Discordant xenoislets from a large animal donor undergo accelerated graft failure rather than hyperacute rejection: impact of immunosuppression, islet mass, and transplant site on early outcome.

BACKGROUND

It is not known whether discordant, free, nonvascularized xenoislets-akin to discordant, vascularized, solid xenoorgans-are hyperacutely rejected. Quantitative xenoislet requirements and the optimal transplant site also remain to be defined.

METHODS

We studied these questions with a discordant dog-to-diabetic Lewis rat xenoislet model, using (1) functional (cure of streptozotocin-induced diabetes) and (2) histologic (biopsies of intraportal grafts) parameters. WF-to-Lewis alloislet recipients served as histologic controls.

RESULTS

(1) We found that 5000 xenoislet equivalents (IEs) transplanted into the portal veins of nonimmunosuppressed rats never functioned. Peritransplant combination therapy (rapamycin, cyclosporin A, anti-rat lymphocyte serum) significantly prolonged graft survival of 5000 intraportal IEs (median, 3 days) but not of 2500 intraportal or of 5000 intraperitoneal or renal subcapsular IEs. (2) By means of immunofluorescence (at 1 hour after transplantation), we noted immunoglobulin M (IgM) and IgG binding to islets in xenografts but not allografts; we noted complement and fibrinogen binding in both xenografts and allografts. Insulin-positive islet cells within intact xenoislets were demonstrated in nonimmunosuppressed rats up to 48 hours after transplantation. Cellular xenograft infiltration and inflammation, beginning at 6 hours, were observed even in immunosuppressed rats. (3) Thus, in spite of IgM and IgG binding, intraportal discordant xenoislets were not hyperacutely rejected and destroyed. Nevertheless, universal xenoislet nonfunction in nonimmunosuppressed rats was immune mediated. A large xenoislet mass (more than 10,000 IEs/kg), the intraportal site, and combination therapy were absolute prerequisites for immediate function. But even if the prerequisites were all fulfilled, accelerated xenoislet graft failure occurred.

CONCLUSIONS

This outcome suggests that the specific binding of IgM and IgG to xenoislets, in conjunction with the binding of complement and fibrinogen, contributed to accelerated graft failure. Thus distinction between discordant and concordant species combinations is important for free, nonvascularized xenoislet transplants. These findings and the steroid-free combination protocol (rapamycin, cyclosporin A, anti-T-cell therapy) warrant further testing in preclinical discordant xenoislet studies.