Abstract:
:The improvement of graft survival over the past decade has mainly been due to the development of more highly specific immunosuppressive agents, such as cyclosporine (CsA) and FK506. CsA and FK506 inhibit T cell activation by interfering with the calcium-mediated pathway, one of two pathways needed for T cell activation. The other pathway, mediated by protein kinase C (PKC), is not currently a target of any clinically used immunosuppressive agent. The purpose of this study was to assess the immunosuppressive properties of Ro 31-8220, a member of a new family of potent and selective PKC inhibitors. Peripheral blood mononuclear cells were isolated from the blood of normal human donors and utilized in a series of standard immunological assays. Three discrete activation events were inhibited by Ro 31-8220: mitogen-induced interleukin (IL)-2 production (IC50 80 nM), IL-2-dependent T lymphoblast proliferation (IC50 350 nM), and IL-2Ralpha (CD25) expression (control cells were 83% CD25+, mean fluorescence intensity = 163 +/- 4, 400-nM-treated cells were 56% CD25+, mean fluorescence intensity = 130 +/- 7). Noninhibitory doses of CsA (8 nM) or FK506 (0.2 nM) suppressed mitogen-induced IL-2 production by 60-80% when combined with a noninhibitory dose (25 nM) of Ro 31-8220, indicating the potent synergy between these agents. The ability of Ro 31-8220 to inhibit both early and late activation events and to synergize with CsA/FK506 suggests that this family of compounds has great potential as immunosuppressive agents and as probes with which to elucidate the role of PKC in T cell activation.
journal_name
Transplantationjournal_title
Transplantationauthors
Geiselhart L,Conti DJ,Freed BMdoi
10.1097/00007890-199606150-00015subject
Has Abstractpub_date
1996-06-15 00:00:00pages
1637-42issue
11eissn
0041-1337issn
1534-6080journal_volume
61pub_type
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