title: Human dominant-negative class II transactivator transgenic pigs - effect on the human anti-pig T-cell immune response and immune status.
abstract: Swine leucocyte antigen (SLA) class II molecules on porcine (p) cells play a crucial role in xenotransplantation as activators of recipient human CD4(+) T cells. A human dominant-negative mutant class II transactivator (CIITA-DN) transgene under a CAG promoter with an endothelium-specific Tie2 enhancer was constructed. CIITA-DN transgenic pigs were produced by nuclear transfer/embryo transfer. CIITA-DN pig cells were evaluated for expression of SLA class II with/without activation, and the human CD4(+) T-cell response to cells from CIITA-DN and wild-type (WT) pigs was compared. Lymphocyte subset numbers and T-cell function in CIITA-DN pigs were compared with those in WT pigs. The expression of SLA class II on antigen-presenting cells from CIITA-DN pigs was significantly reduced (40-50% reduction compared with WT; P < 0·01), and was completely suppressed on aortic endothelial cells (AECs) even after activation (100% suppression; P < 0·01). The human CD4(+) T-cell response to CIITA-DN pAECs was significantly weaker than to WT pAECs (60-80% suppression; P < 0·01). Although there was a significantly lower frequency of CD4(+) cells in the PBMCs from CIITA-DN (20%) than from WT (30%) pigs (P < 0·01), T-cell proliferation was similar, suggesting no significant immunological compromise. Organs and cells from CIITA-DN pigs should be partially protected from the human cellular immune response.
authors.affiliation: Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA. harah@upmc.edu
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Hara
authors.forename: William
authors.initials: W
authors.lastname: Witt
authors.forename: Tanner
authors.initials: T
authors.lastname: Crossley
authors.forename: Cassandra
authors.initials: C
authors.lastname: Long
authors.forename: Kumiko
authors.initials: K
authors.lastname: Isse
authors.forename: Liming
authors.initials: L
authors.lastname: Fan
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Phelps
authors.forename: David
authors.initials: D
authors.lastname: Ayares
authors.forename: David K C
authors.initials: DK
authors.lastname: Cooper
authors.forename: Yifan
authors.initials: Y
authors.lastname: Dai
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Starzl
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015478:Antigens, Heterophile / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D015870:Gene Expression; D005802:Genes, MHC Class II; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D008213:Lymphocyte Activation; D009687:Nuclear Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034421:Sus scrofa / Q000235:genetics* / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics*; D014183:Transplantation, Heterologous
chemical_list: D015478:Antigens, Heterophile; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; C438668:swine leukocyte antigen
keywords: MHC class II transactivator; genetic engineering; immune response; pig; swine leucocyte antigens; xenotransplantation