The homing of naïve lymphocytes to the lymph node (LN) is fundamental to the priming of alloreactive T cells. LNs possess highly restricted high endothelial venules (HEV) which exclusively express sugar-coated molecules referred to as peripheral node addressins (PNAd). Lymphocytes use their L-selectin to bind to the PNAd of HEV to initiate rolling and tethering in order to traverse across HEV into the LN. PNAd are recognized by the MECA79 monoclonal antibody (mAb). We have engineered microparticles (MPs) which bear MECA79 mAb on the surface and contain Tacrolimus (MP-MECA79-TAC). MPs show high levels of efficacy in retaining and releasing TAC and in vitro, suppress alloreactive T cell proliferationin a dose dependent fashion starting at 0.5 ng/ml TAC equivalent concentration (p<0.05). Following systemic administration of rhodamine-labeled MP-MECA79-TAC into skin allograft recipients, we observe more than 5-fold greater trafficking of MP-MECA79-TAC to draining LN (DLN) as compared to non DLN. To test the functionality of MECA79 mAb, we injected recipients with PNAd blocking mAb prior to injection of MPs. By flow cytometry and immunohistology analysis, we found a significant abrogation in trafficking of MP-MECA79-TAC to DLN after PNAd blockade. To examine the therapeutic efficacy of MPs, we treated heart allograft recipient mice with MP-MECA79-TAC. We observe a significant prolongation of heart allograft survival in MP-MECA79-TAC treated recipients as compared to free TAC treatment. MP-MECA79-TAC treated mice also had more than 15 fold lower blood TAC levels. We recently developed nanoparticles (NP) and tested the trafficking of NP-MECA79 in both small and large animal (pig heterotopic hind limb transplant), which showed promising trafficking result to the DLN of pig. This is the first report of immune targeted delivery to HEV/lymphoid tissue in medicine/transplantation following systemic delivery (not through skin absorption). We have demonstrated efficacy of this strategy and shown it holds great potential to increase the efficacy of ISA while reducing their toxicity.

CITATION INFORMATION: Uehara M, Azzi J, Bahmani B, Cheng J, Yin Q, Tang L, Cai K, Sun Q, Kwon M, Xu Q, Brandacher G, Abdi R. Emerging Application of Active Immune Targeted Delivery in Transplantation. Am J Transplant. 2017;17 (suppl 3).

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