereof,
wherein the antigen, or the antigenic fragment thereof, of the fusion polypeptide is localized on the surface of the enucleated erythroid cells; the fusion polypeptide does not comprise a ligand binding domain; the fusion polypeptide was expressed from a transgene introduced into an erythroid cell precursor used to generate the plurality of enucleated erythroid cells, and
the pharmaceutical composition is administered in an amount and frequency sufficient to mediate the induction of the immune tolerance in the subject.
2. The method of claim 1 , wherein the subject has the autoimmune disease.
3. The method of claim 1 , wherein the subject has multiple sclerosis.
4. The method of claim 3 , wherein the antigen is a myelin basic protein, a proteolipid protein, or a myelin oligodendrocyte glycoprotein.
5. The method of claim 1 , wherein the subject has type 1 diabetes.
6. The method of claim 5 , wherein the antigen is a preproinsulin, a proinsulin, or an insulin.
7. The method of claim 1 , wherein the subject has membranous nephropathy.
8. The method of claim 7 , wherein the antigen is a phospholipase A2 receptor.
9. The method of claim 1 , wherein the subject has antiphospholipid syndrome (APS) or catastrophic APS.
10. The method of claim 9 , wherein the antigen is a beta-2 glycoprotein 1.
11. The method of claim 1 , wherein the plurality of enucleated erythroid cells are not hypotonically loaded.
12. The method of claim 1 , wherein a cell of the plurality of enucleated erythroid cells exhibits substantially the same osmotic membrane fragility as an isolated, uncultured erythroid cell not comprising the fusion polypeptide.
13. The method of claim 1 , wherein the plurality of enucleated erythroid cells comprises erythrocytes.
14. The method of claim 1 , wherein the plurality of enucleated erythroid cells are human cells.
15. The method of claim 1 , wherein the fusion polypeptide comprises an A domain and an S domain, wherein the surface domain comprises the antigen, or the antigenic fragment thereof.
16. The method of claim 1 , wherein the fusion polypeptide comprises at least one of an S domain, an A domain or a U domain, wherein the S domain is a surface domain on the enucleated erythroid cell, wherein the A domain is an anchor in or on the cell membrane, wherein the U domain faces the intracellular, unexposed side of the enucleated erythroid cell, and wherein at least one of the S domain, the A domain, and the U domain are of different polypeptide origin.
17. The method of claim 16 , wherein at least one of the S domain and the A domain comprises at least 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, or at least 500 amino acids.
18. The method of claim 1 , wherein the fusion polypeptide comprises a transmembrane domain.
19. The method of claim 2 , wherein the method comprises administering the pharmaceutical composition at least twice over a treatment period to the subject.
20. The method of claim 1 , comprising administering the pharmaceutical composition a sufficient number of times over a treatment period such that the percentage of antigen-specific immune cells is substantially decreased during the treatment period.
21. The method of claim 1 , wherein the pharmaceutical composition is administered intravenously.
22. The method of claim 1 , wherein at least 90% of enucleated erythroid cells in the pharmaceutical composition comprise the fusion polypeptide comprising the antigen, or the antigenic fragment thereof.
23. The method of claim 1 , wherein the plurality of enucleated erythroid cells comprises reticulocytes.
24. The method of claim 1 , wherein the antigen is a myelin basic protein, a proteolipid protein, a myelin oligodendrocyte glycoprotein, a preproinsulin, a proinsulin, an insulin, a phospholipase A2 receptor, or a beta-2 glycoprotein 1.
25. The method of claim 1 , wherein the subject is a human subject.