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

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 2

Transient anti-CD45RC mAb treatment preserves humoral and memory immunity toward cognate antigen.

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Transient anti-CD45RC mAb treatment preserves humoral and memory immunit...
(A) Left: Model depicting memory humoral response immunization and monitoring at late time point. Right: Recipients were treated or not with anti-CD45RC for 10 days and KLH immunized on day 120 after transplantation, and sera were analyzed for IgM and IgG reactivity against KLH, respectively, 4 days and 13 days after immunization. Serum from naive animals was used as negative control. n = 3 for all groups. Results are expressed as optical density ± SEM for the indicated dilution of serum. (B) Left: Model depicting memory humoral response immunization and monitoring. Right: Recipients were immunized with HRBC 7 days before transplantation and at day 3, and they were treated with anti-CD45RC mAb (n = 3) or isotype control mAb (n = 2) from day 0–10. Sera were analyzed for IgM and IgG reactivity against HRBC, respectively, 4 days and 13 days after the second immunization. Serum from naive animals was used as negative control (n = 3). Results are expressed in MFI ± SEM. (C) Analysis of kinetic of anti-HRBC IgG production in the sera of recipients immunized with HRBC 7 days before transplantation and at day 3, and treated with anti-CD45RC mAb (n = 3) or isotype control mAb (n = 2) from day 0–10. (D) Left: Model depicting naive humoral responses immunization and monitoring during the treatment. Right: Recipients were treated or not with anti-CD45RC for 10 days and immunized at day 3 during treatment, and sera were analyzed for IgG reactivity against KLH 14 days after immunization. Serum from naive animals was used as negative control. n = 3 for all groups. Results are expressed as optical density ± SEM for the indicated dilution of serum. Two-way repeated measures ANOVA, *P < 0.05, ***P < 0.001, ****P < 0.0001.