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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Research Article Immunology

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 6

MECA79-NP traffic to the DLN of a pig with a vascularized allogeneic limb transplant.

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MECA79-NP traffic to the DLN of a pig with a vascularized allogeneic lim...
(A) Representative figures of vascularized composite allotransplant (VCA) in swine leukocyte antigen–defined (SLA-defined) MGH miniature swine. Top left: Dissection of VCA containing skin, muscle, and bone from the donor hind limb. Bottom left: Inset of the VCA into the groin and lateral abdominal wall of the recipient animal. Top right: Final skin inset in the lateral abdominal wall. Bottom right: Long-term follow-up by visual monitoring of the donor skin component in the lateral abdominal wall of the recipient. (B–D) MECA79-IR800-NP was injected i.v. 147 days after VCA. DLN, NDLN, liver, spleen, and lung were harvested at 24 hours after injection. (B) Immunofluorescence staining of DLN. Arrows point to the MECA79-IR800-NPs in the proximity of the HEVs in the DLN. Scale bars: 100 μm. (C) Immunofluorescence staining of DLN and NDLN. The bar graph shows percentage area per each image positive for MECA79-IR800-NPs, quantified using ImageJ software (NIH). A significantly higher quantity of NPs was observed in the DLN as compared with the NDLN (NDLN vs. DLN: 0.12% ± 0.03% vs. 2.28% ± 0.21%, mean ± SEM, Student’s t test, ***P < 0.001, n = 3 images per section, total 5 sections per LN). (D) Immunofluorescence staining of liver, spleen, and lung displays the preferential accumulation of MECA79-IR800-NPs in the liver and spleen, as demonstrated by asterisks.