Models of chronic and acute inflammatory diseases

Abstract

Methods and compositions are provided for the creation and screening of non-human animal models having chronic inflammation. Immunocompromised host animals are injected with a population of immunocompetent effector cells, depleted of CD25+ T cells. The effector cells are tolerant of the host major histocompatibility antigens, but reactive to at least one antigen present in the host animal. The transferred cells are preferably stimulated and localized by administration of an immunostimulant at a local site. The animals are useful for a variety of screening assays and for investigation into disease causes and pathways. A variety of chronic inflammatory diseases may be studied with this model, including psoriasis, rheumatoid arthritis, diabetes, inflammatory bowel disease and multiple sclerosis.

What is claimed is:  
     
         1 . A non-human mammal comprising: 
 exogenous immunocompetent effector cells, wherein said effector cells were depleted of cells expressing CD25 prior to introduction into said non-human mammal;    antigen presenting cells to which said immunocompetent effector cells are tolerant and which are capable of initiating an inflammatory response by said immunocompetent effector cells; and    inflamed tissue as a result of said inflammatory response.    
     
     
         2 . The non-human mammal according to  claim 1 , wherein said immunocompetent effector cells comprise human T cells.  
     
     
         3 . The non-human mammal of  claim 2 , wherein said T cells comprise CD4 +  T cells.  
     
     
         4 . The non-human mammal of  claim 3 , wherein said mammal is a rodent.  
     
     
         5 . The non-human mammal of  claim 4 , wherein said rodent is a mouse.  
     
     
         6 . A panel for compound testing, comprising at least mammals according to  claim 1 , wherein at least one of said mammals comprises a known immunomodulatory compound, and at least one of said mammals comprises a test compound suspected of immunomodulatory activity.  
     
     
         7 . A method for inducing chronic inflammation in an non-human mammal, the method comprising: 
 transferring a cell population comprising immunocompetent effector cells and lacking CD25 positive T cells, from a donor non-human mammal to an immunocompromised non-human mammal host, wherein said immunocompetent effector cell population is tolerant of the host major histocompatibility antigens but is immunoreactive with one or more antigens present in said host;    wherein said host develops chronic inflammation.    
     
     
         8 . The method according to  claim 7 , wherein said immunocompetent effector cells comprise T cells.  
     
     
         9 . The method according to  claim 8 , wherein said T cells comprise CD4+ T cells.  
     
     
         10 . The method according to  claim 9 , further comprising administering an immunostimulatory co-factor to said mammal.  
     
     
         11 . The method according to  claim 9 , wherein said CD4 +  T cells are reactive to minor histocompatibility antigens present in said host.  
     
     
         12 . The method according to  claim 10 , wherein said immunostimulant is administered at a targeted site, and said chronic inflammation develops at said targeted site.  
     
     
         13 . The method of  claim 7 , wherein said host is a rodent.  
     
     
         14 . The method of  claim 13 , wherein said rodent is a scid-scid mouse.  
     
     
         15 . The method of  claim 10 , wherein said immunostimulant is a non-replicating virus.  
     
     
         16 . The method of  claim 15 , wherein said virus is an adenovirus.  
     
     
         17 . The method of  claim 10 , wherein said immunostimulant is an immunostimulatory oligonucleotide sequence.  
     
     
         18 . The method of  claim 10 , wherein said immunostimulant is a polyclonal activating agent.  
     
     
         19 . The method of  claim 18 , wherein said polyclonal activating agent is an endotoxin.  
     
     
         20 . T he method of  claim 18 , wherein said polyclonal activating agent is a superantigen.  
     
     
         21 . The method of  claim 20 , wherein said superantigen is a bacterial superantigen.  
     
     
         22 . A method for screening a candidate therapy for efficacy in treatment of chronic inflammation, the method comprising: 
 transferring a cell population comprising immunocompetent effector cells and lacking CD25 positive T cells, from a donor non-human mammal to an immunocompromised non-human mammal host, wherein said immunocompetent effector cell population is tolerant of the host major histocompatibility antigens but is immunoreactive with one or more antigens present in said host;    wherein said host develops chronic inflammation;    treating said animals with said candidate therapy;    determining the severity of disease in the presence of said therapy,    wherein a decrease in severity of disease in the treated animals relative to control animals is indicative of efficacy in treatment.    
     
     
         23 . The method according to  claim 22 , wherein said immunocompetent effector cells comprise T cells.  
     
     
         24 . The method according to  claim 23 , wherein said T cells comprise CD4+ T cells.  
     
     
         25 . The method according to  claim 22 , further comprising administering an immunostimulatory co-factor to said mammal.  
     
     
         26 . The method according to  claim 22 , wherein said CD4 +  T cells are reactive to minor histocompatibility antigens present in said host.  
     
     
         27 . The method according to  claim 10 , wherein said immunostimulant is administered at a targeted site, and said chronic inflammation develops at said targeted site.  
     
     
         28 . The method according to  claim 22 , wherein said candidate therapy comprises administration of one or a combination of candidate immunosuppressant drugs.  
     
     
         29 . The method according to  claim 22 , further comprises comparison of said disease severity to a positive control animal treated with a known immunomodulatory compound.