Accommodation of vascularized xenografts: Expression of “protective genes” by donor endothelial cells in a host Th2 cytokine environment

Abstract

Organ xenografts under certain circumstances survive in the presence of anti-graft antibodies and complement, a situation referred to as "accommodation." We find that the endothelial cells (ECs) in hamster hearts that accommodate themselves in rats express genes, such as A20 and bcl-2, that in vitro protect ECs from apoptosis and prevent upregulation in those cells of proinflammatory genes such as cytokines, procoagulant and adhesion molecules. Hearts that are rejected do not express these genes. In addition, vessels of rejected hearts show florid transplant arteriosclerosis whereas those of accommodated hearts do not. Accommodated xenografts have an ongoing T helper cell type 2 (Th2) cytokine immune response, whereas the rejected grafts have a Th1 response. We propose a model for factors that contribute to the survival of xenografts and the avoidance of transplant arteriosclerosis.

Antigen Modulation Confers Protection to Red Blood Cells from Antibody through Fcγ Receptor Ligation

“…Such pathways have been observed for nicotinic cholinergic receptors in myasthenia gravis (19,20), Ags on platelets during idiopathic thrombocytopenic purpura (21), and Ags on RBCs during autoimmune hemolytic anemia (22). Similar pathways have been observed in response to alloantibodies as well, which may play a role in transplanted organs "accommodating" over time to alloantibodies (23,24). Finally, certain types of neoplasia can co-opt the pathways to escape mAb therapy, such as the selective shedding/shaving of CD20 by chronic lymphocytic leukemia (25).…”

Apoptosis in the vasculature: mechanisms and functional importance

“…De®ciency in HO-1 is associated with severe endothelial damage (Ferris et al, 1999;Hancock et al, 1998), while overexpression of HO-1 is associated with expression of various cytoprotective genes, such as Bcl-2, and prevents from transplant arteriosclerosis (Hancock et al, 1998). Moreover, endothelial integrity in this setting is associated with the expression of anti-in¯ammatory cytokines including IL-10 ( Bach et al, 1997).…”

Long-Term Survival of Hamster Hearts in Presensitized Rats

“…For one protective gene, heme oxygenase-1 (HO-1), we have direct evidence that expression of the gene in the graft can be essential for graft survival (30). In the present study, we have used as one hypothesis our earlier stated idea that a slow return of anti-graft Abs after their depletion may help allow the graft to accommodate (15,31).…”

“…We have shown that treatment with just two doses of cobra venom factor (CVF) plus daily cyclosporin A (CyA) blocks complement activation for a few days and IgG synthesis permanently, respectively, and results in long-term survival of the grafts (15,16). The grafts continue to survive in the presence of anti-donor IgM Abs and complement, a phenomenon we refer to as accommodation (17).…”

“…Accommodation may lessen the need for prolonged, heavy immunosuppression. A key feature of accommodation as we have studied it in the hamster-to-rat or mouseto-rat models is expression in the endothelial cells (EC) and smooth muscle cells (SMC) of the accommodated grafts of protective genes (15,25). Based on past studies by others and ourselves (26 -29), the expression of these genes in EC and perhaps SMC may well protect the graft from an insult such as that delivered by anti-graft (anti-EC) Abs plus complement.…”