Use of IL-15 preparations to treat lymphopenia
The present invention provides method for promoting the maturation and export of T cells from thymic tissue by contacting the thymic tissue with supraphysiological levels of interleukin (IL)-15. The present invention also provides methods for preventing, alleviating, reducing, and/or inhibiting lymphopenia or peripheral depletion of lymphocytes in a patient in need thereof by administering to the patient IL-15.
1. A method of treating lymphopenia in an individual in need thereof comprising systemically administering to the individual a heterodimer comprising (i) an interleukin-15 (IL-15) and (ii) an IL-15Rα-Fc fusion protein that comprises a soluble IL-15Rα fused to an Fc region; wherein the IL-15 has at least 95% amino acid sequence identity to the region of SEQ ID NO:2 that corresponds to mature IL-15; and the IL-15Rα-Fc fusion protein comprises an amino acid sequence that has at least 95% amino acid sequence identity to the IL-15Rα-Fc fusion protein sequence of SEQ ID NO:17 or SEQ ID NO:20;
wherein the heterodimer is administered at a dose that maintains supraphysiological plasma levels of IL-15 for two or more days.
2. The method of claim 1 , wherein the lymphopenia is drug-induced lymphopenia.
3. The method of claim 1 , wherein the individual is receiving anticancer drugs that induce lymphopenia.
4. The method of claim 1 , wherein the heterodimer is administered subcutaneously.
5. The method of claim 1 , wherein the supraphysiological plasma levels of IL-15 are in the range of 1 ng/ml to 1000 ng/ml.
6. The method of claim 1 , wherein the heterodimer is administered in an amount of 0.01 mg/kg.
7. The method of claim 1 , wherein the individual is a human.
8. The method of claim 1 , wherein the IL-15 comprises the region of SEQ ID NO:2 that corresponds to mature IL-15 and the IL-15Rα-Fc fusion protein comprises the IL-15Rα-Fc fusion protein sequence of SEQ ID NO:17 or SEQ ID NO:20.
9. A method of treating lymphopenia in an individual in need thereof comprising administering: (i) a nucleic acid sequence that encodes an IL-15 and (ii) a nucleic acid sequence that encodes an IL-15Rα-Fc fusion protein that comprises soluble IL-15Ra fused to an Fc region; wherein the IL-15 has at least 95% amino acid sequence identity to the region of SEQ ID NO:2 that corresponds to mature IL-15 and the IL-15Rα-Fc fusion protein has at least 95% identity to the IL-15Rα-Fc fusion protein sequence of SEQ ID NO:17 or SEQ ID NO:20;
wherein the nucleic acid sequence that encodes the IL-15 and the nucleic acid sequence that encodes the IL-15Rα-Fc fusion protein are administered at a dose that maintains supraphysiological plasma levels of IL-15 for two or more days.
10. The method of claim 9 , wherein the IL-15 and the IL-15Rα-Fc fusion protein are co-expressed from a single vector comprising the nucleic acid sequence that encodes the IL-15 and the nucleic acid sequence that encodes the IL IL-15Rα-Fc fusion protein.
11. The method of claim 9 , wherein the IL-15 and the IL-15Rα-Fc fusion protein are expressed from separate vectors, wherein one vector comprises the nucleic acid sequence that encodes the IL-15 and a separate vector comprises the nucleic acid sequence that encodes the IL-15Rα-Fc fusion protein.
12. The method of claim 9 , wherein the IL-15 comprises the region of SEQ ID NO:2 that corresponds to mature IL-15 and the IL-15Rα-Fc fusion protein comprises the IL-15Rα-Fc fusion protein sequence of SEQ ID NO:17 or SEQ ID NO:20.
13. The method of claim 12 , wherein the nucleic acid sequence that encodes IL-15 comprises the region of SEQ ID NO:3 or SEQ ID NO:4 that encodes mature IL-15; and the nucleic acid sequence that encodes the IL-15Rα-Fc fusion protein comprises the nucleic acid sequence of SEQ ID NO:16 or SEQ ID NO:19 that encodes the IL-15Rα-Fc fusion protein.
14. The method of claim 9 , wherein the supraphysiological plasma levels of IL-15 are in the range of 1 ng/ml to 1000 ng/ml.
15. The method of claim 9 , wherein the individual is a human.