Identification of porcine xenoantigens

Abstract

Provided herein are genetically modified pigs, porcine organs, tissue, and cells having a reduced propensity to cause a rejection response in a human subject following xenotransplantation. In particular, provided herein are genetically modified pigs lacking nonGal xenoantigens, and porcine cells, tissues, and organs obtained from such genetically modified pigs that are suitable for transplantation into a human. Also provided herein are methods of improving a rejection related symptom in a human subject.

We claim: 
     
         1 . A transgenic pig whose genome comprises genetic modifications that result in one or more of a disrupted porcine CD37 (pCD37) gene and a disrupted porcine CD81 (pCD81) gene, wherein no detectable level of one or both of pCD37 and pCD81 protein is present as compared to a wild-type pig, and when tissue from said transgenic pig is transplanted into a human, a rejection related symptom is improved as compared to when tissue from a wild-type pig is transplanted into a human. 
     
     
         2 . The transgenic pig of  claim 1  whose genome further comprises genetic modifications that result in lack of any expression of functional α(1,3)-galactosyltransferase (αGT), cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH), and β1,4 N-acetylgalactosaminyl transferase (B4GalNT2) relative to a porcine cell lacking said modifications to the genome, the transgenic pig exhibiting reduced levels of αGal antigen, Neu5GC antigen, and B4GalNT2 antigens as compared to a pig lacking said genetic modifications. 
     
     
         3 . The transgenic pig of  claim 1 , wherein cells of the transgenic pig exhibit reduced binding to human immunoglobulins as compared to cells from a wild-type pig. 
     
     
         4 . Porcine organ, tissue, or cell obtained from the transgenic pig of  claim 1 . 
     
     
         5 . The porcine organ, tissue, or cell of  claim 4 , wherein said porcine organ, tissue, or cell is selected from skin, heart, liver, kidneys, lung, pancreas, thyroid, and small bowel, or portions thereof. 
     
     
         6 . A genetically modified porcine cell, wherein the genetic modifications comprise modifications to the genome of the porcine cell that result in one or more of (i) the lack of any expression of functional pCD37 (pCD37KO) and (ii) the lack of any expression of functional pCD81 (pCD81KO), wherein said genetically modified porcine cell exhibits reduced binding to human immunoglobulins relative to a porcine cell lacking said genetic modifications. 
     
     
         7 . The genetically modified porcine cell of  claim 6 , further comprising modifications to the genome of the porcine cell that result in lack of any expression of functional α(1,3)-galactosyltransferase (αGT), cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH), and β1,4 N-acetylgalactosaminyl transferase (B4GalNT2) relative to a porcine cell lacking said modifications to the genome, wherein the modified porcine cell exhibits a reduced level of αGal antigens, a reduced level of Neu5GC antigens, and a reduced level of B4GalNT2 antigens as compared to a porcine cells lacking said genetic modifications. 
     
     
         8 . A transgenic pig derived from the genetically modified porcine cell of  claim 6 . 
     
     
         9 . A porcine organ, tissue, or cell obtained from the genetically modified pig of  claim 8 . 
     
     
         10 . The porcine organ, tissue or cell of  claim 9 , wherein said porcine organ, tissue or cell is selected from skin, heart, liver, kidneys, lung, pancreas, thyroid, small bowel, and components thereof. 
     
     
         11 . A method of improving a rejection related symptom in a human subject comprising transplanting porcine transplant material having reduced levels of pCD37 antigens and reduced levels of pCD81 antigens into a human subject in need of a transplant, wherein a rejection related symptom is improved as compared to when porcine transplant material from a wild-type pig is transplanted into a human subject. 
     
     
         12 . The method of  claim 11 , wherein the rejection related symptom is selected from a cellular rejection response related symptom, a humoral rejection response related symptom, a hyperacute rejection related symptom, an acute humoral xenograft reaction rejection related symptom, and an acute vascular rejection response related symptom.