Compositions and methods for inducing chimerism in a subject

Abstract

Prevention of autoimmune disease and induction of transplantation tolerance in a recipient can be achieved by induction of mixed chimerism via bone marrow transplantation (BMT), but this procedure requires total body irradiation (TBI)-conditioning of the recipient. The toxicity of radiation and potential for graft versus host disease (GVHD) prevents its clinical application. Donor CD8 + T cells play a critical role in facilitation of engraftment, but also contribute to induction of GVHD in TBI-conditioned recipients. It is disclosed herein that high doses of donor CD8 + T cells in combination with donor bone marrow (BM) cells induces mixed chimerism without GVHD in recipients conditioned with anti-CD3 mAb. These chimeric recipients display donor specific tolerance and reversal of insulitis. These results establish that donor CD8 + T cell-mediated facilitation of engraftment can be separated from GVHD in non-irradiated recipients. This regimen has application in the treatment of autoimmune disorders and the induction of transplantation tolerance.

1 . A composition comprising bone marrow cells and CD8 +  T cells.  
   
   
       2 . A method of conditioning a recipient for bone marrow transplantation comprising administering a therapeutically effective amount of anti-CD3 mAb.  
   
   
       3 . A method of generating chimerism in a recipient comprising: 
 a) administering a therapeutically effective amount of anti-CD3 mAb;    b) administering a therapeutically effective amount of donor bone marrow cells; and    c) administering a therapeutically effective amount of donor CD8 +  T cells.    
   
   
       4 . The method of  claim 3  wherein said donor bone marrow cells and said donor CD8 +  T cells are administered simultaneously.  
   
   
       5 . The method of  claim 3  wherein steps (b) and (c) are carried out seven days after step (a).  
   
   
       6 . The method of  claim 3  further comprising repeating steps (b) and (c).  
   
   
       7 . The method of  claim 6  wherein said repeating of steps (b) and (c) is carried out 14 days after step (a).