Involvement of interleukin-18 in acute graft-versus-host disease in mice.
BACKGROUND
Interleukin (IL)-18 stimulates T helper 1 (Th1)-mediated immune responses and the development of cytotoxic T lymphocytes (CTLs). Antihost CTLs are major effectors in acute graft-versus-host disease (aGvHD), a potentially fatal complication after allogeneic stem-cell transplantation. We investigated the relevant role of IL-18 in the development of aGvHD in mice.


METHODS
Irradiated (C57BL/6x DBA/2) F1 (BDF1) mice transplanted with wild-type (WT) C57BL/6 (B6) splenocytes were compared with those transplanted with IL-18Ralpha-deficient B6 splenocytes with respect to Th1 development, CTL activity, severity of aGvHD, and survival.


RESULTS
Transplantation of WT B6 spleen cells into BDF1 mice induced aGvHD that was accompanied by elevation of both serum IL-18 levels and IL-18 receptor alpha chain (IL-18Ralpha) expression on engrafted T cells. The transplantation of WT B6 cells also induced high antihost CTL activity in host spleen, whereas transplantation of IL-18Ralpha-deficient B6 cells exhibited significantly reduced antihost-specific CTL activity, indicating that IL-18Ralpha-deficient CTLs were less cytotoxic than IL-18Ralpha-expressing CTLs. Moreover, the hosts receiving transplants with the IL-18Ralpha-deficient B6 cells had fewer fatal tissue injuries and increased their survival rates as compared with those receiving transplants with WT cells. Nevertheless, Th1 development in the hosts was the same, regardless of the type of donor cells.


CONCLUSIONS
These results suggest that Th1 induction and baseline CTL activity in aGvHD occur in the absence of IL-18, but endogenous IL-18 further accelerates aGvHD reaction to its full-blown manifestation. Thus, IL-18 may be involved in the development aGvHD by enhancing CTL activity.
Itoi
Hisayuki
H
Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
Fujimori
Yoshihiro
Y
Tsutsui
Hiroko
H
Matsui
Kiyoshi
K
Sugihara
Ayako
A
Terada
Nobuyuki
N
Hada
Toshikazu
T
Kakishita
Eizo
E
Okamura
Haruki
H
Hara
Hiroshi
H
Nakanishi
Kenji
K
D000208:Acute Disease; D000818:Animals; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology*; D020382:Interleukin-18 / Q000502:physiology*; D053727:Interleukin-18 Receptor alpha Subunit; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018123:Receptors, Interleukin / Q000502:physiology; D053724:Receptors, Interleukin-18; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology
C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18