Models for vaccine assessment

Abstract

The present invention is directed to methods for constructing and using in vivo and in vitro models of aspects of human immunity and, in particular, construction of a human immune system model for the testing of, for example, vaccines, adjuvants, immunotherapy candidates, cosmetics, drugs, biologics and other chemicals. The present invention comprises both in vivo and in vitro models of aspects of human immunity that are useful for assessing the interaction of substances with the immune system, and thus can be used to accelerate and improve the accuracy and predictability of, for example, vaccine, drug, biologic, immunotherapy, cosmetic and chemical development. The invention is also useful for the generation of human monoclonal and polyclonal antibodies.

1 . An irradiated mouse comprising an immune model system, wherein said irradiated mouse comprises:
 a) native radiation-resistant mouse follicular dendritic cells (FDCs);   b) a population of human peripheral blood lymphocytes (PBLs); and   c) antigen/antibody immune complexes, wherein said mouse is immunocompetent before irradiation.   
     
     
         2 . A method for producing the irradiated mouse of  claim 1 , comprising
 a) co-culturing in vitro a population of human T cells and a population of antigen-pulsed dendritic cells (DC) for sufficient time to produce primed CD4 +  helper T cells in the T cell/DC co-culture;   b) combining a population of antigen-pulsed human B cells with the T cell/DC co-culture of a) to produce a B cell/T cell/DC co-culture;   c) inserting the B cell/T cell/DC co-culture of b) into the lymph system of an irradiated mouse, wherein said mouse is immunocompetent before irradiation.   
     
     
         3 . An irradiated mouse comprising an immune model system produced by the method of  claim 2 . 
     
     
         4 . A method of producing human antibodies comprising collecting antibodies produced within the irradiated mouse of  claim 3 , wherein said antibodies are polyclonal antibodies. 
     
     
         5 . A method of producing human antibodies comprising:
 a) isolating a population of B cells from the irradiated mouse of  claim 3 ;   b) immortalizing the B cells of a) to form hybridomas;   c) culturing the hybridomas of b) under conditions promoting antibody production; and   d) collecting monoclonal antibodies from the cultures of c).   
     
     
         6 . A method of screening a candidate composition for an effect on an immune model system in an animal having a disease, said method comprising:
 a) administering a candidate composition to an irradiated mouse comprising an immune model system of  claim 1 , wherein said mouse further has a disease; and   b) comparing a response of the immune model system to the disease in said mouse of a) with a response of an immune model system in an irradiated mouse of  claim 1  and having the disease to which the candidate composition was not administered, thereby screening a candidate composition for an effect on an immune model system in an animal having a disease.   
     
     
         7 . The method of  claim 6 , wherein said candidate composition is selected from the group consisting of vaccines, adjuvants, immunotherapy candidates, cosmetics, drugs, biologics, other chemicals and combinations thereof. 
     
     
         8 . The method of  claim 6 , wherein the effect is therapeutic efficacy, prophylactic efficacy, toxicity or a dose effect. 
     
     
         9 . The method of  claim 6 , wherein the disease is an infectious disease. 
     
     
         10 . The method of  claim 9 , wherein the infectious disease is selected from the group consisting of avian flu, SARS, HIV, West Nile virus, influenza, lassa, malaria, yellow fever, hepatitis A, B and C, tuberculosis, smallpox, herpes, Ebola, dengue fever, chickenpox, measles, mumps, and rubella. 
     
     
         11 . The method of  claim 6 , wherein the disease is a tumor or a cancer. 
     
     
         12 . A method of determining an effect of a candidate composition on an immune model system, said method comprising:
 a) administering a candidate composition to an irradiated mouse comprising an immune model system of  claim 1 ; and   b) comparing a response of the immune model system in said mouse of a) with a response of an immune model system in an irradiated mouse of  claim 1  to which the candidate composition was not administered, thereby determining an effect of a candidate composition on an immune model system.   
     
     
         13 . The method of  claim 12 , wherein said candidate composition is selected from the group consisting of vaccines, adjuvants, immunotherapy candidates, cosmetics, drugs, biologics, other chemicals, and combinations thereof. 
     
     
         14 . The method of  claim 12 , wherein said effect is toxicity or a dose effect. 
     
     
         15 . A method of inducing an immune response in an animal, comprising administering a composition comprising at least one antigen to an irradiated mouse of  claim 1 . 
     
     
         16 . The method of  claim 15 , wherein the immune response is a primary antibody response by B cells. 
     
     
         17 . The method of  claim 15 , wherein the antigen is selected from the group consisting of tumor cells, biopsy samples, PMBCs, and proteins. 
     
     
         18 . The method of  claim 16 , further comprising isolating the primary antibodies produced to the antigen from the mouse. 
     
     
         19 . The method of  claim 18 , wherein the antibodies are polyclonal. 
     
     
         20 . The method of  claim 16 , further comprising:
 a) isolating a population of B cells from the mouse,   b) immortalizing the B cells of a) to form hybridomas,   c) culturing the hybridomas of b) under conditions promoting antibody production, and   d) collecting monoclonal antibodies from the cultures of c).