Portal venous donor-specific transfusion in conjunction with sirolimus prolongs renal allograft survival in nonhuman primates

Abstract

Pretransplant exposure to donor antigen is known to modulate recipient alloimmunity, and frequently results in sensitization. However, donor-specific transfusion (DST) can have a protolerant effect that is dependent on route, dose and coadministered immunosuppression. Rodent studies have shown in some strain combinations that portal venous (PV) DST alone can induce tolerance, and uncontrolled clinical use of PVDST has been reported. In order to determine if pretransplant PVDST has a clinically relevant salutary effect, we studied it and the influence of concomitant immunosuppression in rhesus monkeys undergoing renal allotransplantation. Animals received PVDST with unfractionated bone marrow and/or tacrolimus or sirolimus 1 week prior to transplantation. Graft survival was assessed without any posttransplant immunosuppression. PVDST alone or in combination with tacrolimus was ineffective. However, PVDST in combination with sirolimus significantly prolonged renal allograft survival to a mean of 24 days. Preoperative sirolimus alone had no effect, and peripheral DST with sirolimus prolonged graft survival in 2/4 animals, but resulted in accelerated rejection in 2/4 animals. These data demonstrate that PVDST in combination with sirolimus delays rejection in a modest but measurable way in a rigorous model. It may thus be a preferable method for donor antigen administration.

Figure 1. Percentage of animals showing posttransplant rejection-free survival, by treatment group

Pretransplant portal vein administration of donor whole bone marrow (PVDST) paired with sirolimus prolonged rejection free renal allograft survival compared to pretransplant sirolimus alone (p = 0.009), PVDST alone (p = 0.005), or PVDST paired with tacrolimus (p = 0.019). In all PVDST groups, whole bone marrow DST was administered on pretransplant day −7 via the portal vein and day −2 via peripheral vein, unless noted in the legend. Immunosuppressive agents, sirolimus and tacrolimus, were given day −7 to day 0 unless otherwise noted in the legend.

Figure 2. The relationship between cell dose of PVDST and graft survival

Shown are the nucleated cell counts in cells infused per kilogram animal body weight versus days of survival post transplant. The trend line is a best-fit logarithmic equation y = −50Ln(x) + 237, R² = 0.28.

Figure 3

Donor-specific hyporesponsiveness in the longest surviving animal as measured by serial donor and third-party MLR.