Induction of xenograft accommodation by modulation of elicited antibody responses1 2

We have established that the timing of splenectomy influences the magnitude of the xenoreactive antibody (XAb) response and thus hamster heart survival in cyclosporine (CyA)-treated rats. This model has been used to test our hypothesis that modulation of XAb responses without perturbation of complement may influence the development of graft accommodation.

Pretransplantation splenectomy (day -1/day 0) fully abrogated anti-graft IgM response, whereas a delayed procedure (day 1/day 2) caused significantly delayed (3-4 days) and decreased levels (two- to threefold) of XAb. Both interventions resulted in long-term graft survival. After surviving for 7 or more days, xenografts in CyA-treated rats with post-, but not pre-, transplantation splenectomy were also resistant to exogenous anti-graft XAb. Such grafts meet the criteria for accommodation. Accommodating hearts displayed progressive and increasing expression of protective genes, such as heme oxygense (HO)-1 and A20, in endothelial cells and smooth muscle cells.

Our results suggest that XAb responses may influence the kinetics of accommodation development possibly by promoting protective gene expression. This hypothesis was directly tested in vitro. Pretreatment of porcine aortic endothelial cells with sublytic amounts of baboon anti-pig serum for 24 hr induced HO-1 expression; this was associated with cell resistance to lytic amounts of such serum. Overexpression of HO-1 by adenoviral-mediated gene transfer in porcine aortic endothelial cells resulted in similar protective effects.

Delayed and relatively low levels of XAb IgM promote expression of protective genes in the graft and thereby aid in the progress of accommodation. Expression of HO-1 protects xenoserum-mediated endothelial cell destruction.