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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 1

Transient anti-CD45RC mAb treatment induces donor-specific transplant tolerance in a fully mismatched cardiac allograft model in the rat.

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Transient anti-CD45RC mAb treatment induces donor-specific transplant to...
(A) Analysis of CD45RC expression on rat peripheral blood PBMCs. CD4+ and CD8+ T cells, B cells, NK cells, NKT cells, monocytes, granulocytes, pDCs, CD4+ or CD4– cDCs, and CD4+CD25+Foxp3+ Tregs were analyzed for CD45RC marker expression by flow cytometry. Left: A representative experiment of 6 rats. Right: Mean expression ± SEM of CD45RC+ or CD45RClow/– in each cell population. (B) Left: Model depicting allograft transplantation in MHC-incompatible rats, antibody treatment, and monitoring. Right: Recipients were either untreated (n = 11) or treated 5 days (n = 3), 10 days (n = 6), or 20 days (n = 9) in the LEW.1W/LEW.1A strain combination or treated 20 days in the more stringent LEW.1A/LEW.1W strain combination. Log rank (Mantel Cox) test, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. (C) Representative histological analysis of graft for signs of chronic rejection lesions performed at >120 days on syngeneic graft recipient, allogeneic long-term chronic rejection graft recipient, and anti-CD45RC–treated recipients at magnification ×100 and ×40. A, Adventitia; M, Media. The arrows show the intima wall. (D) IgG, IgG1, IgG2a, or IgG2b alloantibody production was evaluated in naive, untreated, 10-day, and 20-day anti-CD45RC–treated animals >120 days after transplantation (n = 3 for all groups). Graph represents MFI ± SEM. Two-way repeated measures ANOVA, **P < 0.01.

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