Cytokine and chemokine profiles in autologous graft-versus-host disease (GVHD): interleukin 10 and interferon gamma may be critical mediators for the development of autologous GVHD.
Administration of the immunosuppressive drug cyclosporine A (CsA) following autologous stem cell transplantation paradoxically elicits a systemic autoimmune syndrome resembling graft-versus-host disease (GVHD). This syndrome, termed autologous GVHD, is associated with autoreactive CD8(+) T cells that recognize major histocompatibility complex (MHC) class II determinants in association with a peptide from the invariant chain. To investigate the potential role of cytokines and chemokines in autologous GVHD, interleukin 2 (IL-2), IL-4, IL-10, interferon gamma (IFN-gamma), and macrophage inflammatory protein-1alpha (MIP-1alpha) gene expression in peripheral blood mononuclear cells (PBMCs) was determined in 36 patients treated with CsA following transplantation and correlated with the induction of cytolytic activity against autologous phytohemagglutinin-stimulated lymphocytes (PHA-blasts) and the breast cancer cell line (T47D). The determination of gene expression by real-time polymerase chain reaction (PCR) revealed that IL-10 mRNA levels by PBMCs in patients with autologous GVHD were 29-fold higher than in healthy individuals. IFN-gamma (4-fold), IL-2 (3-fold), and MIP-1alpha (44-fold) mRNA levels were also increased in GVHD-induced patients compared with healthy individuals. The ability of PBMCs to lyse autologous PHA-blasts and T47D tumor cells exhibited an identical temporal relationship with expression of IL-10 and IFN-gamma during autologous GVHD. Moreover, the susceptibility to autologous GVHD as assessed in 75 patients was significantly associated with the IL-10(-1082) G/G polymorphic alleles, allelic variants in the promoter region that govern IL-10 production. These findings indicate that IL-10 may play an unexpected but critical role in autologous GVHD and could be utilized to enhance a graft-versus-tumor effect after transplantation. Interestingly, polymorphisms in the IL-10 promoter region may also explain differences in the susceptibility of patients to autologous GVHD induction.
Miura
Yuji
Y
Johns Hopkins University School of Medicine, Oncology Center and the Kanazawa University Graduate School of Medical Science, Cellular Transplantation Biology.
Thoburn
Christopher J
CJ
Bright
Emilie C
EC
Chen
Weiran
W
Nakao
Shinji
S
Hess
Allan D
AD
D000293:Adolescent; D000328:Adult; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000473:pathology; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018925:Chemokines / Q000235:genetics*; D016207:Cytokines / Q000235:genetics*; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000235:genetics*; D016753:Interleukin-10 / Q000235:genetics*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014182:Transplantation, Autologous / Q000276:immunology* / Q000473:pathology / Q000502:physiology
D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D016753:Interleukin-10; D007371:Interferon-gamma; D004247:DNA