Synergy in induction of increased renal allograft survival after portal vein infusion of dendritic cells transduced to express TGFbeta and IL-10, along with administration of CHO cells expressing the regulatory molecule OX-2.
Dendritic cells (DC), generated from C57BL/6 mouse bone marrow cells cultured with GM-CSF and IL-4 for 9 days, were engineered to express constitutively the cytokines TGFbeta, IL-10, and IL-12, using adenovirus vectors constructed using an E1-deleted replication-deficient recombinant adenovirus carrying the appropriate cDNA for the relevant cytokines (Ad-TGFbeta, Ad-IL-12, or Ad-IL-10). C3H mice receiving nontransduced DC or pretransplant infusion of DC-Ad-LacZ showed increased survival of C57BL/6 renal grafts relative to that of control nonimmunized mice. Transfusion of Ad-IL-12-transduced DC abolished this increased survival, leading to a graft survival equivalent to that of controls with no DC. Optimal graft survival was seen in the group receiving a mixture of DC transduced with constructs for both IL-10 and TGFbeta. There was a correlation between increased graft survival and both inhibition of the induction of CTL and enhancement of a polarization to produce type-2 cytokines (IL-4, IL-10, and TGFbeta) on antigen-specific restimulation in vitro. These effects were more pronounced following concomitant infusion of CHO cells transfected with a full-length cDNA for murine OX-2.
Gorczynski
R M
RM
Transplant Research Division, The Toronto Hospital and the University of Toronto, Canada.
Bransom
J
J
Cattral
M
M
Huang
X
X
Lei
J
J
Xiaorong
L
L
Min
W P
WP
Wan
Y
Y
Gauldie
J
J
D000256:Adenoviridae; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD; D000954:Antigens, Surface / Q000235:genetics; D016466:CHO Cells / Q000378:metabolism*; D006224:Cricetinae; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006085:Graft Survival; D007114:Immunization; D016753:Interleukin-10 / Q000235:genetics* / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011169:Portal Vein / Q000166:cytology*; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000276:immunology*
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000954:Antigens, Surface; D016207:Cytokines; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; C042739:antigens, CD200