Antigens targeted by pathogenic AI4 T cells in type 1 diabetes and uses thereof
View Patent ↗Provided are oligopeptide antigens to AI4-like T cells, and mouse proteins comprising those antigens. The oligopeptide antigens comprise the amino acid sequence XX(I/D/F/L)ENY(I/L)(E/W/Y)(L/M) or VMLENYTHL. Additionally provided are methods for treating a mammal having or at risk for type 1 diabetes using these antigens, or compounds which reduce or eliminate expression of these antigens. Kits comprising these antigens, and methods for determining whether a mammal is at risk for or has type 1 diabetes are also provided.
1. An isolated and purified oligopeptide or polypeptide comprising a sequence of less than 552 amino acids and comprising an amino acid sequence selected from the group consisting of XX(I/L)ENY(I/L)(E/Y)(L/M) (SEQ ID NO:56) and VMLENYTHL (SEQ ID NO:12), wherein if the sequence is VMLENYTHL (SEQ ID NO:12), then the oligopeptide or polypeptide is less than 51 amino acids.
2. The oligopeptide or polypeptide of claim 1 , comprising the amino acid sequence YAIENYLEL (SEQ ID NO:13), VMLENYTHL (SEQ ID NO:12), or YFIENYLEL (SEQ ID NO:14).
3. An isolated and purified oligopeptide of 9-10 amino acids comprising FQDENYLYL (SEQ ID NO:9), RLFENYIEL (SEQ ID NO:10), or QYLENYLWM (SEQ ID NO:11).
4. The oligopeptide or polypeptide of claim 1 , completely homologous to a mammalian DMK or MRCKβ polypeptide and having at least 90% homology to at least one of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 or SEQ ID NO:4.
5. The oligopeptide or polypeptide of claim 1 , wherein the oligopeptide or polypeptide comprises VMLENYTHL (SEQ ID NO:12) and comprises 13-25 amino acids.
6. The oligopeptide or polypeptide of claim 1 , comprising 9-10 amino acids.
7. The oligopeptide or polypeptide of claim 1 , further comprising an antigenic carrier.
8. The oligopeptide or polypeptide of claim 6 , further comprising a detectable label.
9. The oligopeptide or polypeptide of claim 6 , further comprising an MHC class I molecule that is capable of binding the oligopeptide.
10. The oligopeptide or polypeptide of claim 9 , further comprising a cytotoxic molecule.
11. The oligopeptide or polypeptide of claim 5 , further comprising an MHC class II molecule that is capable of binding the oligopeptide.
12. The oligopeptide or polypeptide of claim 11 , further comprising a cytotoxic molecule.
13. An isolated and purified oligopeptide 9-10 amino acids in length, completely homologous with a mammalian MRCKβ, (SEQ ID NO:5) or a mammalian analog thereof, (SEQ ID NO:6) or a mammalian analog thereof, or (SEQ ID NO:7) or a mammalian analog thereof, and having at least 90% homology to at least one of SEQ ID NO:1, SEQ ID NO:3, or SEQ ID NO:4 wherein the oligopeptide is capable of binding an MHC class I molecule of the mammal.
14. The oligopeptide of claim 13 , comprising the amino acid sequence XX(I/D/F/L)ENY(I/L)(E/W/Y)(L/M) (SEQ ID NO:16) or VMLENYTHL (SEQ ID NO:12).
15. The oligopeptide of claim 13 , comprising an amino acid sequence selected from the group consisting of YAIENYLEL (SEQ ID NO:13), FQDENYLYL (SEQ ID NO:9), RLFENYIEL (SEQ ID NO:10), VMLENYTHL (SEQ ID NO:12), YFIENYLEL (SEQ ID NO:14), and QYLENYLWM (SEQ ID NO:11).
16. The oligopeptide of claim 13 , further comprising a detectable label.
17. The oligopeptide of claim 13 , further comprising an MHC class I molecule that is capable of binding the oligopeptide.
18. The oligopeptide of claim 17 , further comprising a cytotoxic molecule.
19. A method of treating a mammal, wherein the mammal is at risk for or has type 1 diabetes, the method comprising administering an oligopeptide to the mammal in a manner sufficient to reduce CD8 + T cells reactive to a DMK, an MRCKβ, a (SEQ ID NO:5) or analog thereof in the mammal, a (SEQ ID NO:6) or analog thereof in the mammal, or a (SEQ ID NO:7) or analog thereof in the mammal, wherein the oligopeptide is 9-10 amino acids in length, and comprises the amino acid sequence XX(I/D/F/L)ENY(I/L)(E/W/Y)(L/M) (SEQ ID NO:16) or VMLENYTHL (SEQ ID NO:12).
20. An isolated and purified oligopeptide or polypeptide comprising a sequence of less than 25 amino acids and comprising an amino acid sequence selected from the group consisting of XX(I/D/F/L)ENY(I/L)(E/W/Y)(L/M) (SEQ ID NO:16).
21. The isolated and purified oligopeptide or polypeptide of claim 20 comprising (Y/F)(F/A/Q)(I/D)ENYL(E/Y)L (SEQ ID NO:20).
22. The isolated and purified oligopeptide or polypeptide of claim 20 comprising (Y/F)(A/Q)(I/D)ENYL(E/Y)L (SEQ ID NO:22).