Method of treating psoriasis using anti-interleukin 12 antibody

Abstract

Methods and compositions are provided for the creation and screening of non-human animal models having many of the histologic characteristics of human psoriasis. Immunocompromised host animals are injected with a purified population of CD45Rb positive cells, which are tolerant of the host major histocompatibility antigens, but are mismatched at one or more minor antigens. The injected cells are stimulated with a pro-inflammatory cytokine, e.g. IL-12, and a polyclonal activating agent. The injected animals develop a chronic skin disorder that includes histological features observed in human psoriasis, e.g. rete pegs, severe acanthosis and infiltration of Th1 cells into the dermis.

What is claimed is:  
     
         1 . A method for inducing a psoriasis-like syndrome in an animal, the method comprising: 
 transferring a purified CD45Rb positive T cell population from a donor animal to an immunocompromised animal host, wherein said T cell population is tolerant of the host major histocompatibility antigens but is immunoreactive with one or more of the host minor histocompatibility antigens;    administering at least one pro-inflammatory cytokine and at least one polyclonal activating agent to said immunocompromised animal host;    wherein said host develops a disease having characteristics of human psoriasis.    
     
     
         2 . The method of  claim 1 , wherein said T cell population is CD4 +  CD45Rb hi .  
     
     
         3 . The method of  claim 1  wherein the donor and host animals are MHC matched.  
     
     
         4 . The method of  claim 1 , wherein said immunodeficient animal is an immunodeficient rodent.  
     
     
         5 . The method of  claim 4 , wherein said immunodeficient animal is a scid-scid mouse.  
     
     
         6 . The method of  claim 1 , wherein said pro-inflammatory cytokine is interleukin-12.  
     
     
         7 . The method of  claim 6 , wherein the dose of said IL-12 is at least about 0.1 ng/gram weight of host, and not more than about 2 ng/gram weight of host.  
     
     
         8 . The method of  claim 7 , wherein said IL-12 is administered at about one day and at about three days after transferring said T cell population.  
     
     
         9 . The method of  claim 1 , wherein said polyclonal activating agent is an endotoxin.  
     
     
         10 . The method of  claim 9 , wherein the dose of said endotoxin is from about 0.1 μg/g weight of host to about 5 μg/g weight of host.  
     
     
         11 . The method of  claim 1 , wherein said polyclonal activating agent is a superantigen.  
     
     
         12 . The method of  claim 11 , wherein said superantigen is a bacterial superantigen.  
     
     
         13 . The method of  claim 12 , wherein the dose of said superantigen is from about 0.1 μg/g weight of host to about 5 μg/g weight of host.  
     
     
         14 . A method for screening a candidate therapy for efficacy in treatment of psoriasis, the method comprising: 
 transferring a purified CD45Rb positive T cell population from a donor animal to at least one immunocompromised animal host, wherein said T cell population is tolerant of the host major histocompatibility antigens but is immunoreactive with one or more of the host minor histocompatibility antigens;    administering at least one pro-inflammatory cytokine and at least one polyclonal activating agent to said immunocompromised animal host; wherein said host develops a disease having characteristics of human psoriasis;    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.    
     
     
         15 . The method of  claim 14 , wherein said T cell population is CD4 +  CD45Rb hi .  
     
     
         16 . The method of  claim 14  wherein said donor and host animals are MHC matched.  
     
     
         17 . The method of  claim 14 , wherein said therapy is treatment with a candidate pharmaceutical agent.  
     
     
         18 . The method of  claim 17  wherein said candidate pharmaceutical agent is a monoclonal antibody.  
     
     
         19 . A method of  claim 18  wherein said antibody binds to an antigen selected from-the group of interferon gamma, interleukin 12, E-selectin, P-selectin, CD3 or alphaE integrin subunit.  
     
     
         20 . The method of  claim 14 , wherein said immunodeficient animal is an immunodeficient mouse or rat.  
     
     
         21 . The method of  claim 20 , wherein said immunodeficient animal is a scid-scid mouse.  
     
     
         22 . The method of  claim 14 , wherein said pro-inflammatory cytokine is interleukin-12.  
     
     
         23 . The method of  claim 14 , wherein said polyclonal activating agent is an endotoxin.  
     
     
         24 . The method of  claim 14 , wherein said polyclonal activating agent is a superantigen.  
     
     
         25 . A method of treating a patient suffering from psoriasis comprising the step of administering to the patient an antibody that binds to an antigen selected from the group of interferon gamma, interleukin 12, E-selectin, P-selectin, CD3 or alphaE integrin subunit.  
     
     
         26 . A method of  claim 25  wherein said antibody is a humanized antibody.  
     
     
         27 . A method of  claim 26  wherein said antibody is the HuZAF, HuEP5C7, or HuM291 antibody.  
     
     
         28 . An immunodeficient mouse induced to exhibit a psoriasis-like syndrome by transfer of minor histocompatability mismatched murine CD4 +  CD45RB hi  T cells and administration of a proinflammatory lymphokine and a polyclonal lymphocyte activator.  
     
     
         29 . A method of reducing the PASI of a patient suffering from psoriasis by at least 50%, comprising treating the patient with a neutralizing monoclonal antibody to interleukin 12.  
     
     
         30 . The method of  claim 29 , wherein said antibody is humanized or human.  
     
     
         31 . A method of treating psoriasis patients comprising the steps of (1) administering to the patients therapies that induce remission of their psoriasis, and then (2) treating the patients with a neutralizing monoclonal antibody to interleukin 12, wherein treatment with said antibody prolongs the median time to relapse by at least 50%.  
     
     
         32 . The method of claim  31 , wherein said antibody is humanized or human.