Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival
JournalJournal of Clinical Investigation
PublisherAmerican Society for Clinical Investigation
MetadataShow full item record
AbstractThe targeted delivery of therapeutic drugs to lymph nodes (LNs) provides an unprecedented opportunity to improve the outcomes of transplantation and immune-mediated diseases. The high endothelial venule is a specialized segment of LN vasculature that uniquely expresses peripheral node addressin (PNAd) molecules. PNAd is recognized by MECA79 mAb. We previously generated a MECA79 mAb-coated microparticle (MP) that carries tacrolimus. Although this MP trafficked to LNs, it demonstrated limited therapeutic efficacy in our transplant model. Here, we have synthesized a nanoparticle (NP) as a carrier of anti-CD3, and optimized the conjugation strategy to coat the NP surface with MECA79 mAb (MECA79-anti- CD3-NP) to enhance LN accumulation. As compared with nonconjugated NPs, a significantly higher quantity of MECA79- NPs accumulated in the draining lymph node (DLN). Many MECA79-NPs underwent internalization by T cells and dendritic cells within the LNs. Short-term treatment of murine cardiac allograft recipients with MECA79-anti-CD3-NP resulted in significantly prolonged allograft survival in comparison with the control groups. Prolonged graft survival following treatment with MECA79-anti-CD3-NP was characterized by a significant increase in intragraft and DLN Treg populations. Treg depletion abrogated the prolongation of heart allograft survival. We believe this targeted approach of drug delivery could redefine the methods of administering immune therapeutics in transplantation. Copyright 2018 American Society for Clinical Investigation. All rights reserved.
SponsorsThis work is in part supported by NIH grant T32-EB016652 (to BB), National Institute of Allergy and Infectious Diseases grants R01-AI126596 and R01-HL141815 (to RA), aa Brigham Research Institute Stepping Strong Innovator Award (to RA), the BWH Health & Technology Innovation Fund (to RA), and National Priorities Research Program (NPRP) grant 9-350-3-074 (to RA).
KeywordDrug Delivery Systems--methods
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85055824754&doi=10.1172%2fJCI120923&partnerID=40&md5=1593ab52d835453b4134d034a8e2837b; http://hdl.handle.net/10713/9728