Cytolytic effector mechanisms and gene expression in autologous graft-versus-host disease: distinct roles of perforin and Fas ligand.
The administration of cyclosporin A (CsA) after autologous stem cell transplantation (SCT) paradoxically elicits a systemic autoimmune syndrome that resembles graft-versus-host disease (GVHD); this is termed autologous GVHD (autoGVHD). Although dominated by activated CD8+ cytotoxic T lymphocytes, the complex cellular reaction also includes CD4+ T cells and involves multiple effector mechanisms. To determine the temporal development and relative importance of these mechanisms in autoGVHD, perforin/granzyme, Fas ligand (FasL), interferon-gamma (IFN-gamma), tumor necrosis factor (TNF)-alpha, and interleukin-18 gene expression in peripheral blood mononuclear cells was examined in 36 patients treated with CsA after SCT. Quantitative real-time polymerase chain reaction analysis revealed that perforin/granzyme B, TNF-alpha, and interleukin-18 messenger RNA (mRNA) levels in peripheral blood mononuclear cells from patients in whom autoGVHD developed were markedly higher (and temporally associated with the onset of autoaggression) compared with the levels detected in healthy individuals and in control, non-CsA-treated SCT patients. It is interesting to note that patients in whom autoGVHD did not develop also demonstrated increased mRNA levels for these cytokines: however, expression was substantially lower compared with that in patients with autoGVHD. It is important to note that IFN-gamma mRNA levels were selectively increased in CD8+ cells only from patients in whom autoGVHD developed. The development of autocytolytic T cells in autoGVHD correlated with increased expression of perforin, IFN-gamma, and TNF-alpha mRNA. Furthermore, enhanced autoreactive T-cell activity and the induction of autoGVHD was also concordant with perforin and TNF-alpha mRNA upregulation in CD4+ cells. Surprisingly, FasL mRNA levels were significantly decreased, with a progressive loss of FasL mRNA expression as autocytolytic activity increased. These findings suggest that IFN-gamma/perforin-based CD8+ cytotoxic T lymphocytes seem to play a dominant role in autoGVHD and that TNF-alpha/perforin-based CD4+ cells may amplify this autoaggressive syndrome. The FasL pathway may play an important role in the regulation of this immune syndrome.
The Sidney Kimmel Comprehensive Cancer Research Center at Johns Hopkins University, Baltimore, MD 21231, USA.
Yuji
Y
Miura
Christopher J
CJ
Thoburn
Emilie C
EC
Bright
Allan D
AD
Hess
D000293:Adolescent; D000328:Adult; D000368:Aged; D016026:Bone Marrow Transplantation; D001943:Breast Neoplasms / Q000601:surgery; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016572:Cyclosporine / Q000627:therapeutic use; D016207:Cytokines / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics* / Q000276:immunology; D053804:Granzymes; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014182:Transplantation, Autologous
D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D016572:Cyclosporine; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human