Interleukin-1 is a critical effector molecule during cytokine dysregulation in graft versus host disease to minor histocompatibility antigens.
Cytokines are believed to cause a number of inflammatory diseases. We have investigated the role of 3 inflammatory cytokines, IL-1, IL-2, and TNF alpha, during graft-versus-host disease (GVHD), a paradigm disease of cytokine dysregulation in vivo. Measuring cytokine mRNA transcripts with a quantitative polymerase chain reaction technique, we demonstrate that IL-1 transcript levels are increased several hundred-fold in GVHD target organs, whereas TNF alpha transcripts increase only 4- to 6-fold. Kinetic studies during the first month after transplant unexpectedly show that GVHD never induces IL-2 transcripts in the skin and only induces IL-2 transcripts in the spleen during the first week, whereas levels of IL-1 transcripts continue to increase throughout the entire 4 weeks. Administration of an IL-1 receptor antagonist after the termination of the IL-2 response and after the establishment of GVHD significantly increases long-term survival, confirming the central role of IL-1 as an effector molecule of GVHD and suggesting new therapeutic strategies for this disorder.
Abhyankar
S
S
Division of Pediatric Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115.
Gilliland
D G
DG
Ferrara
J L
JL
D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology*; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008808:Mice, Inbred CBA; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000276:immunology; D013154:Spleen / Q000276:immunology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D016207:Cytokines; D017931:DNA Primers; D007375:Interleukin-1; D007376:Interleukin-2; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha