Inhibition of the human allogeneic mixed lymphocyte response by cyclosporin A: relationship with the IL-12 pathway.
Interleukin-12 (IL-12) is an important cytokine in the control of cell-mediated immunity. We have previously shown that endogenous IL-12 plays a role in the development of human allogeneic response. In the present study, we investigated the relationship between Cyclosporin A (CsA)-inhibitory effect and IL-12 pathway during human alloreaction in vitro. CsA addition at the sensitizing phase of primary mixed lymphocyte reaction (MLR) resulted in the inhibition of both p40 and p70 IL-12 production in a dose-dependent manner. In contrast, CsA had no effect on IL-12-receptor beta 1 chain (IL-12 R beta 1) expression in T cells induced upon allogeneic activation. Addition of exogenous IL-12 significantly restored CsA-inhibited alloreactive cytotoxic T lymphocyte (CTL) generation and had a marginal effect on T cell proliferative response. The IL-12-induced restoration of CTL generation was IFN gamma-mediated, as it was significantly altered when anti-IFN gamma was added. The restoration of CTL activity by exogenous IL-12 correlated with the capacity of this cytokine to partially restore granzyme B mRNA expression in alloreactive CTL. This study indicates that inhibition of IL-12 production is a novel additional mechanism for the inhibitory effect of CsA on the development of human allogeneic cytotoxic response.
Bonnotte
B
B
CJF 94-8 INSERM, Faculté de Médicine, Dijon, France.
Pardoux
C
C
Bourhis
J H
JH
Caignard
A
A
Burdiles
A M
AM
Chehimi
J
J
Mami-Chouaib
F
F
Chouaib
S
S
D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D053804:Granzymes; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D051381:Rats; D018123:Receptors, Interleukin / Q000276:immunology*; D053707:Receptors, Interleukin-12; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology
C508444:Il12rb2 protein, rat; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D007371:Interferon-gamma; D016572:Cyclosporine; C509213:GZMB protein, human; D053804:Granzymes; C509215:Gzmb protein, rat; D012697:Serine Endopeptidases