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Transient antibody targeting of CD45RC induces transplant tolerance and potent antigen-specific regulatory T cells
Elodie Picarda, … , Ignacio Anegon, Carole Guillonneau
Elodie Picarda, … , Ignacio Anegon, Carole Guillonneau
Published February 9, 2017
Citation Information: JCI Insight. 2017;2(3):e90088. https://doi.org/10.1172/jci.insight.90088.
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Research Article Therapeutics Transplantation

Transient antibody targeting of CD45RC induces transplant tolerance and potent antigen-specific regulatory T cells

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Abstract

Rat and human CD4+ and CD8+ Tregs expressing low levels of CD45RC have strong immunoregulatory properties. We describe here that human CD45 isoforms are nonredundant and identify distinct subsets of cells. We show that CD45RC is not expressed by CD4+ and CD8+ Foxp3+ Tregs, while CD45RA/RB/RO are. Transient administration of a monoclonal antibody (mAb) targeting CD45RC in a rat cardiac allotransplantation model induced transplant tolerance associated with inhibition of allogeneic humoral responses but maintained primary and memory responses against cognate antigens. Anti-CD45RC mAb induced rapid death of CD45RChigh T cells through intrinsic cell signaling but preserved and potentiated CD4+ and CD8+ CD45RClow/– Tregs, which are able to adoptively transfer donor-specific tolerance to grafted recipients. Anti-CD45RC treatment results in distinct transcriptional signature of CD4+ and CD8+ CD45RClow/– Tregs. Finally, we demonstrate that anti-human CD45RC treatment inhibited graft-versus-host disease (GVHD) in immune-humanized NSG mice. Thus, short-term anti-CD45RC is a potent therapeutic candidate to induce transplantation tolerance in human.

Authors

Elodie Picarda, Séverine Bézie, Laetitia Boucault, Elodie Autrusseau, Stéphanie Kilens, Dimitri Meistermann, Bernard Martinet, Véronique Daguin, Audrey Donnart, Eric Charpentier, Laurent David, Ignacio Anegon, Carole Guillonneau

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Figure 5

Transient anti-CD45RC mAb treatment results in sustained transcriptional changes in long-term CD8+ and CD4+ CD45RClow/– Tregs.

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Transient anti-CD45RC mAb treatment results in sustained transcriptional...
(A) 3′DGE RNA-seq analysis was performed on CD4+ and CD8+ CD45RClow/– Tregs from anti-CD45RC mAb treated vs. untreated rats. Expression levels of differentially expressed genes are presented as a heatmap; low expression levels are in blue, mean expression levels are in white, and high expression levels are in red. Venn diagrams highlight unique and shared genes upregulated by CD4+ and CD8+ CD45RClow/– Tregs from anti-CD45RC mAb treated vs. untreated rats. (B and C) Volcano plot representation of differentially expressed genes between treated and untreated CD4+ Tregs (B) or CD8+ Tregs (C). The q value (adjusted P value) cut-off is 0.05 and the log2 fold-change cutoff value is ±0.5. Red dots, genes overexpressed in Tregs; blue dots, genes downregulated in Tregs.

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