Expression changes in tolerant murine cardiac allografts after gene therapy with a lentiviral vector expressing alpha1,3 galactosyltransferase.
Comparison of intragraft gene expression changes in tolerant cardiac allograft models may provide the basis for identifying pathways involved in graft survival. Our laboratory has previously demonstrated that tolerance to the gal alpha1,3 gal epitope, the major target of rejection of wild-type pig hearts in human cardiac transplantation, can be achieved after transplantation with bone marrow transduced with a lentiviral vector expressing alpha1,3 galactosyltransferase. We now present intracardiac gene expression changes associated with long-term tolerance in this model. Biotin-labeled cRNA was hybridized to Affymetrix GeneChip 430 2.0 Mouse Genome Arrays. Data were subjected to functional annotation analysis to identify genes of known function in which expression was increased or decreased by at least 2-fold (t-test, P < .05) in tolerant gal+/+ wild-type hearts as compared to transplanted syngeneic controls. Tolerant hearts demonstrated increased expression of genes associated with the stress response, modulation of immune function and cell survival (HSPa9a, CD56, and Akt1s1), and decreased expression of several immunoregulatory genes (CD209, CD26, and PDE4b). These data suggest that tolerance may be associated with activation of immunomodulatory and survival pathways.
Evans
J M
JM
Department of Anesthesiology Critical Care Medicine, Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California 90027, USA. jaevans@chla.usc.edu
Doki
T
T
Fischer-Lougheed
J
J
Davicioni
E
E
Kearns-Jonker
M
M
D000818:Animals; D016026:Bone Marrow Transplantation; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics*; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy; D005822:Genetic Vectors; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance; D016086:Lentivirus / Q000201:enzymology / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D020411:Oligonucleotide Array Sequence Analysis; D013552:Swine; D014184:Transplantation, Homologous / Q000276:immunology
D005700:Galactosyltransferases; C487611:alpha 1,3 galactosyltransferase, mouse; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase