Glycosphingolipids and methods of use thereof
The invention provides, inter alia, immunoinhibitory glycosphingolipids and immunoinhibitory alpha-galactosylceramides and compositions and preparations thereof, and methods of use thereof including in the treatment of conditions characterized by increased iNKT cells and/or activity.
1. A method comprising
administering to a subject having or at risk of developing a condition characterized by increased invariant natural killer T (iNKT) cell numbers or activity an isolated immune inhibitory alpha-galactosylceramide in an effective amount to decrease iNKT cell numbers or activity,
wherein the isolated alpha-galactosylceramide has the structure
wherein m is any integer from 11 to 15, L is any integer from 0 to 2, and n+L is any integer from 13 to 17.
2. The method of claim 1 , wherein the fatty acid or sphingosine chain length is 16, 17, 18 or 19 carbons.
3. The method of claim 1 , wherein the fatty acid or sphingosine chain length is 17 carbons.
4. The method of claim 1 , wherein each of the fatty acid and sphingosine chain lengths is 17 carbons.
5. The method of claim 1 , wherein the alpha-galactosylceramide has a fatty acid or sphingosine chain that is branched.
6. The method of claim 5 , wherein the fatty acid or sphingosine chain is branched at the omega-2 (iso) position or omega-3 (anteiso) position.
7. The method of claim 5 , wherein the fatty acid or sphingosine chain comprises a terminal isomethyl or anteisomethyl group.
8. The method of claim 5 , wherein each of the fatty acid or sphingosine chain comprises a terminal isomethyl or anteisomethyl group.
9. The method of claim 1 , wherein the condition is an autoimmune disease.
10. The method of claim 1 , wherein the condition is inflammatory bowel disease.
11. The method of claim 10 , wherein the isolated alpha-galactosylceramide is administered to gut of the subject.
12. The method of claim 1 , wherein the subject is human.
13. The method of claim 1 , wherein the subject is administered another immunosuppressant.
14. The method of claim 1 , wherein the alpha-galactosylceramide has the structure:
wherein R is defined as C n H 2n , wherein R′ is defined as C m H 2m , wherein n is any integer from 10 to 13, and wherein m is any integer from 9 to 12.
15. The method of claim 1 , wherein the alpha-galactosylceramide has the structure:
wherein R is defined as C n H 2n , wherein R′ is defined as C m H 2m , wherein n is any integer from 10 to 13, and wherein m is any integer from 9 to 12.
16. The method of claim 1 , wherein the fatty acid C3′ position of the isolated alpha-galactosylceramide has
(a) R-chirality, or
(b) S-chirality, and
wherein the sphingosine C3 position has
(a) R-chirality, or
(b) S-chirality.
17. The method of claim 1 , wherein the condition characterized by increased iNKT cell numbers or activity is an inflammatory condition or an autoimmune disease.
18. The method of claim 1 , wherein the condition is:
(a) asthma;
(b) inflammatory bowel disease; or
(c) colitis.