Paradoxical effects of interleukin-18 on the severity of acute graft-versus-host disease mediated by CD4+ and CD8+ T-cell subsets after experimental allogeneic bone marrow transplantation.
Administration of exogenous interleukin-18 (IL-18) regulates experimental acute graft-versus-host disease (GVHD) in a Fas-dependent manner when donor CD4(+) T cells are required for mortality after experimental allogeneic bone marrow transplantation (BMT). However, CD4(+) and CD8(+) T cells can induce acute GVHD after clinical allogeneic BMT, and the role of IL-18 in CD8(+)-mediated acute GVHD is unknown. We, therefore, determined the role of IL-18 in GVHD mediated by CD4(+) or CD8(+) T cells across major histocompatibility complex (MHC) class II- and class I-disparate allogeneic BMT, respectively. Administering IL-18 significantly increased survival in CD4(+)-mediated GVHD but reduced survival in CD8(+)-mediated GVHD. This increase in deaths was associated with significantly greater clinical, biochemical, and histopathologic parameters of GVHD damage and was independent of Fas expression on donor T cells. Administering IL-18 significantly enhanced allospecific cytotoxic function and expansion of CD8(+) cells. Endogenous IL-18 was critical to GVHD mediated by CD8(+) donor T cells because IL-18 receptor-deficient donors caused significantly less GVHD but exacerbated CD4(+)-mediated, GVHD-related death. Furthermore, administering anti-IL-18 monoclonal antibody significantly reduced CD8(+)-mediated, GVHD-related death. Together these findings demonstrate that IL-18 has paradoxical effects on CD4(+) and CD8(+) cell-mediated GVHD.
Department of Internal Medicine, 6310 CCGC, University of Michigan Cancer Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0942, USA.
Chang-Ki
CK
Min
Yoshinobu
Y
Maeda
Kathleen
K
Lowler
Chen
C
Liu
Shawn
S
Clouthier
David
D
Lofthus
Elizabeth
E
Weisiger
James L M
JL
Ferrara
Pavan
P
Reddy
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology*; D053727:Interleukin-18 Receptor alpha Subunit; D051379:Mice; D008810:Mice, Inbred C57BL; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics; D053724:Receptors, Interleukin-18; D012720:Severity of Illness Index; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18