Method for restoring dendritic cell populations
View Patent ↗The present invention provides methods for restoring and increasing dendritic cell populations in a subject by modulation of the lymphotoxin-β receptor (LTβR) via LTβR agonists. The invention also provides methods for screening for agents capable of restoring or increasing dendritic cell populations. The invention further provides a method for the treatment of immunodeficiency by administration of an LTβR agonist.
1. A method for increasing a CD8α negative (CD8α−) dendritic cell subpopulation in a subject, comprising:
a) administering to the subject a lymphotoxin-β receptor (LTβR) agonist, wherein the agonist is an antibody or a fragment thereof; and
b) detecting an increase in the CD8α− subpopulation, organogenesis, or expression of a LTβR mediated gene, thereby increasing the CD8α− subpopulation in the subject.
2. The method of claim 1 , wherein the reduced dendritic cell population is due to a reduction in lymphotoxin-β receptor (LTβR) induced proliferation.
3. The method of claim 2 , wherein the reduced dendritic cell population comprises a reduction in a CD8α negative (CD8α−) dendritic cell subpopulation.
4. The method of claim 1 , wherein the CD8α negative (CD8α−) dendritic cell subpopulation comprises CD4 positive (CD4+) dendritic cells, CD8α negative/CD4 negative (CD8α−/CD4−) dendritic cells, or a combination thereof.
5. The method of claim 4 , wherein the CD4 positive (CD4+) dendritic cells and CD8α negative/CD4 negative (CD8α−/CD4−) dendritic cells are increased.
6. The method of claim 5 , wherein the ratio of CD4 positive (CD4+) dendritic cells and CD8α negative/CD4 negative (CD8α−/CD4−) dendritic cells is similar to the subject in a non-immunodeficient state.
7. The method of claim 1 , further comprising increasing expression of a lymphotoxin-β receptor (LTβR) mediated gene.
8. The method of claim 7 , wherein the gene is a cytokine or chemokine.
9. The method of claim 7 , wherein the gene is selected from the group consisting of: LTβ, LTα, LIGHT, IL7Rα, RORγt, CCL21, CXCL13, or CCL19.
10. The method of claim 9 , wherein the gene is CCL21-ser or CCL21-leu.
11. The method of claim 1 , further comprising inducing organogenesis.
12. The method of claim 11 , wherein organogenesis occurs in a lymphoid tissue or organ.
13. The method of claim 12 , wherein the tissue or organ is a bone marrow, a lymph node, a spleen, a thymus, or combination thereof.
14. The method of claim 1 , wherein the antibody or fragment thereof is monoclonal.
15. The method of claim 1 , wherein the antibody or fragment thereof is humanized.
16. The method of claim 1 , wherein the antibody or fragment thereof is synthetic.
17. A method for inducing proliferation of a CD8α negative (CD8α−) dendritic cell in a sample, comprising:
a) contacting a sample comprising a CD8α− dendritic cell with a lymphotoxin-β receptor (LTβR) agonist, wherein the agonist is an antibody or a fragment thereof; and
b) detecting an increase in the CD8α− subpopulation, organogenesis, or expression of a LTβR mediated gene, thereby inducing proliferation of the CD8α− dendritic cell.
18. The method of claim 17 , wherein proliferation is of CD4 positive (CD4+) dendritic cells, CD8α negative/CD4 negative (CD8α−/CD4−) dendritic cells, or a combination thereof.
19. The method of claim 17 , wherein the sample further comprises a lymphoid tissue or organ.
20. The method of claim 17 , wherein the lymphoid tissue or organ is a bone marrow, a lymph node, a spleen, a thymus, or combination thereof.
21. The method of claim 17 , wherein the antibody or fragment thereof is monoclonal.
22. The method of claim 17 , wherein the antibody or fragment thereof is humanized.
23. The method of claim 17 , wherein the antibody or fragment thereof is synthetic.
24. A method of treating immunodeficiency in a subject, comprising, administering to the subject a lymphotoxin-β receptor (LTβR) agonist, wherein the agonist is an antibody or a fragment thereof.
25. The method of claim 24 , wherein the immunodeficiency comprises a reduced dendritic cell population.
26. The method of claim 25 , wherein the reduced dendritic cell population comprises a reduction in a CD8α negative (CD8α−) dendritic cell subpopulation.
27. The method of claim 26 , wherein the CD8α negative (CD8α−) dendritic cell subpopulation comprises CD4 positive (CD4+) dendritic cells, CD8α negative/CD4 negative (CD8α−/CD4−) dendritic cells, or a combination thereof.
28. The method of claim 24 , wherein the immunodeficiency is a primary immunodeficiency.
29. The method of claim 28 , wherein the primary immunodeficiency is selected from the group consisting of: combined T- and B-cell immunodeficiencies, antibody deficiencies, and well-defined immunodeficiency syndromes.
30. The method of claim 29 , wherein the primary immunodeficiency is severe combined immune deficiency disorder (SCID).
31. The method of claim 24 , wherein the antibody or fragment thereof is monoclonal.
32. The method of claim 24 , wherein the antibody or fragment thereof is humanized.
33. The method of claim 24 , wherein the antibody or fragment thereof is synthetic.
34. The method of claim 24 , further comprising administering a chemotherapeutic agent, immunostimulatory agent, or combination thereof.
35. The method of claim 24 , wherein the subject is mammalian.
36. The method of claim 35 , wherein the subject is human.