The CCL3/macrophage inflammatory protein-1alpha-binding protein evasin-1 protects from graft-versus-host disease but does not modify graft-versus-leukemia in mice.
CCL3 is a protein of the CC chemokine family known to be important for T cell recruitment in inflammatory diseases. The aim of the current study was to evaluate the effects and putative mechanism of action of evasin-1, a novel CCL3-binding protein, in the pathogenesis of acute graft-versus-host disease (GVHD). GVHD was induced by the transplantation of splenocytes from C57BL/6J to B6D2F1 mice. Treatment of recipient mice with evasin-1 prevented mortality associated with GVHD. This was correlated with reduced weight loss and clinical disease severity. Analysis of the small intestine showed that evasin-1 treatment reduced the histopathological score and decreased levels of IFN-gamma and CCL5. Mechanistically, evasin-1 treatment reduced the number of CD4(+) and CD8(+) T cells infiltrating the small intestine, as assessed by immunohistochemistry, and the adhesion of leukocytes to intestinal venules of recipient mice, as assessed by intravital microscopy. Evasin-1 was also able to decrease liver damage, as seen by reduction of inflammatory infiltrate and IFN-gamma levels. Treatment with evasin-1 did not interfere with graft-versus-leukemia. Altogether, our studies demonstrate that CCL3 plays a major role in mediating GVHD, but not graft-versus-leukemia in mice and suggest that blockade of CCL3 with evasin-1 has potential therapeutic application in patients undergoing bone marrow transplantation.
Castor
Marina G M
MG
Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, BeloHorizonte, Brazil.
Rezende
Bárbara
B
Resende
Carolina B
CB
Alessandri
Ana L
AL
Fagundes
Caio T
CT
Sousa
Lirlândia P
LP
Arantes
Rosa M E
RM
Souza
Danielle G
DG
Silva
Tarcília A
TA
Proudfoot
Amanda E I
AE
Teixeira
Mauro M
MM
Pinho
Vanessa
V
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017690:Cell Transplantation; D054405:Chemokine CCL3 / Q000172:deficiency* / Q000235:genetics; D018946:Chemokine CCL5 / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D006086:Graft vs Host Disease / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D020544:Graft vs Leukemia Effect / Q000187:drug effects; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D007421:Intestine, Small / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D019707:Receptors, Chemokine / Q000378:metabolism*; D013154:Spleen / Q000166:cytology
D000893:Anti-Inflammatory Agents; C496534:Ccl3 protein, mouse; C503460:Ccl5 protein, mouse; D054405:Chemokine CCL3; D018946:Chemokine CCL5; C523601:Evasin-1, Rhipicephalus sanguineus; D019402:Macrophage Inflammatory Proteins; D019707:Receptors, Chemokine; D003907:Dexamethasone; D007371:Interferon-gamma