Selective immunodepletion of endogenous stem cell niche for engraftment

Abstract

The present invention provides a clinically applicable method of stem cell transplantation that facilitates engraftment and reconstitutes immunocompetence of the recipient without requiring radiotherapy or chemotherapy, and without development of GVHD or graft rejection. Aspects of the present invention are based on the discovery that the depletion of the endogenous stem cell niche facilitates efficient engraftment of stem cells into that niche. In particular, the present invention combines the use of selective ablation of endogenous stem cells, in combination with the administration to the recipient of exogenous stem cells, resulting in efficient, long-term engraftment and tolerance.

1 . A method of stem cell engraftment in a mammal, the method comprising:
 contacting said mammal with an agent that selectively ablates endogenous stem cells in a targeted tissue;   introducing exogenous stem cells to said mammal after a period of time sufficient to substantially eliminate said agent from the patient circulation.   
   
   
       2 . The method according to  claim 1 , wherein said agent that selectively ablates endogenous stem cells is an antibody that selectively binds to said stem cells. 
   
   
       3 . The method according to  claim 2 , wherein said antibody is a monoclonal antibody. 
   
   
       4 . The method according to  claim 1 , wherein said agent is systemically administered. 
   
   
       5 . The method according to  claim 1 , wherein said targeted tissue is bone marrow. 
   
   
       6 . The method of  claim 1 , wherein the agent selectively blocks growth factor signaling required for stem cell maintenance or growth. 
   
   
       7 . The method of  claim 6 , wherein the agent is an antibody. 
   
   
       8 . The method of  claim 7 , wherein the antibody binds to and inhibits the signaling activity of c-kit. 
   
   
       9 . The method of  claim 6 , wherein the agent is a drug that inhibits growth factor signaling. 
   
   
       10 . The method of  claim 9 , wherein the drug inhibits c-kit signaling. 
   
   
       11 . The method of  claim 10 , further comprising administering a monoclonal antibody that selectively ablates endogenous stem cells. 
   
   
       12 . The method according to  claim 1 , wherein said stem cells are hematopoietic stern cells. 
   
   
       13 . The method according to  claim 11 , wherein said mammal is a mouse. 
   
   
       14 . The method according to  claim 13 , wherein said agent is an antibody that selectively binds c-kit, sca-1, or CD34. 
   
   
       15 . The method according to  claim 12 , wherein said mammal is a human. 
   
   
       16 . The method according to  claim 14 , wherein said agent is an antibody that selectively binds c-kit, CD90, CD34, or CD59. 
   
   
       17 . The method according to  claim 1 , wherein said exogenous stem cells are genetically modified stem cells. 
   
   
       18 . The method according to  claim 17 , wherein said exogenous stem cells are allogeneic stem cells. 
   
   
       19 . The method according to  claim 15 , wherein said human suffers from a genetic blood disorder. 
   
   
       20 . The method according to  claim 19 , wherein said genetic blood disorder is a hemoglobinopathy. 
   
   
       21 . The method according to  claim 1 , wherein the agent that selectively ablates stem cells is delivered directly to the targeted tissue. 
   
   
       22 . The method according to  claim 1 , wherein the method is repeated at least twice. 
   
   
       23 . The method according to  claim 1 , wherein a conditioning agent is administered prior to infusion of exogenous stem cells. 
   
   
       24 . The method of  claim 23 , wherein the conditioning agent is an antibody specific for one or more of CD4; an NK cell specificity, a macrophage specificity, and CD8.