Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes

Abstract

We investigated the pathogenesis of chronic allograft rejection in mouse cardiac allografts. Long-term survival occurred after administration of monoclonal antibody to CD4 or CD40-ligand (CD40L) plus donor cells. Both treatments induced permanent graft survival, but, in contrast to transplants in mice treated with CD4 monoclonal antibody, grafts in mice treated with CD40L monoclonal antibody lacked evidence of chronic rejection, including transplant arteriosclerosis. Freedom from chronic rejection in the group treated with CD40L monoclonal antibody correlated with vascular expression of the 'protective' genes heme oxygenase-1 (HO-1), Bcl-xL and A20. Moreover, arteriosclerosis was induced in allografts in immunoglobulin-deficient mice by antibody transfer only when the transfer was done before expression of protective genes. A direct role for protective gene expression in endothelial cells was demonstrated by in vitro experiments in which induction of HO-1 or Bcl-xL suppressed alloantibody-stimulated endothelial activation. Finally, induction of HO-1 in vivo protected allografts against chronic injury. These data show a role for protective genes in the prevention of chronic rejection, and indicate new approaches to protect grafts against development of transplant arteriosclerosis.

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

“…The antiapoptotic effect of HO-1 is reversed in the presence of HO-1 inhibitors or in cells overexpressing antisense HO-1 (Petrache et al, 2000). Inhibition of apoptosis following the expression of HO-1 has also been reported in animal models of inflammation, ischemia-reperfusion, hypoxia, and organ transplantation while inhibition of HO-1 activity or deletion of the HO-1 gene promotes apoptosis in these animal models (Hancock et al, 1998;Soares et al, 1998;Yet et al, 1999;Ke et al, 2002;Vulapalli et al, 2002).…”

“…Induction of HO-1 by chemical inducers results in the reduction of atherosclerotic lesions in LDL-receptor knockout mice and prevents transplant arteriosclerosis in mouse cardiac allografts (Hancock et al, 1998;Ishikawa et al, 2001). Similarly, adenovirus-mediated transfer of HO-1 to arteries significantly attenuates the development of atherosclerosis in apoE null mice and graft arteriosclerosis in a rat model of chronic allogeneic aorta rejection (Juan et al, 2001;Bouche et al, 2002).…”

Programmed cell death 1 (PD‐1) and its ligand PD‐L1 are required for allograft tolerance

“…Since the requirements and conditions required for maintenance of anergy differ somewhat between CD4 and CD8 T cells, and given the CD4-predominant nature of allograft rejection in this well-established model [23], we focused on induction of CD4 T cell anergy. The PD-1/ PD-L1 pathway has received attention as a key mechanism of "immune exhaustion" in chronic infections and malignancies [24][25][26].…”

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

“…Similar to our findings, increased HO-1 expression following the administration of immunoregulatory peptides or metalloporphyrins has been shown to prolong allograft survival moderately. [3][4][5][6][7] While these results suggest a potential role for HO-1 in prolonging allograft survival, immunomodulatory peptides and metalloprotoporphyrins exert other functions. [7][8][9] .…”

“…1,2 This suggests that HO-1 is involved not only in heme degradation and iron reutilization but also in tissue protection against a variety of cell injuries. 1,2 Recently, the overexpression of HO-1 has been associated with prolongation of graft survival following the administration of metalloporphyrins [3][4][5] or immunomodulatory peptides, 6,7 which modulate HO-1 activity. Unfortunately, metalloporphyrins can also modulate the action of other heme-containing molecules such as NO synthases (NOS) or soluble guanylate cyclases 8,9 and immunomodulatory peptides may have effects on other molecules independent of HO-1.…”