Modulation of graft arteriosclerosis in a rat carotid transplantation model.
BACKGROUND
Venous autografts used in cardiovascular surgery tend to deteriorate over time due to arteriosclerotic complications. Cadaveric vascular allografts represent a possible alternative for this application, but donor endothelial cells (ECs) and antigen presenting cells of the graft trigger alloresponses mediated by MHC class I (MHC I) antigen, leading to graft failure. Vascular allograft rejection might be prevented by reducing cell surface expression of MHC I and thereby lowering the immunogenicity of the grafts.


METHODS
An Intrabody approach was used to reduce MHC I expression in vascular allografts. The efficacy of an adenovirus (Ad) carrying an anti-MHC I Intrabody gene (Ad-Intrabody) was first tested in vitro using rat aortic ECs. The effect of the Ad-Intrabody was then studied in vivo by a model of rat carotid artery transplantation. Grafts were analyzed 7 and 28 days after transplantation by immunohistochemistry and real time reverse transcriptase-polymerase chain reaction.


RESULTS
Ad-Intrabody gene transfer reduced MHC I surface expression of rat ECs and inhibited in vivo alloimmune responses to carotid allografts. Decreased T cell and macrophage infiltration was observed within Ad-Intrabody transduced arterial allografts at day 28. This was associated with an inhibition of intimal thickening formation. Analysis of mRNA showed diminished levels of T cell markers and Interferon-gamma expression in the Ad-Intrabody-treated group compared with control groups.


CONCLUSIONS
Ex vivo adenoviral gene transfer of an Intrabody against MHC I into rat carotid arteries prior to transplantation reduced both graft arteriosclerosis and inflammation in the absence of any systemic immunosuppression.
Zdoroveac
Andrei
A
Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
Doebis
Cornelia
C
Laube
Horst
H
Brösel
Sabine
S
Schmitt-Knosalla
Isabela
I
Volk
Hans-Dieter
HD
Seifert
Martina
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000378:metabolism*; D001161:Arteriosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017252:CD3 Complex / Q000378:metabolism; D002339:Carotid Arteries / Q000473:pathology / Q000637:transplantation*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D018014:Gene Transfer Techniques; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D014181:Transplantation Immunology
D000906:Antibodies; D017252:CD3 Complex; D015395:Histocompatibility Antigens Class I; D012333:RNA, Messenger; D007371:Interferon-gamma