Prevention of human helper T-cell clone activation by cyclosporin A also blocks secretion of granulocyte/macrophage colony stimulating activity.
Cyclosporin A (CsA) blocks stimulation and growth of alloreactive T helper cell clones (Th-TCC), even in the presence of exogenous Interleukin-2 (IL-2). To examine whether this might reflect a generalised inhibition of cytokine production by these cells, their production of granulocyte/macrophage colony-stimulating factors (GM-CSF), thought not to be involved in the autocrine proliferation of the clones themselves, was investigated. Contrary to the prediction that only pathways relevant to T cell clonal expansion would be blocked by CsA, it was found that this immunosuppressive substance exerted a profound inhibitory activity on GM-CSF secretion, even in the presence of exogenous IL-2. Although a higher concentration of CsA was required to block GM-CSF secretion than to block proliferation, the former was not due to toxic effects on the cells, or permanently switching off the genes for GM-CSF, since upon further cultivation of the clones without CsA, alloantigen-specific responsiveness was restored. These results therefore show that clonal human T helper cell populations are sensitive to inhibition of GM-CSF secretion by CsA. Part of the immunosuppressive mechanism of action of CsA may therefore reside in this activity, since blockade of GM-CSF secretion by T helper cells would influence functional activities of antigen presenting cells.
Pawelec
G
G
Immunology Laboratory, 2nd Department of Internal Medicine, University Medical Clinic, Tübingen, F.R.G.
Rehbein
A
A
Katrilaka
K
K
Balko
I
I
Busch
F W
FW
D002999:Clone Cells; D003115:Colony-Stimulating Factors / Q000378:metabolism*; D003198:Computer Simulation; D003524:Cyclosporins / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008954:Models, Biological; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism
D003115:Colony-Stimulating Factors; D003524:Cyclosporins; D006133:Growth Substances; D007376:Interleukin-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor