Introduction: The interaction of the CXCR4/SDF1α axis plays a critical role in the retention of hematopoietic stem cells in bone marrow. We hypothesized that the immunotolerogenic effects of rapamycin may synergize with plerixafor, a CXCR4 antagonist, leading to the mobilisation of bone marrow and/or secondary lymphoid organ residing expanded CD4+FoxP3+ regulatory T cells (Tregs).

Methods: In a fully mismatched murine heart transplant model inbred BALB/c mice served as donors and C57BL/6J mice as transplant recipients. Animals were treated in four groups (all n=6): Plerixafor (5mg/kg, s.c.) plus rapamycin (0.4mg/kg, i.p.), plerixafor plus rapamycin vehicle, plerixafor vehicle plus rapamycin and a vehicle control group. Drugs and vehicle injections were administered two days before heart transplantation and subsequently every second day until day 14 post transplant.

Results: As observed by flow cytometry, animals treated with a combination of rapamycin and plerixafor exhibited more CD4+FoxP3+ Tregs in the peripheral circulation (12.78% vs. 6.44%; 65.9 vs. 22.0 cells/mm3, p<0.01) compared to rapamycin alone. In histology, allografts harvested at day 14 from mice treated with plerixafor exhibited (1) less fibrosis (area percentage: 4.0% vs. 9.3%, p<0.01), (2) fewer myocyte lesions (score [0-3]: 0.97 vs. 1.4, p<0.05), (3) less lymphocyte infiltration (score [0-3]: 1.00 vs. 1.3, p<0.05) and (4) less CD3+ T-cells (554.6 vs. 868.6 cells/ mm2, p<0.05), but more Foxp3+ Tregs (72.83 vs. 28.06, cells/ mm2, p<0.01). Therefore, the combined treatment with rapamycin plus plerixafor reduced the severity of allograft rejection 14 days after transplantation.

Conclusion: Rapamycin synergizes with the interruption of the CXCR4-SDF1α axis leading to a significant reduction of heart allograft rejection. This effect is accompanied by an enrichment of CD4+FoxP3+ Tregs within the peripheral blood and accumulation inside the allograft potentially suppressing the local alloimmune response.

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