GM-CSF restores innate, but not adaptive, immune responses in glucocorticoid-immunosuppressed human blood in vitro.
Infection remains the major complication of immunosuppressive therapy in organ transplantation. Therefore, reconstitution of the innate immunity against infections, without activation of the adaptive immune responses, to prevent graft rejection is a clinically desirable status in transplant recipients. We found that GM-CSF restored TNF mRNA and protein expression without inducing IL-2 production and T cell proliferation in glucocorticoid-immunosuppressed blood from either healthy donors or liver transplant patients. Gene array experiments indicated that GM-CSF selectively restored a variety of dexamethasone-suppressed, LPS-inducible genes relevant for innate immunity. A possible explanation for the lack of GM-CSF to restore T cell proliferation is its enhancement of the release of IL-1betaR antagonist, rather than of IL-1beta itself, since exogenously added IL-1beta induced an IL-2-independent Con A-stimulated proliferation of glucocorticoid-immunosuppressed lymphocytes. Finally, to test the in vivo relevance of our findings, we showed that GM-CSF restored the survival of dexamethasone- or cyclosporine A-immunosuppressed mice from an otherwise lethal infection with Salmonella typhimurium. In addition to this increased resistance to infection, GM-CSF did not induce graft rejection of a skin allotransplant in cyclosporine A-immunosuppressed mice. The selective restoration potential of GM-CSF suggests its therapeutic use in improving the resistance against infections upon organ transplantation.
Xu
Jian
J
Biochemical Pharmacology, University of Konstanz, Konstanz, Germany.
Lucas
Rudolf
R
Schuchmann
Marcus
M
Kühnle
Simone
S
Meergans
Thomas
T
Barreiros
Ana P
AP
Lohse
Ansgar W
AW
Otto
Gerd
G
Wendel
Albrecht
A
D000276:Adjuvants, Immunologic / Q000097:blood* / Q000502:physiology; D000328:Adult; D000368:Aged; D000818:Animals; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002469:Cell Separation; D003208:Concanavalin A / Q000494:pharmacology; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis; D003907:Dexamethasone / Q000097:blood* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000401:mortality / Q000517:prevention & control; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood* / Q000502:physiology; D006801:Humans; D007110:Immunity, Active / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000097:blood* / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007376:Interleukin-2 / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008808:Mice, Inbred CBA; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D012481:Salmonella Infections, Animal / Q000276:immunology / Q000401:mortality / Q000517:prevention & control; D016038:Skin Transplantation / Q000276:immunology / Q000401:mortality; D015996:Survival Rate; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D007376:Interleukin-2; D008070:Lipopolysaccharides; D025521:Tumor Suppressor Proteins; D003208:Concanavalin A; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases