The protein kinase C inhibitor sotrastaurin allows regulatory T cell function.
The novel immunosuppressant sotrastaurin is a selective inhibitor of protein kinase C isoforms that are critical in signalling pathways downstream of the T cell receptor. Sotrastaurin inhibits nuclear factor (NF)-κB, which directly promotes the transcription of forkhead box protein 3 (FoxP3), the key regulator for the development and function of regulatory T cells (Tregs). Our center participated in a randomized trial comparing sotrastaurin (n = 14) and the calcineurin inhibitor Neoral (n = 7) in renal transplant recipients. We conducted ex vivo mixed lymphocyte reaction (MLR) and flow cytometry studies on these patient samples, as well as in vitro studies on samples of blood bank volunteers (n = 38). Treg numbers remained stable after transplantation and correlated with higher trough levels of sotrastaurin (r = 0·68, P = 0·03). A dose-dependent effect of sotrastaurin on alloresponsiveness was observed: the half maximal inhibitory concentration (IC50 ) to inhibit alloactivated T cell proliferation was 45 ng/ml (90 nM). In contrast, Treg function was not affected by sotrastaurin: in the presence of in vitro-added sotrastaurin (50 ng/ml) Tregs suppressed the proliferation of alloactivated T effector cells at a 1:5 ratio by 35 versus 47% in the absence of the drug (P = 0·33). Signal transducer and activator of transcription 5 (STAT)-5 phosphorylation in Tregs remained intact after incubation with sotrastaurin. This potent Treg function was also found in cells of patients treated with sotrastaurin: Tregs inhibited the anti-donor response in MLR by 67% at month 6, which was comparable to pretransplantation (82%). Sotrastaurin is a potent inhibitor of alloreactivity in vitro, while it did not affect Treg function in patients after kidney transplantation.
['de Weerd|A|A|', 'Kho|M|M|', 'Kraaijeveld|R|R|', 'Zuiderwijk|J|J|', 'Weimar|W|W|', 'Baan|C|C|']
D000328:Adult D015704:CD4 Antigens D049109:Cell Proliferation D016572:Cyclosporine D005260:Female D005434:Flow Cytometry D051858:Forkhead Transcription Factors D006801:Humans D007166:Immunosuppressive Agents D053645:Interleukin-2 Receptor alpha Subunit D016030:Kidney Transplantation D018655:Lymphocyte Count D007959:Lymphocyte Culture Test, Mixed D008297:Male D008875:Middle Aged D016328:NF-kappa B D010766:Phosphorylation D011493:Protein Kinase C D011758:Pyrroles D011799:Quinazolines D050799:STAT5 Transcription Factor D015398:Signal Transduction D050378:T-Lymphocytes, Regulatory
sotrastaurin regulatory T cells kidney transplantation autoimmunity