Immunocompromised Ungulates

Abstract

Porcine animals, tissue and organs as well as cells and cell lines derived from such animals are provided that lack functional endogenous immunoglobulin loci and are deficient in immunoglobulin expression and B-cells. These animals are useful as model systems for research and for development of new pharmaceutical and biological agents. In addition, methods are provided to prepare such animals.

1 . A genetically modified porcine animal which lacks native immunoglobulin gene expression. 
     
     
         2 . The animal of  claim 1  wherein the animal lacks functional native immunoglobulin proteins. 
     
     
         3 . The animal of  claim 1  wherein the animal has reduced, abnormal or lacks B-cell production. 
     
     
         4 . The animal of  claim 1  wherein the animal has reduced, abnormal or lacks a humoral immune response. 
     
     
         5 . The animal of  claim 1  wherein the animal has a disruption in a gene encoding an immunoglobulin heavy chain locus in its genome. 
     
     
         6 . The animal of  claim 5  wherein the animal has a disruption in an immunoglobulin heavy chain joining region in its genome. 
     
     
         7 . The animal of  claim 1 - 6  wherein the animal has a further disruption in at least one additional native gene in its genome. 
     
     
         8 . The animal of  claim 7  which lacks or has a reduced cellular immune response. 
     
     
         9 . The animal of  claim 7  wherein the further gene is an α-1,3-galactosyltransferase gene. 
     
     
         10 . The animal of  claim 1 - 9  wherein the animal further includes at least one xenogenous gene or transgene. 
     
     
         11 . The animal of  claim 10  wherein the animal further expresses at least one xenogenous protein. 
     
     
         12 . The animal of  claim 11  wherein the further protein is an immunoglobulin or fragment thereof. 
     
     
         13 . The animal of  claim 12  wherein the further protein is a human immunoglobulin or fragment thereof. 
     
     
         14 . The animal of  claim 11  wherein the further protein is a costimulatory blockage molecule. 
     
     
         15 . A method of testing the immune response of an animal to an antigen comprising providing a genetically modified porcine animal lacking production of native immunoglobulin expression with the antigen and assessing a response of the animal to the antigen. 
     
     
         16 . A method of testing the utility of a prophylactic or therapeutic against a infectious agent comprising exposing a genetically modified porcine animal lacking production of native immunoglobulin expression with the infectious agent; treating the animal with the prophylactic or therapeutic; and assessing the immune response and course of infection in the animal. 
     
     
         17 . The method of  claim 15  or  16  wherein the animal is challenged with an infectious agent or surface antigen thereof. 
     
     
         18 . The method of  claim 15  or  16  wherein the assessment includes examination of cellular and humoral responses. 
     
     
         19 . The method of  claim 15  or  16  wherein the infectious agent is a virus. 
     
     
         20 . The method of  claim 15  or  16  wherein the prophylactic or therapeutic is a vaccine. 
     
     
         21 . The method of any of  claim 15 - 20  wherein the animal further expresses an exogenous protein. 
     
     
         22 . The method of  claim 21  wherein the further protein is a human immunoglobulin or fragment thereof. 
     
     
         23 . A method of producing a human immunoglobulin comprising providing a genetically modified porcine animal lacking native immunoglobulin expression and further expressing and recovering a human immunoglobulin from the animal. 
     
     
         24 . The method of  claim 23  wherein the human immunoglobulin is intravenous immunoglobulin (WIG). 
     
     
         25 . The method of  claim 23  wherein the human immunoglobulin is antigen specific.