Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival
Baharak Bahmani, … , Martina M. McGrath, Reza Abdi
Baharak Bahmani, … , Martina M. McGrath, Reza Abdi
Published October 2, 2018
Citation Information: J Clin Invest. 2018;128(11):4770-4786. https://doi.org/10.1172/JCI120923.
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Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival

Abstract

The 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.

Authors

Baharak Bahmani, Mayuko Uehara, Liwei Jiang, Farideh Ordikhani, Naima Banouni, Takaharu Ichimura, Zhabiz Solhjou, Georg J. Furtmüller, Gerald Brandacher, David Alvarez, Ulrich H. von Andrian, Kenji Uchimura, Qiaobing Xu, Ishaan Vohra, Osman A. Yilmam, Yousef Haik, Jamil Azzi, Vivek Kasinath, Jonathan S. Bromberg, Martina M. McGrath, Reza Abdi

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Figure 1

Targeted delivery of NPs to DLNs.

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Targeted delivery of NPs to DLNs. (A) Schematic of IR800-NP synthesis an...
(A) Schematic of IR800-NP synthesis and conjugation with MECA79 mAb. (B) Hydrodynamic size distribution and ζ-potential of the IR800-NPs and MECA79-IR800-NPs (mean ± SEM, Student’s t test, **P < 0.01, ***P < 0.001). (C) Representative transmission electron microscopy image of IR800-NPs. (D) Skin allograft recipients were injected i.v. with either IR800-NPs or MECA79-IR800-NPs at day 7 after transplantation. Live fluorescence imaging at 24 hours after administration (i.v.) showed greater fluorescence signal in the DLNs (Axi LN and Bra LN) of mice injected with MECA79-IR800-NPs. (E) Biodistribution of MECA79-conjugated and nonconjugated NPs, in addition to uninjected control, assessed via fluorescence imaging at 24 hours after injection (i.v.) of NPs (DLN: control vs. IR800-NP vs. MECA79-IR800-NP: 6,179 ± 2,307 vs. 12,033 ± 766.1 vs. 33,779 ± 3,096, mean ± SEM, ANOVA test, *P < 0.05, ***P < 0.001, n = 3 mice per group, 1–2 LNs from each mouse). (F) Trafficking of MECA79-conjugated NPs into DLNs and NDLNs (NDLN vs. DLN: 11,536 ± 732.1 vs. 33,264 ± 2,046, mean ± SEM, Student’s t test, ***P < 0.001, n = 4–6 mice per group, 2 LNs from each mouse).