Antagonist of secondary lymphoid-tissue chemokine (CCR ligand 21) prevents the development of chronic graft-versus-host disease in mice.
The use of receptor antagonists for chemokines is an alternative approach to blocking chemokine actions and has the potential to provide novel therapeutics. We determined the receptor antagonist properties of murine N-terminally truncated secondary lymphoid tissue chemokine (SLC)/6Ckine/CCR ligand 21 analogs and evaluated the preventive effects of SLC antagonists on chronic graft-vs-host disease (GVHD) in a murine model by blocking the homing of donor CCR7-expressing T cells into the recipient's lymphoid organs. SLC analogs truncated >4 aa residues from the N terminus showed a loss of chemotaxis and Ca2+ influx of CCR7-expressing cells and also inhibited SLC-stimulated chemotaxis and SLC-induced Ca2+ influx completely. To determine whether SLC antagonist inhibits the development of chronic GVHD, chronic GVHD was induced by injecting DBA/2 spleen cells into (C57BL/6 x DBA/2) F1 mice. Total numbers of spleen cells and host B cells, serum levels of IgE, and of total IgG and IgG1 of anti-DNA Abs in SLC antagonist-treated GVHD mice were significantly lower than those in control PBS-treated GVHD mice. This was due to a reduction in the levels of activated donor CD4+ T cells and a decrease in IL-4 production, resulting in a reduction in the numbers of activated host B cells. Therefore, our results suggest that SLC antagonist has beneficial effects for the prevention of chronic GVHD.
Sasaki
Miho
M
First Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Ehime, Japan.
Hasegawa
Hitoshi
H
Kohno
Masashi
M
Inoue
Atsushi
A
Ito
Mitsuko R
MR
Fujita
Shigeru
S
D000818:Animals; D001692:Biological Transport / Q000276:immunology; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000637:transplantation; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D002908:Chronic Disease; D004334:Drug Administration Schedule; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007275:Injections, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010446:Peptide Fragments / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D017384:Sequence Deletion
C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D010446:Peptide Fragments; D002118:Calcium