Control of NK cell function and survival by modulation of ship activity

Abstract

Inhibition of dendritic cell function in solid organ grafts or allogeneic bone marrow transplants prior to or during engraftment by blocking SH2-containing inositol phosphatase (SHIP) expression or function is taught as a method of abrogating immune rejection and thereby increasing the efficacy of engraftment of an allogeneic bone marrow transplant or solid organ allograft or xenograft. Also disclosed is a transgenic mouse having the genotype SHIP −/− which exhibits enhanced survival following mismatched allogeneic marrow grafts.

What is claimed is:  
     
         1 . A transgenic mouse, wherein the mouse has a genotype of SHIP −/− .  
     
     
         2 . The transgenic mouse of  claim 1 , wherein the mouse does not express SHIP protein.  
     
     
         3 . The transgenic mouse of  claim 2 , wherein said mouse comprises a compromised ability to reject allogeneic bone marrow grafts.  
     
     
         4 . The transgenic mouse of  claim 2 , wherein said mouse comprises NK cells, and wherein said NK cells fail to produce inflammatory cytokines in response to allogeneic blood marrow cells.  
     
     
         5 . The transgenic mouse of  claim 2 , wherein said mouse comprises antigen presenting cells, and wherein said antigen presenting cells are altered.  
     
     
         6 . The transgenic mouse of  claim 2 , wherein said mouse is an transplantation model.  
     
     
         7 . The transgenic mouse of  claim 2 , wherein the transgenic mouse has decreased numbers of dendritic cells.  
     
     
         8 . The transgenic mouse of  claim 2 , wherein the transgenic mouse exhibits depressed stimulation of allogeneic T cell response in the mixed leukocyte reaction.  
     
     
         9 . A method of abrogating immune rejection in solid organ grafts comprising: 
 inhibiting dendritic cell function prior to or during engraftment, wherein said inhibiting is accomplished by blocking SHIP expression or function.    
     
     
         10 . A method of inhibiting antigen presenting cell (APC) function before or during allogeneic transplants of solid organs, skin and bone marrow, comprising: 
 blocking SHIP expression or function.    
     
     
         11 . The method of inhibiting of  claim 10 , wherein said blocking is effected through the administration of peptidomimetic inhibitors of SHIP function, ribozymes, an RNA aptamer, or a combination thereof