Only therapeutic ICOS:ICOSL blockade alleviates acute graft versus host disease.
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-gamma and chemokine up-regulation in spleen cells of prophylactically treated mice, emphasizing kinetic dependence of acute GVHD modulation via blockade of ICOS:ICOSL interaction.
Mollweide
A
A
Technische Universität München, Pediatrics and Children's Cancer Research Center, München, Germany.
Staege
M S
MS
Hoeschen
C
C
Hideo
Y
Y
Burdach
S
S
Richter
G H S
GH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000187:drug effects*; D016026:Bone Marrow Transplantation; D018925:Chemokines / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000037:antagonists & inhibitors*; D013154:Spleen / Q000276:immunology / Q000637:transplantation; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018925:Chemokines; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D011506:Proteins; D007371:Interferon-gamma