Background:

In patients, allograft survival requires a cocktail of immunosuppressive drugs, while experimentally antibodies targeting the innate immune system have been shown to induce long-term tolerance, with severe side effects. We here induced long-term tolerance by nanomedicine delivery of rapamycin to myeloid cells.

Methods:

We developed a hybrid nanoparticle encapsulating rapamycin (R-HDL), which has inherent affinity for innate immune cells. In a mouse allogeneic heart transplantation model, we applied this nanotherapy using a regimen involving 3 intravenous tail vein injections of 5 mg/Kg rapamycin during the first week. Using a combination of radiolabeling, in vivo PET-CT imaging and flow cytometry, we evaluated allograft and cellular specificity. Subsequently, the innate immune system's response and allograft survival were extensively monitored.

Results:

R-HDL nanoparticles, ~30 nm in diameter, had a high rapamycin encapsulation efficiency of ~65%. Radiolabeled R-HDL was observed to specifically accumulate in the transplanted heart and to be mainly associated with myeloid cells.

We showed in the transplanted heart, a significant reduction of Ly-6C^hi / Ly-6C^low as well as CD25^– / CD25⁺ cells. Most excitingly, our nanomedicine treatment resulted in a dramatic enhancement of allograft survival.

Conclusion:

We here presented a novel nanomedicine treatment paradigm to redirect rapamycin to innate immune cells and induce long-term allograft survival.

CITATION INFORMATION: Braza M, Lameijer M, Perez-Medina C, Reiner T, Nahrendorf M, Fayad Z, Duivenvoorden R, Ochando J, Mulder W. Rapamycin Nanotherapy Delays Heart Transplant Rejection. Am J Transplant. 2016;16 (suppl 3).

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