Ceramide derivatives as modulators of immunity and autoimmunity
AssigneeAlbert Einstein College of Medicine of Yeshiva University
InventorSteven A. Porcelli
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Abstract
α-Galactosylceramides and glycosylceramides (“ceramide-like glycolipids”) that modulate NK T cells. The ceramide-like glycolipids vary in the cytokines induced in NK T cells and vary in the antigen-presenting cells that are capable of efficiently presenting the compounds to NK T cells. Pharmaceutical compositions of the ceramide-like glycolipids are provided, as are pharmaceutical compositions of the ceramide-like glycolipids combined with dendritic cells. Methods utilizing the ceramide-like glycolipids in vaccines, to activate NK T cells, to stimulate the immune system, and to treat mammals are also provided. The invention also provides methods of evaluating a compound for its ability to activate an NK T cell in the presence of a cell expressing a CD1d protein.
Claims54
A method of activating a NK T cell, the method comprising contacting the NK T cell with an α-galactosylceramide of Formula I:
- wherein
- R1 is a linear or branched C2-C27 alkene with at least two C═C bonds wherein R1 includes at least two C═C bonds that are conjugated with each other;
- and
- R2 is —CH(OH)(CH2)xCH3,
- wherein X is an integer ranging from 5-17.
A method of activating a NK T cell, the method comprising contacting the NK T cell with an α-galactosylceramide of Formula I:
- wherein
- R1 is a linear or branched C2-C27 alkene with at least two C═C bonds;
- and
- R2 is one of the following (a)-(c):
- (a) —CH(OH)(OH)(CH2)XCH3,
- (b) —CH(OH)(CH2)XCH(CH1)2,
- (c) —CH(OH)(CH1)XCH(CH3)CH2CH3,
- wherein X is an integer ranging from 5-17,
- wherein the NK T cell is in a living mammal, and
- wherein the α-galactosylceramide is contacted with dendritic cells ex vivo before the α-galactosylceramide is contacted with the NK T cell and then injecting the dendritic cells into the mammal.
A method of activating a NK T cell, the method comprising contacting the NK T cell with an α-galactosylceramide of Formula I:
- wherein
- R1 is C(OH)—R3 where R3 is a linear or branched C2-C26 alkene;
- and
- R2 is one of the following (a)-(e):
- (a) —CH2(CH2)XCH3,
- (b) —CH(OH)(CH2)XCH3,
- (c) —CH(OH)(CH2)XCH(CH3)2,
- (d) —CH═CH(CH2)XCH3,
- (e) —CH(OH)(CH2)XCH(CH3)CH2CH3,
- wherein X is an integer ranging from 5-17.
A method of activating a NK T cell, the method comprising contacting the NK T cell with an α-galactosylceramide comprising Formula I:
- wherein
- R1 is a C6-C27 alkane or alkene wherein (i) the C6-C27 alkane or alkene is substituted with a C5-C15 cycloalkane, C5-C15 cycloalkene, heterocycle, or aromatic ring or (ii) the C6-C27 alkane or alkene includes, within the C6-C27 alkyl or alkenyl chain, a C5-C15 cycloalkane, C5-C15 cycloalkene, heterocycle, or aromatic ring;
- and
- R2 is one of the following (a)-(e):
- (a) —CH2(CH2)XCH3,
- (b) —CH(OH)(CH2)XCH3,
- (c) —CH(OH)(CH2)XCH(CH3)2,
- (d) —CH═CH(CH2)XCH3,
- (e) —CH(OH)(CH2)XCH(CH3)CH2CH3,
- wherein X is an integer ranging from 5-17.
A method of activating a NK T cell, the method comprising contacting the NK T cell with an α-galactosylceramide comprising Formula I:
- wherein
- R1 is selected from the group consisting of —C(═O)OCH2CH3, —(CH2)6CH3, —(CH2)4Cl, —(CH2)16CH3, —(CH2)5CH3, —(CH2)2CH3, —(CH2)4CH3, —(CH2)8CH3, —(CH2)10CH3, and —(CH2)12CH3;
- and
- R2 is —CH(OH)(CH2)13CH3.
A method of activating a NK T cell, the method comprising contacting the NK T cell with an α-galactosylceramide comprising Formula I:
- wherein
- R1 is selected from the group consisting of
- where ( ) represent the point of attachment of R1 to the compound of Formula I;
- and
- R2 is one of the following (a)-(e):
- (a) —CH2(CH2)XCH3,
- (b) —CH(OH)(CH2)XCH3,
- (c) —CH(OH)(CH2)XCH(CH3)2,
- (d) —CH═CH(CH2)XCH3,
- (e) —CH(OH)(CH2)XCH(CH3)CH2CH3,
- wherein X is an integer ranging from 5-17.
An α-galactosylceramide of Formula I:
- wherein
- R1 is a linear or branched C2-C27 alkene with at least two C═C bond, wherein said at least two C═C bonds are conjugated with each other, or R1 is C(OH)—R3, wherein R3 is a linear or branched C2-C26 alkene with at least two C═C bond, and wherein said at least two C═C bonds are conjugated with each other;
- and
- R2 is one of the following (a)-(e):
- (a) —CH2(CH2)XCH3,
- (b) —CH(OH)(CH2)XCH3,
- (c) —CH(OH)(CH2)XCH(CH3)2,
- (d) —CH═CH(CH2)XCH3,
- (e) —CH(OH)(CH2)XCH(CH3)CH2CH3,
- wherein X is an integer ranging from 5-17.
Dependencies are inferred from the claim text.