Abstract
Xenoantibodies to the galα1,3 gal (gal) epitope impede the use of pig tissues for xenotransplantation, a procedure that may help overcome the shortage of human organ donors. Stable gal chimerism and tolerance to gal+ hearts could be achieved in α1,3-galactosyltransferase (α1,3GT)-/- mice using lentiviral vectors expressing porcine α1,3GT, the enzyme that synthesizes the gal carbohydrate. In this study, we evaluated whether chimerism sufficient to inhibit anti-gal xenoantibody responses can be achieved using lentivectors in non-human primates. Rhesus macaques were transplanted with autologous, α1,3GT-transduced bone marrow (BM) following sublethal irradation. Simian immunodeficiency virus (SIV)- and human immunodeficiency virus (HIV)-1-derived lentiviral constructs were compared. Chimerism was observed in several hematopoietic lineages in all monkeys. Engraftment in animals receiving SIV-based α1,3GT constructs was similar to that achieved using the HIV-1-derived lentivector for the first 2 months post-transplantation, but increased thereafter to reach higher levels by 5 months. Upon immunization with porcine hepatocytes, the production of anti-gal immunoglobulin M xenoantibody was substantially reduced in the gal+ BM recipients compared to controls. This study is the first to report the application of gene therapy to achieve low-level, long-term gal chimerism sufficient to inhibit production of anti-gal antibodies after immunization with porcine cells in rhesus macaques.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 49-57 |
| Number of pages | 9 |
| Journal | Gene Therapy |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2007 |
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Keywords
- Chimerism
- Lentiviral vector
- Primate
- Rhesus monkeys
- Xenotransplanation
ASJC Scopus subject areas
- Genetics
Cite this
Gene therapy to inhibit xenoantibody production using lentiviral vectors in non-human primates. / Fischer-Lougheed, J. Y.; Tarantal, Alice F; Shulkin, I.; Mitsuhashi, N.; Kohn, D. B.; Lee, Charles C; Kearns-Jonker, M.
In: Gene Therapy, Vol. 14, No. 1, 01.2007, p. 49-57.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Gene therapy to inhibit xenoantibody production using lentiviral vectors in non-human primates
AU - Fischer-Lougheed, J. Y.
AU - Tarantal, Alice F
AU - Shulkin, I.
AU - Mitsuhashi, N.
AU - Kohn, D. B.
AU - Lee, Charles C
AU - Kearns-Jonker, M.
PY - 2007/1
Y1 - 2007/1
N2 - Xenoantibodies to the galα1,3 gal (gal) epitope impede the use of pig tissues for xenotransplantation, a procedure that may help overcome the shortage of human organ donors. Stable gal chimerism and tolerance to gal+ hearts could be achieved in α1,3-galactosyltransferase (α1,3GT)-/- mice using lentiviral vectors expressing porcine α1,3GT, the enzyme that synthesizes the gal carbohydrate. In this study, we evaluated whether chimerism sufficient to inhibit anti-gal xenoantibody responses can be achieved using lentivectors in non-human primates. Rhesus macaques were transplanted with autologous, α1,3GT-transduced bone marrow (BM) following sublethal irradation. Simian immunodeficiency virus (SIV)- and human immunodeficiency virus (HIV)-1-derived lentiviral constructs were compared. Chimerism was observed in several hematopoietic lineages in all monkeys. Engraftment in animals receiving SIV-based α1,3GT constructs was similar to that achieved using the HIV-1-derived lentivector for the first 2 months post-transplantation, but increased thereafter to reach higher levels by 5 months. Upon immunization with porcine hepatocytes, the production of anti-gal immunoglobulin M xenoantibody was substantially reduced in the gal+ BM recipients compared to controls. This study is the first to report the application of gene therapy to achieve low-level, long-term gal chimerism sufficient to inhibit production of anti-gal antibodies after immunization with porcine cells in rhesus macaques.
AB - Xenoantibodies to the galα1,3 gal (gal) epitope impede the use of pig tissues for xenotransplantation, a procedure that may help overcome the shortage of human organ donors. Stable gal chimerism and tolerance to gal+ hearts could be achieved in α1,3-galactosyltransferase (α1,3GT)-/- mice using lentiviral vectors expressing porcine α1,3GT, the enzyme that synthesizes the gal carbohydrate. In this study, we evaluated whether chimerism sufficient to inhibit anti-gal xenoantibody responses can be achieved using lentivectors in non-human primates. Rhesus macaques were transplanted with autologous, α1,3GT-transduced bone marrow (BM) following sublethal irradation. Simian immunodeficiency virus (SIV)- and human immunodeficiency virus (HIV)-1-derived lentiviral constructs were compared. Chimerism was observed in several hematopoietic lineages in all monkeys. Engraftment in animals receiving SIV-based α1,3GT constructs was similar to that achieved using the HIV-1-derived lentivector for the first 2 months post-transplantation, but increased thereafter to reach higher levels by 5 months. Upon immunization with porcine hepatocytes, the production of anti-gal immunoglobulin M xenoantibody was substantially reduced in the gal+ BM recipients compared to controls. This study is the first to report the application of gene therapy to achieve low-level, long-term gal chimerism sufficient to inhibit production of anti-gal antibodies after immunization with porcine cells in rhesus macaques.
KW - Chimerism
KW - Lentiviral vector
KW - Primate
KW - Rhesus monkeys
KW - Xenotransplanation
UR - http://www.scopus.com/inward/record.url?scp=33845683007&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845683007&partnerID=8YFLogxK
U2 - 10.1038/sj.gt.3302818
DO - 10.1038/sj.gt.3302818
M3 - Article
C2 - 16886002
AN - SCOPUS:33845683007
VL - 14
SP - 49
EP - 57
JO - Gene Therapy
JF - Gene Therapy
SN - 0969-7128
IS - 1
ER -