COMPOSITIONS AND METHODS FOR DIMINISHING AN IMMUNE RESPONSE
The invention is based upon the discovery that T regulatory type 1 (Tr1) cells express particular cell surface markers that allow for their selection, enrichment, isolation, purification and administration. The ability to use the particular markers described herein to select, enrich, isolate, purity and administer Tr1 cells allows for improved methods of Tr1 therapies for treating a wide variety of diseases and disorders.
1 . A composition comprising an enriched population of T regulatory type 1 (Tr1) cells, wherein the Tr1 cells in the enriched population of Tr1 cells express the cell surface markers CD4, and CD49b, and LAG-3.
2 . The composition of claim 1 , wherein the Tr1 cells also express the cell surface marker CD226.
3 . The composition of claim 2 , wherein the Tr1 cells express the cell surface marker CD226 at a level greater than the level of CD226 expressed by a comparator cell population.
4 . (canceled)
5 . The composition of claim 1 , wherein the Tr1 cells do not constitutively express high levels of Foxp3, as compared with the level of Foxp3 on a comparator cell selected from the group consisting of a CD25bright T cell and a Foxp3+ Treg cell.
6 . The composition of claim 1 , wherein greater than 90% of the cells in the enriched population of Tr1 cells express the cell surface markers CD4, and CD49b, and LAG-3.
7 .- 9 . (canceled)
10 . A method of isolating an enriched population of Tr1 cells from a biological sample of a subject, comprising the steps of:
a. obtaining a T cell-containing biological sample of a subject, and
b. isolating cells from the biological sample of the subject that express the cell surface markers CD4, CD49b, and LAG-3.
11 . The method of claim 10 , comprising the additional step of removing cells that express high levels of Foxp3 from the enriched population of Tr1 cells.
12 . The method of claim 10 , comprising the additional step of isolating cells from the biological sample of the subject that express the cell surface marker CD226.
13 . The method of claim 12 , wherein the cells express the cell surface marker CD226 at a level greater than the level of CD226 expressed by a comparator cell population.
14 . (canceled)
15 . The method of claim 10 , wherein greater than 90% of the cells in the enriched population of Tr1 cells express the cell surface markers CD4, and CD49b, and LAG-3.
16 .- 18 . (canceled)
19 . The method of claim 10 , wherein isolating cells from the biological sample of the subject employs the use of antibody that specifically binds to a cell surface marker.
20 . The method claim 19 , wherein the cell surface marker is at least one selected from the group consisting of CD4, CD49b, and LAG-3.
21 . The method of claim 10 , wherein isolating cells from the biological sample of the subject employs the use of fluorescence-activated cell sorting (FACS).
22 . The method of claim 10 , wherein the biological sample is at least one selected from the group consisting of blood, bone marrow, cord blood, lymph, thymus, and spleen.
23 . A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of CD4+CD49+LAG-3+ Tr1 cells.
24 . The method of claim 23 , wherein the disease or disorder is at least one selected from the group consisting of an inflammatory disease and disorder, an autoimmune disease or disorder, and a disease or disorder associated with transplantation.
25 . The method of claim 23 , wherein the disease or disorder is at least one selected from the group consisting of allergy, asthma, inflammatory bowel disease, autoimmune entheropathy, Addision's disease, alopecia areata, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, Crohn's disease, diabetes mellitus, dystrophic epidermolysis bullosa, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barr syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, psoriasis, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, thyroiditis, vasculitis, vitiligo, myxedema, pernicious anemia, ulcerative colitis, cell and organ transplant rejection and graft versus host disease.
26 . (canceled)
27 . A method of inhibiting alloreactive T cells in a subject in need thereof, the method comprising contacting the alloreactive T cells with an effective amount of CD4+CD49+LAG-3+ Tr1 cells.
28 .- 31 . (canceled)
32 . A method for preventing or treating an alloreactive response, inflammatory response, or autoimmune response in a subject, said method comprising administering to said subject, prior to onset of the alloreactive response, inflammatory response, or autoimmune response, an effective amount of CD4 + CD49 + LAG-3 + Tr1 cells to prevent said response.
33 .- 40 . (canceled)