Tolerogenic synthetic nanocarriers for generating CD8+ regulatory T cells
Disclosed are synthetic nanocarrier methods, and related compositions, comprising administering MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen and immunosuppressants in order to generate tolerogenic immune responses against the antigen, such as the generation of antigen-specific CD8+ regulatory T cells.
1. A method for generating antigen-specific CD8+ regulatory T cells in a mammalian subject comprising:
administering to the mammalian subject a composition that comprises:
(i) a first population of polymeric synthetic nanocarriers coupled to rapamycin, and
(ii) a second population of polymeric synthetic nanocarriers coupled to antigens that comprise MHC Class II-restricted epitopes, wherein the composition is in an amount effective to generate antigen-specific CD8+ regulatory T cells in the subject, wherein the method further comprises assessing the generation of antigen-specific CD8+ regulatory T cells that produce IL-10 prior to and/or after the administration of the composition,
wherein at least 75% of the polymeric synthetic nanocarriers of the first and/or second population of synthetic nanocarriers have a minimum dimension, obtained using dynamic light scattering, that is greater than 110 nm
and a maximum dimension, obtained using dynamic light scattering, that is equal to or less than 500 nm,
wherein the load of the rapamycin on average across the first population of polymeric synthetic nanocarriers is at least 2% but no more than 25% (weight/weight), and
wherein the load of the antigens on average across the second population of polymeric synthetic nanocarriers is between 1% and 10% weight/weight.
2. A method for generating antigen-specific CD8+ regulatory T cells in a mammalian subject comprising:
administering to the mammalian subject a composition according to a protocol that was previously shown to generate antigen-specific CD8+ regulatory T cells that produce IL-10 in one or more test subjects;
wherein the composition comprises:
(i) a first population of polymeric synthetic nanocarriers coupled to rapamycin, and
(ii) a second population of polymeric synthetic nanocarriers coupled to antigens that comprise MHC Class II-restricted epitopes,
wherein at least 75% of the polymeric synthetic nanocarriers of the first and/or second population of synthetic nanocarriers have a minimum dimension, obtained using dynamic light scattering, that is greater than 110 nm
and a maximum dimension, obtained using dynamic light scattering, that is equal to or less than 500 nm,
wherein the load of the rapamycin on average across the first population of polymeric synthetic nanocarriers is at least 2% but no more than 25% (weight/weight), and
wherein the load of the antigens on average across the second population of polymeric synthetic nanocarriers is between 1% and 10% weight/weight.
3. The method of claim 1 or 2 , wherein the antigens are coupled to the same synthetic nanocarriers as to which the rapamycin is coupled of synthetic nanocarriers are the same population.
4. The method of claim 1 or 2 , wherein the antigen is a therapeutic protein, an autoantigen or an allergen, or an antigen associated with an inflammatory disease, an autoimmune disease, organ or tissue rejection or graft versus host disease.
5. The method of claim 2 , wherein the method further comprises assessing the generation of antigen-specific CD8+ regulatory T cells in the subject prior to and/or after the administration of the composition.
6. The method of claim 1 or 2 , wherein the subject has an inflammatory disease, an autoimmune disease, an allergy, organ or tissue rejection or graft versus host disease.
7. The method of claim 1 or 2 , wherein the subject has undergone transplantation.
8. The method of claim 1 or 2 , wherein the subject has an undesired immune response against a therapeutic protein that is being administered to the subject.
9. The method of claim 1 or 2 , wherein the method further comprises administering a transplantable graft or therapeutic protein to the subject.
10. The method of claim 1 or 2 , wherein the administering of the synthetic nanocarriers is by intravenous, intraperitoneal, transmucosal, oral, subcutaneous, pulmonary, intranasal, intradermal or intramuscular administration.
11. The method of claim 1 or 2 , wherein the polymeric synthetic nanocarriers of the first population and/or second population comprise polymer that is a non-methoxy-terminated, polymer.
12. The method of claim 1 or 2 , wherein the polymeric synthetic nanocarriers of the first population and/or second population comprise a polyester, a polyester coupled to a polyether, polycarbonate, polyacetal, polyketal, polysaccharide, polyethyloxazoline or polyethyleneimine.
13. The method of claim 1 or 2 , wherein the aspect ratio of the maximum to minimum dimensions of the synthetic nanocarriers of the first population and/or second population is greater than 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:5, 1:7 or 1:10.
14. The method of claim 1 or 2 , wherein at least 80% of the polymeric synthetic nanocarriers, based on the total number of polymeric synthetic nanocarriers, have a minimum dimension or maximum dimension that falls within 20% of the average minimum dimension or the average maximum dimension, respectively, of the polymeric synthetic nanocarriers.
15. The method of claim 14 , wherein at least 90% of the polymeric synthetic nanocarriers have the minimum dimension or maximum dimension.
16. The method of claim 15 , wherein at least 95% of the polymeric synthetic nanocarriers have the minimum dimension or maximum dimension.
17. The method of claim 15 or 16 , wherein the minimum dimension or maximum dimension falls within 10%.
18. The method of claim 17 , wherein the minimum dimension or maximum dimension falls within 5%.