Use of PLA2G5-deficient suppressive macrophages in suppression of inflammation
Methods to reduce the inflammatory response critical in the pathogenesis of asthma and asthma exacerbations via the introduction of autologous Pla2g5-deficient suppressive macrophages into the airways of patients with asthma.
1. A method of reducing pulmonary inflammation in a subject, the method comprising:
identifying a subject as having an allergen-induced asthma; and
delivering a population of Pla2g5-deficient suppressive macrophages to the subject identified as having an allergen-induced asthma, preferably to a lung or airway of the subject.
2. The method of claim 1 , wherein the population of Pla2g5-deficient suppressive macrophages is autologous to the subject.
3. The method of claim 1 , wherein the population of Pla2g5-deficient suppressive macrophages comprises an inhibitory nucleic acid that reduces expression of Pla2g5.
4. The method of claim 3 , wherein the inhibitory nucleic acid is an antisense oligonucleotide, or siRNA, shRNA.
5. The method of claim 4 , wherein the inhibitory nucleic acid is modified.
6. The method of claim 5 , wherein the inhibitory nucleic acid comprises a modified backbone or at least one modified nucleotide.
7. The method of claim 6 , wherein the inhibitory nucleic acid comprises at least one locked nucleic acid.
8. The method of claim 5 , wherein the inhibitory nucleic acid is a gapmer or mixmer.
9. The method claim 1 , wherein the subject has asthma.
10. The method of claim 1 , wherein the cells are delivered by an aerosol spray of a suspension of cells into a nasal passage of the subject; by intratracheal or intrabracheal distillation; or by intravenous administration.
11. A method of preparing a population of Pla2g5-deficient suppressive macrophages, the method comprising:
obtaining a sample comprising peripheral blood from a subject;
enriching the sample for mononuclear cells;
maintaining the mononuclear cells under conditions to promote differentiation of the mononuclear cells into a population of macrophages, wherein the cells are maintained in the presence of Granulocyte macrophage colony-stimulating factor (GM-CSF), preferably for 13 days;
contacting the population of macrophages with an inhibitory nucleic acid that reduces expression of Pla2g5; and
polarizing the cells with interleukin 4 (IL-4),
thereby preparing a population of Pla2g5-deficient suppressive macrophages.
12. The method of claim 11 , wherein the sample of peripheral blood is obtained from a subject who has pulmonary inflammation.
13. The method of claim 11 , wherein the inhibitory nucleic acid is an antisense oligonucleotide, or siRNA, shRNA.
14. The method of claim 13 , wherein the inhibitory nucleic acid is modified.
15. The method of claim 14 , wherein the inhibitory nucleic acid comprises a modified backbone or at least one modified nucleotide.
16. The method of claim 14 , wherein the inhibitory nucleic acid comprises at least one locked nucleic acid.
17. The method of claim 11 , wherein the inhibitory nucleic acid is a gapmer or mixmer.
18. The method of claim 11 , wherein the subject has asthma.
19. A population of Pla2g5-deficient suppressive macrophages prepared by the method of claim 11 .
20. A method of reducing allergen-induced pulmonary inflammation in a subject, the method comprising administering the population of Pla2g5-deficient suppressive macrophages of claim 19 to a subject in need thereof.