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 4

Transient anti-CD45RC mAb treatment results in long-term dominant tolerance mediated by CD8+ and CD4+ CD45RClow/– Tregs.

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Transient anti-CD45RC mAb treatment results in long-term dominant tolera...
(A and B) CFSE-labeled LEW.1A dividing CD4+CD25– T cells stimulated with donor LEW.1W pDCs were analyzed after 6 days of culture in the absence or presence of LEW.1A naive or day-120 anti-CD45RC–treated CD8+CD45RClow/– (A, n = 4) or CD4+CD45RClow/– (B, n = 3) Tregs in a range of effector/suppressor ratio. The proportion of dividing CD4+CD25– T cells in the control proliferation condition with pDCs only represented about 70% of the cells at day 6 and was given the value 100 in each experiment. Two-way repeated measures ANOVA test. Bonferroni post-test. *P < 0.05, ***P < 0.001, ****P < 0.0001. (C) Schematic representation of adoptive cell transfer from day-120 tolerant transplanted-treated recipients to newly grafted irradiated recipients. (D) LEW.1A recipients were sublethally irradiated (4.5 Gy) at day –1 and received heart allografts from donor type (LEW.1W) or third-party type (BN, n = 4) and i.v. injection of splenocytes from long surviving anti-CD45RC–treated recipients (n = 7) or from naive rats (n = 5). Nonirradiated nontreated recipients (untreated, n = 11) and irradiated nontreated (n = 5) recipients were used as controls. Log rank test (Mantel Cox), **P < 0.01, ***P < 0.001, ****P < 0.0001. (E) LEW.1A recipients were sublethally irradiated (4.5 Gy) at day –1 and received heart allografts and i.v. injections of sorted subpopulations from long surviving anti-CD45RC–treated recipients or from naive rats (n = 2–4). Graft survival was monitored by abdominal palpation. Log rank test (Mantel Cox), *P < 0.05, **P < 0.01.