Complexity of effector mechanisms in cyclosporine-induced syngeneic graft-versus-host disease.
Administration of the immunosuppressive drug cyclosporine after syngeneic or autologous bone marrow transplantation elicits a T-lymphocyte-dependent autoimmune syndrome similar to graft-versus-host disease (GVHD). The onset of this autoaggression syndrome, termed syngeneic GVHD, is associated with the development of a highly restricted repertoire of CD8+ autoreactive T cells that recognize a peptide from the invariant chain, termed CLIP, presented by major histocompatibility complex (MHC) class II molecules. Clonal analysis reveals 2 distinct subsets of autoreactive T cells defined by their activation requirement for either the N-terminal or the C-terminal flanking regions of CLIP and by their cytokine profile. The studies here reveal that the autoreactive T-cell clones requiring the N-terminal flanking region of CLIP produce type 1 cytokines (interferon [IFN]-gamma, interleukin [IL]-2, and tumor necrosis factor-alpha). In contrast, the autoreactive T-cell clones that require the C-terminal flanking region of CLIP produce type 2 cytokines (IL-4, IL-10, transforming growth factor-beta). As assessed in a local graft-versus-host reaction assay, the N-terminal flanking-restricted clones mediate changes consistent with acute GVHD, whereas the clones responsive to the C-terminal flanking region do not. Moreover, the autoreactive T-cell clones restricted by the C-terminal flanking region of CLIP ameliorate the pathogenic potential of the cells responsive to the N-terminal flanking region of CLIP. The mechanism accounting for this regulatory affect appears to be the downregulation of mRNA message for type 1 cytokines (IFN-gamma and IL-2). The C-terminal-restricted autoreactive T-cell clones, however, could manifest disease with dermal changes similar to those seen in chronic syngeneic GVHD, provided that IFN-gamma was present. Consistent with these observations was the demonstration that type 1 cytokines are preferentially detected during the acute phase of syngeneic GVHD, whereas type 2 cytokines dominate during the chronic phase. The results suggest that acute and chronic syngeneic GVHD is mediated by distinct autoreactive T cells, which are separated by their fine specificity for the CLIP-MHC class II complex and by their cytokine profiles.
Hess
A D
AD
Division of Immunology and Hematopoiesis, Oncology Center, The Johns Hopkins University, Baltimore, Maryland 21231, USA. adhess@jhmi.edu
Thoburn
C J
CJ
Chen
W
W
Horwitz
L R
LR
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002999:Clone Cells / Q000276:immunology / Q000637:transplantation; D018920:Coculture Techniques; D016572:Cyclosporine; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006086:Graft vs Host Disease / Q000139:chemically induced / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D007376:Interleukin-2 / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014185:Transplantation, Isogeneic
D016207:Cytokines; D007376:Interleukin-2; D012333:RNA, Messenger; D007371:Interferon-gamma; D016572:Cyclosporine