The Journal of Clinical Investigation (Dec 2022)

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice

  • Jing Zhao,
  • Sungwook Jung,
  • Xiaofei Li,
  • Lushen Li,
  • Vivek Kasinath,
  • Hengcheng Zhang,
  • Said N. Movahedi,
  • Ahmad Mardini,
  • Gianmarco Sabiu,
  • Yoonha Hwang,
  • Vikas Saxena,
  • Yang Song,
  • Bing Ma,
  • Sophie E. Acton,
  • Pilhan Kim,
  • Joren C. Madsen,
  • Peter T. Sage,
  • Stefan G. Tullius,
  • George C. Tsokos,
  • Jonathan S. Bromberg,
  • Reza Abdi

Journal volume & issue
Vol. 132, no. 24

Abstract

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The lymph node (LN) is the primary site of alloimmunity activation and regulation during transplantation. Here, we investigated how fibroblastic reticular cells (FRCs) facilitate the tolerance induced by anti-CD40L in a murine model of heart transplantation. We found that both the absence of LNs and FRC depletion abrogated the effect of anti-CD40L in prolonging murine heart allograft survival. Depletion of FRCs impaired homing of T cells across the high endothelial venules (HEVs) and promoted formation of alloreactive T cells in the LNs in heart-transplanted mice treated with anti-CD40L. Single-cell RNA sequencing of the LNs showed that anti-CD40L promotes a Madcam1+ FRC subset. FRCs also promoted the formation of regulatory T cells (Tregs) in vitro. Nanoparticles (NPs) containing anti-CD40L were selectively delivered to the LNs by coating them with MECA-79, which binds to peripheral node addressin (PNAd) glycoproteins expressed exclusively by HEVs. Treatment with these MECA-79–anti-CD40L-NPs markedly delayed the onset of heart allograft rejection and increased the presence of Tregs. Finally, combined MECA-79–anti-CD40L-NPs and rapamycin treatment resulted in markedly longer allograft survival than soluble anti-CD40L and rapamycin. These data demonstrate that FRCs are critical to facilitating costimulatory blockade. LN-targeted nanodelivery of anti-CD40L could effectively promote heart allograft acceptance.

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