Regulatory b cells and their uses

Abstract

The present invention relates to a distinct B cell subset, B10 cells, that regulate T cell mediated inflammatory responses through the secretion of interleukin-10 (IL-10). The invention also relates to the use of B10 cells in the manipulation of immune and inflammatory responses, and in the treatment of disease. Therapeutic approaches involving adoptive transfer of B10 cells, or expansion of their endogenous levels for controlling autoimmune or inflammatory diseases and conditions are described. Ablation of B10 cells, or inhibition of their IL-10 production can be used to upregulate immunodeficient conditions, ameliorate infectious diseases and/or to treat tumors/cancer. Diagnostic applications are also encompassed.

1 .- 9 . (canceled) 
     
     
         10 . A pharmaceutical composition for treating disorders associated with diminished levels of interleukin-10, comprising a cellular composition comprising B lymphocyte cells wherein at least 50% of the B lymphocyte cells are characterized as CD24 high CD27 + , and a pharmaceutically acceptable carrier. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the cells are producing IL-10. 
     
     
         12 . A method for treating a disease or condition associated with diminished levels of interleukin-10 or ameliorated by increasing levels of IL-10 comprising administering a therapeutically effective amount of the composition of  claim 10  to a subject in need of such treatment, wherein administration of the composition ameliorates the disease or condition. 
     
     
         13 . The method of  claim 12 , wherein the cells produce IL-10 in the subject. 
     
     
         14 .- 18 . (canceled) 
     
     
         19 . The method of  claim 12 , in which the disease or condition is inflammation. 
     
     
         20 . The method of  claim 12 , in which the disease or condition is autoimmune disease. 
     
     
         21 . The method of  claim 12 , in which the subject in need of such treatment is an organ transplant recipient. 
     
     
         22 .- 48 . (canceled) 
     
     
         49 . The pharmaceutical composition of  claim 10 , wherein the B lymphocyte cells are further characterized by a CD1d high CD5 +  phenotype. 
     
     
         50 . The pharmaceutical composition of  claim 10 , wherein the B lymphocyte cells are further characterized by expression of a marker selected from the group consisting of CD19, CD20, CD21, CD22, CD23, CD25, CD38, CD48, and CD148. 
     
     
         51 . The pharmaceutical composition of  claim 10 , wherein the B lymphocyte cells in the composition are contacted ex vivo with a mitogen, a cytokine, a growth factor, a antibody, a CD40 agonist or a TLR agonist. 
     
     
         52 . The pharmaceutical composition of  claim 51 , wherein the CD40 agonist is a CD40L (CD154), or an antibody agonist of CD40. 
     
     
         53 . The pharmaceutical composition of  claim 51 , wherein the TLR agonist is a TLR1 agonist, a TLR4 agonist, a TLR6 agonist, a TLR7 agonist or a TLR9 agonist. 
     
     
         54 . The pharmaceutical composition of  claim 53 , wherein the agonist is selected from lipopolysaccharide, CpG oligodeoxynucleotides, Pam3CSK4, Pam2CGDPKHPKSF, or Imiquimod. 
     
     
         55 . The method of  claim 12 , wherein the B lymphocyte cells are further characterized by a CD1d high CD5 +  phenotype. 
     
     
         56 . The method of  claim 12 , wherein the B lymphocyte cells are further characterized by expression of a marker selected from the group consisting of CD19, CD20, CD21, CD22, CD23, CD25, CD38, CD40, CD48, CD72 and CD148. 
     
     
         57 . The method of  claim 12 , wherein the B lymphocyte cells were contacted ex vivo with a mitogen, a cytokine, a growth factor, a antibody, a CD40 agonist or a TLR agonist. 
     
     
         58 . The method of  claim 57 , wherein the CD40 agonist is a CD40L (CD154), or an antibody agonist of CD40. 
     
     
         59 . The method of  claim 57 , wherein the TLR agonist is a TLR1 agonist, a TLR4 agonist, a TLR6 agonist, a TLR7 agonist or a TLR9 agonist. 
     
     
         60 . The method of  claim 59 , wherein the agonist is selected from lipopolysaccharide, CpG oligodeoxynucleotides, Pam3CSK4, Pam2CGDPKHPKSF, or Imiquimod. 
     
     
         61 . The method of  claim 12 , wherein the B lymphocyte cells were stimulated in vitro or ex vivo with PMA (phorbol 12-myristate 13-acetate) and ionomycin.