REGULATORY B CELLS AND THEIR USE
Isolated regulatory B cells are disclosed, and compositions including these isolated regulatory B cells. The isolated regulatory B cells are mammalian and express T cell immunoglobulin mucin-1 (TIM-1). In some embodiments the regulatory B cells produce IL-10. Methods for treating a subject with an immune-mediated disorder are disclosed. These methods include administering to the subject a therapeutically effective amount of a composition including regulatory B cells, thereby treating the immune mediated disorder in the subject. Methods are also disclosed for treating a subject with an immune-mediated disorder, wherein the methods include administering to the subject a therapeutically effective amount of an antibody that specifically binds TIM-1, wherein the antibody is activates TIM-1 + CD19 + B cells. Methods are also disclosed for assessing the immune status of a subject.
1 . An isolated population of regulatory B cells, wherein the regulatory B cells are mammalian and wherein the regulatory B cells express T cell immunoglobulin mucin-1 (TIM-1).
2 . The isolated population of regulatory B cells of claim 1 , wherein the regulatory B cells produce interleukin-10.
3 . The isolated population of regulatory B cells of claim 1 , wherein the regulatory B cells are CD19 + CD1d high CD5 + .
4 . The isolated population of regulatory B cells of claim 1 , wherein the regulatory B cells are human regulatory B cells.
5 . A method of treating a subject with an immune-mediated disorder, or preventing the development of an immune-mediated disorder, comprising administering to the subject a therapeutically effective amount of a composition comprising the isolated population of regulatory B cells of claim 1 , thereby treating or preventing the immune mediated disorder in the subject.
6 . The method of claim 5 , wherein the immune-mediated disorder is inflammation, allegeric disease, graft-versus host disease, transplant rejection, or an autoimmune disorder.
7 . The method of claim 6 , wherein the immune-mediated disorder is transplant rejection, and wherein the transplant is an organ transplant, bone marrow or other cell transplant, composite tissue transplant, or a skin graft.
8 . The method of claim 6 , wherein the autoimmune disorder, allergic or inflammatory disorder is multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, type I diabetes, systemic lupus erythrematosus, contact hypersensitivity, asthma or Sjogren's syndrome.
9 . The method of claim 5 , wherein the subject is a human.
10 . The method of claim 5 , further comprising administering to the subject a therapeutically effective amount of an immunomodulatory or an immunosuppressive agent.
11 . The method of claim 10 , wherein the immunosuppressive agent is a calcineurin inhibitor, an mTOR inhibitor, an antibody, a chemotherapeutic agent irradiation, a chemokine, an interleukins or an inhibitor of a chemokine or an interleukin.
12 . A method of treating a subject with a cancer, comprising administering to the subject a therapeutically effective amount of an antibody that specifically binds TIM-1, thereby inducing an immune response to the cancer and treating the subject.
13 . The method of claim 12 , wherein the subject is a human.
14 . The method of claim 13 , wherein the antibody is a monoclonal antibody.
15 . The method of claim 14 , wherein the monoclonal antibody is a humanized antibody or a fully human antibody.
16 . The method of claim 12 , wherein the cancer is a solid cancer or a hematological cancer.
17 . The method of claim 12 , further comprising administering to the subject a therapeutically effective amount of a chemotherapeutic agent.
18 . A method for assessing the immune status of a subject, comprising selecting a subject with an immune-mediated disorder or suspected of having or being predisposed to an immune-mediated disorder; and detecting the number of CD19 + TIM-1 + regulatory B cells in an initial biological sample from the subject, thereby assessing the immune status of the subject.
19 . The method of claim 18 , further comprising administering to the subject a therapeutically effective amount of an immunosuppressive agent.
20 . The method of claim 18 , further comprising detecting the number of CD19 + TIM-1 + B cells in a second sample from the subject following administering the immunosuppressive agent, wherein an increase in the number of CD19 + TIM-1 + regulatory B cells in the second sample as compared to the number of CD19 + TIM-1 + regulatory B cells in the initial sample indicates that the immunosuppressive agent is effective for treating the subject.
21 . The method of claim 18 , further comprising measuring the ratio of the number of CD19 + TIM-1 + regulatory B cells to CD19 + TIM-1 − regulatory B cells in the sample from the subject.
22 . The method of claim 18 , wherein detecting the number of CD19 + TIM-1 + regulatory B cells comprises the use of fluorescence activated cell sorting.
23 . The method of claim 18 , further comprising measuring the production of IL-10 in a sample from a subject, wherein the sample comprises CD19 + TIM-1 + regulatory B cells.
24 . The method of claim 18 , wherein a higher number of CD19 + TIM-1 + regulatory B cells, or a higher ratio of regulatory to non-regulatory B cells, as compared to a control indicates the subject is immunosuppressed.
25 . The method of claim 18 , wherein a lower number of CD19 + TIM-1 + regulatory B cells, or a lower ratio of regulatory to non-regulatory B cells, as compared to a control indicates the subject has an immune-mediated disorder.
26 . The method of claim 25 , wherein the immune-mediated disorder is an inflammatory disorder, allergic disorder, graft-versus host disease, transplant rejection, or an autoimmune disorder.
27 . A composition comprising a therapeutically effective amount of isolated regulatory B cells expressing TIM-1 and CD19 in a pharmaceutically acceptable carrier.