Organ transplantation

Thematic

Transient Antibody Targeting of CD45RC Induces Transplantion Tolerance and Potent Donor Antigen-Specific Regulatory T Cells

Thursday, June 15
1:25 PM - 1:40 PM

Rat CD4+ and CD8+ CD45RClow/- have been described as Tregs whereas CD45RC+ are Th1 cells. We reasoned that depletion of CD45RC+ cells with a MAb would eliminate T cell involved in graft rejection and spare Tregs. Transient administration (10 or 20d) of an anti-rat CD45RC MAb in a rat cardiac allotransplantation model (2 different strain combinations in both cases complete MHC mismatch) induced transplant tolerance (>83 % >120 d survival, n=9) whereas isotype-treated controls rejected in + T cells in vitro and in vivo through intrinsic CD45RC+ signaling. In vivo anti-rat CD45RC treatment increased the number of CD4+ and CD8+CD45RClow/- Tregs, potentiated their in vitro suppression, modified their transcriptional signature and potentiated adoptive transfer of donor-specific tolerance to grafted recipients vs. Tregs from controls. We also demonstrate that human CD45 isoforms are expressed differentially by Tregs. Human CD4+ and CD8+Foxp3+ Tregs were both largely CD45RClow/- and CD45RA+RB+RO+. Anti-human CD45RC treatment inhibited GVHD in immune-humanized NSG mice both, when CD45RC+ cells were depleted before and after in vivo PBMC administration (n=4 in each group). Anti-human CD45RC MAb induced apoptosis of only human CD45RC+ T cells. In conclusion, short-term anti-CD45RC MAb administration eliminates cells implicated in organ rejection and GVHD while preserving CD4+ and CD8+ CD45RClow/- Tregs that become primed to donor alloantigens and is thus a potent novel therapeutic candidate to favor transplantation tolerance in humans.

Ignacio Anegon

Head of laboratory
INSERM UMR 1064-CRTI and Nantes University

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Elodie Picarda

INSERM UMR 1064-CRTI and Nantes University

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Laetitia Boucault

INSERM UMR1064 - CRTI

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Elodie Autrusseau

Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France

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Stéphanie Kilens

INSERM UMR 1064-CRTI and Nantes University

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Dimitri Meistermann

INSERM UMR 1064-CRTI and Nantes University

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Bernard Martinet

INSERM UMR 1064-CRTI and Nantes University

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Véronique Daguin

INSERM UMR 1064-CRTI and Nantes University

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Audrey Donnart

INSERM UMR 1087

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Eric Charpentier

INSERM UMR 1087 and Nantes University

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Laurent David

INSERM UMR 1064-CRTI and Nantes University

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Carole Guillonneau

CNRS
Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France

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Transient Antibody Targeting of CD45RC Induces Transplantion Tolerance and Potent Donor Antigen-Specific Regulatory T Cells



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