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 inhibit s in vitro and in vivo immune responses, In vivo gene transfer using adenov irus vector achieves a high transfection rate into organ cells that usually contain adenoviral receptors, In this study, we investigated expression le vels of the transfected gene and the survival times of the allografts in ca rdiac recipients systemically administered adenoviral vectors containing CT LA4Ig. Methods. Hearts from DA rats (RT-1(a)) were transplanted into a cervical lo cation in LEW recipients (RT-1(1)), The adenoviral vectors containing CTLA4 Ig was injected via a recipient rein immediately after grafting, Results. The serum level of CTLA4Ig reached to maximum at 51-93 mu g/ml 3 t o 7 days after gene-transfection and declined after 14 days, although detec table levels were observed up to 49 days. The median survival time of the a llografts in the gene-transfected group were significantly prolonged (27 da ys) 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 TL-10 transcripts were observed in the graft infiltrating cells. Conclusion. The adenovirous-mediated CTLA4Ig gene transfer into a recipient liver by systemic administration resulted in remarkable prolongation of ca rdiac allograft survival. Its action mechanisms may be mediated by inhibiti on of CD28-associated signal transduction, reduction of Th1-type cytokine p roduction, and continuous expression of Th2 type cytokines in the activatin g lymphocytes.