Method of treating autoimmune disease with mesenchymal stem cells

Abstract

Methods and compositions for treating an autoimmune disease, such as new onset type 1 diabetes (T1D) in a subject using autologous or allogeneic mesenchymal stem cells administered to the subject prior to autoimmune-induced complete depletion of insulin-producing pancreatic beta cells, e.g., within six months of new onset type 1 diabetes (T1D) diagnosis or prior to the onset of disease in a subject determined to be at high risk for T1D.

1 . A method of treating new onset type 1 diabetes (T1D) in a subject comprising administering autologous or allogeneic mesenchymal stem cells to the subject prior to autoimmune-induced complete depletion of insulin-producing pancreatic beta cells. 
     
     
         2 . A method of treating new onset type 1 diabetes (T1D) in a human subject comprising administering autologous or allogeneic mesenchymal stem cells to the subject within six months of new onset type 1 diabetes (T1D) diagnosis. 
     
     
         3 . A method of treating new onset type 1 diabetes (T1D) in a human subject determined to be at high risk for the disease comprising administering autologous or allogeneic mesenchymal stem cells to the subject. 
     
     
         4 . The method of  claim 2 , wherein the mesenchymal stem cells are administered within 10 days of T1D diagnosis. 
     
     
         5 . The method of  claim 2 , wherein the mesenchymal stem cells are administered within 24 hours of T1D diagnosis. 
     
     
         6 . The method of  claim 2 , wherein the mesenchymal stem cells are administered at the time of or before T1D diagnosis. 
     
     
         7 . The method of  claim 2 , further comprising a second administration of autologous or allogeneic mesenchymal stem cells within ten days of the first administration of autologous or allogeneic mesenchymal stem cells. 
     
     
         8 . The method of  claim 2 , further comprising a second administration of autologous or allogeneic mesenchymal stem cells within one month of the first administration of autologous or allogeneic mesenchymal stem cells. 
     
     
         9 . The method of  claim 2 , further comprising a second administration of autologous or allogeneic mesenchymal stem cells within three months of the first administration of autologous or allogeneic mesenchymal stem cells. 
     
     
         10 . The method of  claim 2 , further comprising a second administration of autologous or allogeneic mesenchymal stem cells within six months of the first administration of autologous or allogeneic mesenchymal stem cells. 
     
     
         11 . The method of  claim 2 , further comprising a second administration of autologous or allogeneic mesenchymal stem cells within one year of the first administration of autologous or allogeneic mesenchymal stem cells. 
     
     
         12 . The method of  claim 2 , further comprising a second administration of autologous or allogeneic mesenchymal stem cells within two years of the first administration of autologous or allogeneic mesenchymal stem cells. 
     
     
         13 . The method of  claim 2 , further comprising a second administration of autologous or allogeneic mesenchymal stem cells within five years of the first administration of autologous or allogeneic mesenchymal stem cells. 
     
     
         14 . The method of  claim 2 , wherein the mesenchymal stem cells are derived from bone marrow or peripheral blood. 
     
     
         15 . The method of  claim 14 , wherein the bone marrow derived cells comprise CD271-positive mesenchymal stem cells. 
     
     
         16 . The method of  claim 2 , wherein the mesenchymal stem cells are derived from umbilical cord blood cells. 
     
     
         17 . The method of  claim 2 , wherein the mesenchymal stem cells are derived from a population of cells selected from the group consisting of muscle cells, fat cells, embryonic yolk sac cells, placenta cells, fetal blood cells, fetal skin cells, and adult skin cells. 
     
     
         18 . The method of  claim 2 , wherein the mesenchymal stem cells are administered to a subject having an abnormally low, but measurable, serum C-peptide level. 
     
     
         19 . The method of  claim 18 , wherein the subject further has an abnormally high blood glucose level in the absence of exogenous insulin administration. 
     
     
         20 . The method of  claim 18 , wherein the abnormally high blood glucose level is a fasting blood glucose level of greater than about 120 mg/dl in the absence of exogenous insulin administration. 
     
     
         21 . The method of  claim 18 , wherein the subject has a fasting C-peptide level of 0.1 nmol/L or greater. 
     
     
         22 . The method of  claim 18 , wherein the subject has a fasting C-peptide level of about 0.033 nmol/L or greater. 
     
     
         23 . The method of  claim 18 , wherein the subject has a stimulated C-peptide test integrated C-peptide level of 1.0 nmol/L or less. 
     
     
         24 . The method of  claim 23 , wherein the subject has a measurable increase in stimulated C-peptide test integrated C-peptide. 
     
