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.
| Original language | English |
|---|---|
| Pages (from-to) | 4770-4786 |
| Number of pages | 17 |
| Journal | The Journal of clinical investigation |
| Volume | 128 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 1 Nov 2018 |
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Keywords
- Immunology
- Nanotechnology
- Transplantation
ASJC Scopus subject areas
- Medicine(all)
Cite this
Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival. / Bahmani, Baharak; Uehara, Mayuko; Jiang, Liwei; Ordikhani, Farideh; Banouni, Naima; Ichimura, Takaharu; Solhjou, Zhabiz; Furtmüller, Georg J.; Brandacher, Gerald; Alvarez, David; von Andrian, Ulrich H.; Uchimura, Kenji; Xu, Qiaobing; Vohra, Ishaan; Yilmam, Osman A.; Haik, Yousef; Azzi, Jamil; Kasinath, Vivek; Bromberg, Jonathan S.; McGrath, Martina M.; Abdi, Reza.
In: The Journal of clinical investigation, Vol. 128, No. 11, 01.11.2018, p. 4770-4786.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival
AU - Bahmani, Baharak
AU - Uehara, Mayuko
AU - Jiang, Liwei
AU - Ordikhani, Farideh
AU - Banouni, Naima
AU - Ichimura, Takaharu
AU - Solhjou, Zhabiz
AU - Furtmüller, Georg J.
AU - Brandacher, Gerald
AU - Alvarez, David
AU - von Andrian, Ulrich H.
AU - Uchimura, Kenji
AU - Xu, Qiaobing
AU - Vohra, Ishaan
AU - Yilmam, Osman A.
AU - Haik, Yousef
AU - Azzi, Jamil
AU - Kasinath, Vivek
AU - Bromberg, Jonathan S.
AU - McGrath, Martina M.
AU - Abdi, Reza
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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.
KW - Immunology
KW - Nanotechnology
KW - Transplantation
UR - http://www.scopus.com/inward/record.url?scp=85055824754&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055824754&partnerID=8YFLogxK
U2 - 10.1172/JCI120923
DO - 10.1172/JCI120923
M3 - Article
VL - 128
SP - 4770
EP - 4786
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 11
ER -