Prolonged cardiac allograft survival in rats systemically injected adenoviral vectors containing CTLA4Ig-gene.
BACKGROUND
CTLA4Ig, a soluble recombinant fusion protein that contains the extracellular domain of the CTLA4 and Fc portion of IgG1, strongly adheres to the B7 molecule to block CD28-mediated costimulatory signals and inhibits in vitro and in vivo immune responses. In vivo gene transfer using adenovirus vector achieves a high transfection rate into organ cells that usually contain adenoviral receptors. In this study, we investigated expression levels of the transfected gene and the survival times of the allografts in cardiac recipients systemically administered adenoviral vectors containing CTLA4Ig.


METHODS
Hearts from DA rats (RT-1a) were transplanted into a cervical location in LEW recipients (RT1(1)). The adenoviral vectors containing CTLA4Ig was injected via a recipient vein immediately after grafting.


RESULTS
The serum level of CTLA4Ig reached to maximum at 51-93 microg/ml 3 to 7 days after gene-transfection and declined after 14 days, although detectable levels were observed up to 49 days. The median survival time of the allografts in the gene-transfected group were significantly prolonged (27 days) in compared to the control group (6 days). In addition, down-regulation of IL-2 and IFN-gamma mRNAs and persistence of IL-4 and IL-10 transcripts were observed in the graft infiltrating cells.


CONCLUSIONS
The adenovirous-mediated CTLA4Ig gene transfer into a recipient liver by systemic administration resulted in remarkable prolongation of cardiac allograft survival. Its action mechanisms may be mediated by inhibition of CD28-associated signal transduction, reduction of Th1-type cytokine production, and continuous expression of Th2-type cytokines in the activating lymphocytes.
Kita
Y
Y
Department of Experimental Surgery and Bioengineering, National Children's Medical Research Center, Tokyo, Japan.
Li
X K
XK
Ohba
M
M
Funeshima
N
N
Enosawa
S
S
Tamura
A
A
Suzuki
K
K
Amemiya
H
H
Hayashi
S
S
Kazui
T
T
Suzuki
S
S
D000069594:Abatacept; D000256:Adenoviridae / Q000737:chemistry; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics; D060908:CTLA-4 Antigen; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D009333:Neck; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D011993:Recombinant Fusion Proteins / Q000235:genetics; D016042:Transplantation, Heterotopic
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D000069594:Abatacept