Culture-expanded T suppressor cells and methods of use thereof
This invention relates to culture-expanded T suppressor cells derived from CD25 − CD4 + T cells, and their use in modulating immune responses. This invention provides methods of producing culture-expanded T suppressor cells, which are antigen specific, and their use in modulating autoimmune diseases and transplantation rejection.
1. A method for producing an isolated, antigen specific culture-expanded CD25 + CD4 + T suppressor cell population, comprising:
a) purifying a population of CD25 − CD4 + T cells;
b) purifying a greater than 90% population of immature dendritic cells;
c) contacting the population of CD25 − CD4 + T cells with the immature dendritic cells; an antigen selected from the group consisting of an antigenic peptide or an antigenic protein; and TGF- β1, for a period of time resulting in antigen-specific CD25 + CD4 + T cell differentiation and expansion, wherein the ratio of the immature dendritic cells to the CD25 − CD4 + T cells is between 1:1 and 1:10 and the concentration of the antigen is 30-100 ng/ml; and
d) isolating the expanded CD25 + CD4 + T cells obtained in (c),
thereby producing an isolated, antigen specific culture-expanded CD25 + CD4 + T suppressor cell population with an in vivo immune suppressive activity, wherein the CD25 + CD4 + T suppressor cell population do not express IL-10.
2. The method of claim 1 , wherein said isolated, antigen specific culture-expanded CD25 + CD25 + T suppressor cell population further expresses Foxp3.
3. The method of claim 1 , wherein the dendritic cells are presenting the antigen or a peptide thereof, or are engineered to express the antigen or a peptide thereof.
4. The method of claim 1 , wherein the antigen is a pancreatic beta cell antigen, a transplantation antigen, or a rheumatoid arthritis antigen.
5. The method of claim 1 , wherein said population suppresses or down modulates an inflammatory response, an allergic response, or an immune response.
6. The method of claim 5 , wherein said immune response is graft versus host disease or host versus graft disease.
7. The method of claim 1 , wherein the TGF- β1 is exogenous or expressed by the dendritic cells or other cells.
8. The method of claim 1 , wherein said dendritic cells are isolated from a subject suffering from an autoimmune disease or disorder.
9. The method of claim 8 , wherein said antigenic peptide or antigenic protein is associated with said autoimmune disease or disorder.
10. The method of claim 9 , wherein said autoimmune disease or disorder is type I diabetes, graft-vs.-host disease or host-vs.-graft disease.
11. The method of claim 9 , wherein said antigenic peptide or protein is expressed in pancreatic beta cells.
12. The method of claim 11 wherein said antigenic peptide is a BDC mimetope.
13. The method of claim 2 , wherein said dendritic cells are isolated from a subject with an allergic response, a recipient of a transplant, or a donor providing a transplant to said subject.