Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival

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

doi:10.1172/JCI120923

Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival

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. McGrathReza Abdi

Research output: Contribution to journal › Article

10 Citations (Scopus)

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	https://doi.org/10.1172/JCI120923
Publication status	Published - 1 Nov 2018

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Keywords

Immunology
Nanotechnology
Transplantation

ASJC Scopus subject areas

Medicine(all)

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Bahmani, B., Uehara, M., Jiang, L., Ordikhani, F., Banouni, N., Ichimura, T., Solhjou, Z., Furtmüller, G. J., Brandacher, G., Alvarez, D., von Andrian, U. H., Uchimura, K., Xu, Q., Vohra, I., Yilmam, O. A., Haik, Y., Azzi, J., Kasinath, V., Bromberg, J. S., ... Abdi, R. (2018). Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival. The Journal of clinical investigation, 128(11), 4770-4786. https://doi.org/10.1172/JCI120923

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

Bahmani, B, Uehara, M, Jiang, L, Ordikhani, F, Banouni, N, Ichimura, T, Solhjou, Z, Furtmüller, GJ, Brandacher, G, Alvarez, D, von Andrian, UH, Uchimura, K, Xu, Q, Vohra, I, Yilmam, OA, Haik, Y, Azzi, J, Kasinath, V, Bromberg, JS, McGrath, MM & Abdi, R 2018, 'Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival', The Journal of clinical investigation, vol. 128, no. 11, pp. 4770-4786. https://doi.org/10.1172/JCI120923

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. / Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival. In: The Journal of clinical investigation. 2018 ; Vol. 128, No. 11. pp. 4770-4786.

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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.",

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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

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10.1172/JCI120923