Consequently, it would appear that monocyte synthesis Regorafenib clinical trial of IL-10, in response to TG, is under

direct control of TG-specific cells within the T-cell population. The primary purpose of this study was to determine whether human T cells, responding to in vitro challenge with the autoantigen TG, do so as naive or antigen-experienced cells. Furthermore, it was of interest to establish whether their stimulation results in a pro-inflammatory or an anti-inflammatory cytokine response, indicating inductive or protective roles, respectively, in the development of autoimmunity. The CD4+ T-cell proliferative responses to TG and TT resembled each other closely, whereas CD4+ T-cell proliferation in response to KLH was delayed by approximately 2 days. Given that the kinetics of the TT and KLH responses are typical for memory and naive lymphocytes, respectively, the kinetics of response to TG would indicate that the TG-specific T cells have had previous exposure to this autoantigen in vivo. The possibility that the normal human PBMC might be responding to foreign allelic determinants on the administered

autoantigen19 is, therefore, effectively excluded, because such recognition would be of a primary nature. In keeping with their common status as recall Transmembrane Transporters modulator antigens, TT and TG induced vigorous cytokine production from the first day of challenge, whereas KLH only elicited a small amount of TNF-α. However, the cytokine profiles elicited by TT and TG were quite distinct, in that TT induced the rapid secretion of the Th1 cytokines IL-2 and IFN-γ, whereas TG elicited release of TNF-α, IL-4, IL-10 and only a small OSBPL9 amount of IL-2. While TNF-α is regarded as a pro-inflammatory cytokine, IL-10 (produced by the T-cell subset regulatory type 1 T cells,20 B cells21

and monocytes22) is a potent immunoregulator and may protect against autoimmunity by inducing immature dendritic cells to become tolerogenic.23 Interleukin-4 is a classic Th2-cytokine, implicated in protection against thyroiditis,17,24 diabetes9,16,25 and arthritis15 in mice, and in regulation of Th1-responses in humans.18 The protective effect of IL-4 appears to be exerted in concert with IL-10.15,18 It would therefore appear that the pro-inflammatory response to TG by PBMC from healthy donors is counteracted by an anti-inflammatory response. In the subsequent phase of the responses, IL-10 dominated the cytokine response to TG for most donors (67%), although a low level of TNF-α and traces of IFN-γ and IL-5 (at one or two orders of magnitude lower than those seen with TT stimulation) were also detectable. Furthermore, IL-4 was undetectable at day 5, but showed recovery on day 7.