An immunotherapeutic strategy for prolonging graft survival in mice.

BACKGROUND

Immunological memory is one barrier to inducing immune tolerance in alloantigen primed transplant models. Alloreactive memory cells induced by primary organ transplant are difficult to suppress and contribute to rejection following a retransplant. Here, we assess the effects of a novel immunosuppressive strategy on graft survival and host immune response.

MATERIALS AND METHODS

Alloantigen primed splenocytes were adoptively transferred into naïve B6 mice before heart transplant. Recipient mice were then treated with mitomycin C -pretreated donor-specific transfusion, low dose rapamycin, and anti-OX40L mAb (alone and in combination).

RESULTS

Treatment with donor-specific transfusion+rapamycin+anti-OX40L increased the mean graft survival time from 5.2 days (control group) to 42.5 days (p < 0.05). None of the grafts in the control group survived past 10 days, and only 1 in 3 grafts survived at least 50 days in the combined treatment group. Compared with the control and single treatment groups, the combination of donor-specific transfusion+rapamycin + anti-OX40L inhibited infiltration of inflammatory cells; reduced the percentages of CD4(+) and CD8(+) memory T cells in the blood, spleen, and lymph nodes; suppressed inflammatory cytokines; reduced serum IgG levels; and enhanced the percentage of CD4(+)Foxp3(+) T cells. The percentage of regulatory T cells was the highest in the recipients with long-term graft survival.

CONCLUSIONS

The combination of donor-specific transfusion+rapamycin+anti-OX40L inhibits graft rejection mediated by memory cells and is likely to contribute to prolonged allograft survival.