     
         25 . The method of  claim 23 , wherein the subject has a measurable increase in stimulated C-peptide test integrated C-peptide level of 0.54 nmol/L or less. 
     
     
         26 . The method of  claim 2 , wherein the subject has a detectable level of pancreatic autoantibody. 
     
     
         27 . The method of  claim 26 , wherein the pancreatic autoantibody is selected from the group consisting of GADAb, ICA, IA-2Ab, and IAA. 
     
     
         28 . The method of  claim 2 , wherein the subject has a HbA1c level of 7% or higher. 
     
     
         29 . The method of  claim 2 , wherein the mesenchymal stem cells are autologous. 
     
     
         30 . The method of  claim 29 , wherein the autologous mesenchymal stems cells are derived from umbilical cord blood. 
     
     
         31 . The method of  claim 2 , wherein the mesenchymal stem cells are allogeneic. 
     
     
         32 . The method of  claim 2 , wherein the mesenchymal stem cells are CD105-positive mesenchymal stem cells. 
     
     
         33 . The method of  claim 32 , wherein the CD105 positive mesenchymal stem cells are plastic-adherent and spindle-shaped cells. 
     
     
         34 . The method of  claim 32 , wherein the CD105 positive mesenchymal stem cells are capable of dividing to form a population of CD105 positive mesenchymal stem cells. 
     
     
         35 . The method of  claim 32 , wherein the CD105 positive mesenchymal stem cells are capable of differentiating into a differentiated cell type. 
     
     
         36 . The method of  claim 35 , wherein the CD105 positive mesenchymal stem cells are capable of differentiating into more than one differentiated cell type including at least one differentiated cell type selected from the group consisting of osteoblasts, chondrocytes, myocytes, adipocytes, and neuronal cells. 
     
     
         37 . The method of  claim 35 , wherein the CD105 positive mesenchymal stem cells are capable of differentiating into a tissue type selected from the group consisting of bone, cartilage, muscle, marrow stroma, tendon and connective tissue. 
     
     
         38 . The method of  claim 2 , wherein the mesenchymal stem cells are positive for one or more mesenchymal stem cell markers selected from the group consisting of CD105 (endoglin, SH2), and CD73 (ecto-5′ nucleotidase, SH3, SH4). 
     
     
         39 . The method of  claim 38 , wherein the mesenchymal stem cells are negative for the markers CD45, CD34, and/or CD14. 
     
     
         40 . The method of  claim 2 , wherein the mesenchymal stem cells are positive for the markers CD105, CD73 and CD90. 
     
     
         41 . The method of  claim 40 , wherein the mesenchymal stem cells are negative for the markers CD45, CD34, and CD14. 
     
     
         42 . The method of  claim 40 , wherein the mesenchymal stem cells are plastic-adherent when maintained in standard culture conditions and are capable of differentiating in vitro into osteoblasts, adipocytes and/or chondrobasts. 
     
     
         43 . The method of  claim 2 , further comprising administering to the subject an immunosuppressive agent. 
     
     
         44 . The method of  claim 43 , wherein the immunosuppressive agent is selected from the group consisting of prednisone, azathioprine, cyclosporine, antibodies against CD3, antibodies against CD20, and antithymocyte globulin. 
     
     
         45 . The method of  claim 2 , further comprising administering to the subject a peptide vaccine. 
     
     
         46 . The method of  claim 45 , wherein the vaccine induces tolerance of insulin-producing cells. 
     
     
         47 . The method of  claim 46 , wherein the vaccine comprises an autoimmune Type I diabetes (T1D) autoantigen. 
     
     
         48 . The method of  claim 47 , wherein the vaccine comprises an islet-cell autoantigen selected from the group consisting of insulin, proinsulin, glutamic acid decarboxylase (GAD65), HSP60, and IA-2 protein tyrosine phosphatase. 
     
     
         49 . The method of  claim 2 , further comprising administering a non-mitogenic anti-CD3 active compound selected from the group consisting of CD3 antibodies and fragments of CD3 antibodies. 
     
     
         50 . The method of  claim 49 , wherein the non-mitogenic anti-CD3 active compound is administered in an injectable form comprising 5 to 20 mg of the non-mitogenic anti-CD3 active compound. 
     
     
         51 . The method of  claim 43 , wherein the immunosuppressive agent is administered contemporaneously with the autologous or allogeneic mesenchymal stem cells 
     
     
         52 . The method of  claim 43 , wherein the immunosuppressive agent is administered within one month of the autologous or allogeneic mesenchymal stem cells. 
     
     
         53 - 74 . (canceled)