IL-18 prevents the development of chronic graft-versus-host disease in mice.
The development of chronic graft-versus-host disease (GVHD), which is induced by the transfer of DBA/2 spleen cells into (C57BL/6 x DBA/2)F1 (BDF1) mice, is closely related to diminished donor anti-host CTL activity and host B cell hyperactivation. Therefore, an approach which activates donor CD8+ T cells or suppresses donor CD4+ T cell-host B cell interaction may have clinical utility in the treatment of chronic GVHD. We have previously demonstrated that IL-18 induces the development of naive CD8+ T cells into type I effector cells in DBA/2 anti-BDF1 MLC. In this paper we examined the effect of IL-18 administration on the development of chronic GVHD in mice. The treatment was started before or after the onset of clinical evidence of the disease. Regardless of the treatment schedule, IL-18 significantly decreased immunological parameters indicative of chronic GVHD, such as elevated serum IgG antinuclear Abs, IgG1, and IgE levels, and host B cell numbers and their activation. Importantly, IL-18-treated mice did not show the same acute GVHD-like symptoms reported for IL-12 treatment, because there was no weight loss, death, or severe immunodeficiency as indicated by a decrease in IL-2 and IFN-gamma production by Con A-stimulated spleen cells. In contrast, IL-18 treatment partially but significantly restored the production of these cytokines. Data further suggested that these IL-18-mediated therapeutic effects may be due to the induction of donor CD8+ CTL, the decrease in donor CD4+ T cell numbers, and a down-regulation of host B cell MHC class II expression. Thus, our results suggest that IL-18 has beneficial effects in the prevention and treatment of chronic GVHD.
Okamoto
I
I
Fujisaki Institute, Hayashibara Biochemical Laboratories, Inc., Okayama, Japan. kohnok@hayashibara.co.jp
Kohno
K
K
Tanimoto
T
T
Iwaki
K
K
Ishihara
T
T
Akamatsu
S
S
Ikegami
H
H
Kurimoto
M
M
D000208:Acute Disease; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D004334:Drug Administration Schedule; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D020382:Interleukin-18 / Q000008:administration & dosage*; D008231:Lymphopenia / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D020382:Interleukin-18