Only Therapeutic ICOS:ICOSL Blockade Alleviates Acute Graft versus Host Disease

Abstract

Inducible co-stimulator (ICOS) interaction with its ligand (ICOSL) is involved in several T cell effector functions. While blockade of ICOS:ICOSL interaction in chronic graft versus host disease (GVHD) seems beneficial, results for acute GVHD remain controversial. To further elucidate its role in acute GVHD, C57BL/6 mice were reconstituted with allogeneic spleen cells in the absence or presence of ICOSL-blocking mAb. Mice reconstituted with allogeneic spleen cells experienced severe GVHD and died untreated within 6–9 days after transplantation. Mice treated with an anti-ICOSL mAb starting from day 3 after transplantation gained weight again and survived for at least additional 12 days, although the treatment was already stopped at day 11 after transplantation. In contrast, the anti-ICOSL treatment starting from day 0 did not prevent GVHD. The difference between therapeutic (day 3) and prophylactic (day 0) anti-ICOSL treatment was independent of CD25+CD4+ regulatory T cells since their depletion did not abrogate the therapeutic effect of ICOSL blockade. Microarray analysis revealed IFN-γ and chemokine up-regulation in spleen cells of prophylactically treated mice, emphasizing kinetic dependence of acute GVHD modulation via blockade of ICOS:ICOSL interaction.

Zusammenfassung

Während die Blockade der ICOS:ICOSL-Wechselwirkung bei der chronischen GVHD (graft versus host disease) vorteilhaft erscheint, sind die Ergebnisse für die akute GVHD widersprüchlich. C57BL/6-Mäuse wurden mit allogenen Milzzellen rekonstituiert, ein Teil von ihnen wurde mit ICOSL-blockierenden monoklonalen Antikörpern (mAb) behandelt. Rekonstituierte Mäuse zeigten eine schwere GVHD und starben innerhalb 6–9 Tagen nach Transplantation. Die ab Tag 3 nach Transplantation mit anti-ICOSL mAb behandelten Mäuse nahmen an Gewicht zu und überlebten mindestens 12 weitere Tage nach dem Ende der Behandlung. Im Gegensatz dazu verhinderte die Behandlung ab Tag 0 die Entwicklung einer GVHD nicht. Der Unterschied zwischen therapeutischer (Tag 3) and prophylaktischer (Tag 0) Behandlung mit anti-ICOSL mAb war unabhängig von CD25+CD4+ regulatorischen T-Zellen, da deren Depletion die therapeutische Wirkung von anti-ICOSL nicht beeinflusste. Mikroarray-Analysen zeigten dass Chemokine und IFN-γ in Mäusen nach prophylaktischer Behandlung verstärkt exprimiert werden und deutet auf einen wesentlichen Einfluss des Zeitpunkts der Blockade der ICOS:ICOSL-Wechselwirkung zur Behandlung der akuten GVHD hin.

Key words

bone marrow transplantation - GVHD - ICOS - T cells

Schlüsselwörter

Knochenmark transplantation - GVHD - ICOS - T Zellen

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