Exploiting virus stealth technology for xenotransplantation: reduced human T cell responses to porcine cells expressing herpes simplex virus ICP47.
Direct recognition of porcine major histocompatibility complex (MHC) proteins by human T cells is well documented. Eliminating donor (porcine) MHC proteins may therefore be beneficial in pig-to-human xenotransplants. To this end, we have attempted to exploit viral stealth mechanisms to eliminate pig MHC class I cell-surface expression. PK(15) (pig kidney) cells stably transfected with the herpes simplex virus (HSV) ICP47 gene [PK(15)-ICP47 cells] exhibited a dramatic reduction of MHC class I cell-surface expression when compared with untransfected PK(15) cells. To test the effect of down-regulation of porcine MHC class I on human cellular immune responses, a human CD8+ enriched T cell line (anti-PK15 T cells) with reactivity towards PK(15) cells was derived by repeated stimulation of human T cells with PK(15) cells stably transfected with the costimulatory molecule B7.1 [PK(15)-B7.1 cells]. Anti-PK15 T cells efficiently lyzed PK(15) cells but not PK(15)-ICP47 (class I negative) cells. Consistent with effector function, anti-PK15 T cells showed a robust proliferative response to PK(15)-B7.1 cells but did not proliferate at all to PK(15)-B7.1 cells which also expressed HSV ICP47. These results suggest that virus stealth technology can be exploited for xenotransplantation.
Crew
Mark D
MD
Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA. crewmarkd@uams.edu
Phanavanh
Bounleut
B
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D005814:Genes, Viral / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000276:immunology*; D018139:Simplexvirus / Q000235:genetics / Q000276:immunology; D013552:Swine; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection; D014183:Transplantation, Heterologous / Q000276:immunology*; D014764:Viral Proteins
D015395:Histocompatibility Antigens Class I; C105843:ICP47 protein, Herpes simplex virus; D017874:Immediate-Early Proteins; D014764:Viral Proteins