Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice
Jing Zhao, … , Jonathan S. Bromberg, Reza Abdi
Jing Zhao, … , Jonathan S. Bromberg, Reza Abdi
Published December 15, 2022
Citation Information: J Clin Invest. 2022;132(24):e159672. https://doi.org/10.1172/JCI159672.
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Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice

Abstract

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.

Authors

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

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Figure 2

Anti-CD40L treatment alters the phenotype of FRCs.

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Anti-CD40L treatment alters the phenotype of FRCs. (A) Uniform manifold ...
(A) Uniform manifold approximation and projection (UMAP) displays the stromal cell population map in LNs. (B) UMAP map from A, showing cell events by condition: anti-CD40L (top row) versus isotype control (bottom row). (C) UMAP visualization of clustering of different FRC populations, showing isotype control on left and anti-CD40L on right. The arrow shows the subset of FRCs that increase following anti-CD40L treatment. (D) Bar graph shows comparison of Madcam1+ FRC populations from C. (E) Volcano plot shows comparison of gene expression in Madcam1+ FRCs between the anti-CD40L–treated group and isotype control–treated group. (F) Volcano plot showing gene expression in Madcam1+ FRCs in comparison to other FRC subsets in the anti-CD40L–treated group.