Date: Saturday, May 2, 2015
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Exhibit Hall E
Targeted nanodelivery has created enormous excitement as a transformative approach to deliver therapeutics to tissues of interest. In recent years, we have made significant progress to develop targeted drug delivery as an innovative therapy for transplantation by improving the pharmacokinetics of nanocarriers; developing efficient immunosuppressive agent (ISA) nanocarriers; focusing on mechanisms of targeted delivery.
Presentation of donor alloantigen to recipient T cells in the lymph nodes (LN) is fundamental to priming alloreactive T cells. To achieve LN-targeted delivery, we focused on lymphocyte trafficking to LN; specifically the interaction between lymphocyte expressed L-selectin and its ligand on high endothelial venules, peripheral node addressin (PNAd). PNAd are recognized by the MECA-79 monoclonal antibody (mAb).
We have engineered microparticles (MPs) which bear MECA-79 mAb on the surface and contain Tacrolimus (MP-MECA-79-TAC). MPs show high levels of efficacy in retaining and releasing TAC and in vitro, suppress alloreactive T cell proliferation in a dose dependent fashion starting at 0.5 ng/ml TAC equivalent concentration (p<0.05). Following systemic administration of rhodamine-labeled MP-MECA-79-TAC into skin allograft recipients, we observe more than 5-fold greater trafficking of MP-MECA-79-TAC to draining LN (DLN) as compared to non DLN. To test the functionality of MECA-79 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-MECA-79-TAC to DLN after PNAd blockade. To examine the therapeutic efficacy of MPs, we treated heart allograft recipient mice with MP-MECA-79-TAC. We observe a significant prolongation of heart allograft survival in MP-MECA-79-TAC treated recipients as compared to free TAC treatment. MP-MECA-79-TAC treated mice also had more than 15 fold lower blood TAC levels. This is the first report of immune targeted delivery to lymphoid tissue in transplantation. We have demonstrated efficacy of this strategy and shown it holds great potential to increase the efficacy of ISA while reducing their toxicity.
To cite this abstract in AMA style:Uehara M, Jamil A, McGrath M, Solhjou Z, Banouni N, Tullius S, Jianjun C, Abdi R. Emerging Application of Active Immune Targeted Delivery in Transplantation [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/emerging-application-of-active-immune-targeted-delivery-in-transplantation/. Accessed July 19, 2018.
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