PDF(Pubmed)
Abstract：
UNASSIGNED: Farnesyltransferase inhibitors (FTI), which inhibit the prenylation of Ras GTPases, were developed as anti-cancer drugs. As additional target proteins for prenylation were identified in the past, it is likely that FTI have potential value for therapeutic purposes beyond cancer. The effect of FTI on B-cells remains unclear. To address this issue, we investigated the effects of in vitro FTI treatment on effector and regulatory B-cells in healthy controls and renal transplant patients.
UNASSIGNED: For this purpose, B-cells were isolated from the peripheral blood of healthy controls and renal transplant patients. Purified B-cells were stimulated via Toll-like-receptor 9 (TLR-9) in the presence or absence of FTI. Regulatory functions, such as IL-10 and Granzyme B (GrB) secretion, were assessed by flow cytometry. In addition, effector B-cell functions, such as plasma cell formation and IgG secretion, were studied.
UNASSIGNED: The two FTI Lonafarnib and tipifarnib both suppressed TLR-9-induced B-cell proliferation. Maturation of IL-10 producing B-cells was suppressed by FTI at high concentrations as well as induction of GrB-secreting B-cells. Plasma blast formation and IgG secretion were potently suppressed by FTI. Moreover, purified B-cells from immunosuppressed renal transplant patients were also susceptible to FTI-induced suppression of effector functions, evidenced by diminished IgG secretion.
UNASSIGNED: FTI suppress in vitro B-cell proliferation and plasma cell formation while partially preserving IL-10 as well as GrB production of B-cells. Thus, FTI may have immunosuppressive capacity encouraging further studies to investigate the potential immunomodulatory value of this agent.
UNASSIGNED: For this purpose, B-cells were isolated from the peripheral blood of healthy controls and renal transplant patients. Purified B-cells were stimulated via Toll-like-receptor 9 (TLR-9) in the presence or absence of FTI. Regulatory functions, such as IL-10 and Granzyme B (GrB) secretion, were assessed by flow cytometry. In addition, effector B-cell functions, such as plasma cell formation and IgG secretion, were studied.
UNASSIGNED: The two FTI Lonafarnib and tipifarnib both suppressed TLR-9-induced B-cell proliferation. Maturation of IL-10 producing B-cells was suppressed by FTI at high concentrations as well as induction of GrB-secreting B-cells. Plasma blast formation and IgG secretion were potently suppressed by FTI. Moreover, purified B-cells from immunosuppressed renal transplant patients were also susceptible to FTI-induced suppression of effector functions, evidenced by diminished IgG secretion.
UNASSIGNED: FTI suppress in vitro B-cell proliferation and plasma cell formation while partially preserving IL-10 as well as GrB production of B-cells. Thus, FTI may have immunosuppressive capacity encouraging further studies to investigate the potential immunomodulatory value of this agent.
摘要：
■法尼基转移酶抑制剂（FTI），抑制RasGTPases的戊烯化，被开发为抗癌药物。由于过去发现了用于戊烯化的其他靶蛋白，FTI可能在癌症以外的治疗目的方面具有潜在价值.FTI对B细胞的影响尚不清楚。为了解决这个问题，我们研究了体外FTI治疗对健康对照组和肾移植患者的效应细胞和调节性B细胞的影响.
■为此，从健康对照和肾移植患者的外周血中分离B细胞。在存在或不存在FTI的情况下,通过Toll样受体9(TLR-9)刺激纯化的B细胞。监管职能,如IL-10和颗粒酶B（GrB）的分泌，通过流式细胞术进行评估。此外,效应B细胞功能，如浆细胞形成和IgG分泌，被研究过。
■两种FTILonafarnib和替比法尼均抑制TLR-9诱导的B细胞增殖。高浓度的FTI抑制了产生IL-10的B细胞的成熟以及GrB分泌B细胞的诱导。FTI有效抑制了血浆母细胞的形成和IgG的分泌。此外，来自免疫抑制的肾移植患者的纯化B细胞也容易受到FTI诱导的效应子功能抑制，由减少的IgG分泌证明。
■FTI抑制体外B细胞增殖和浆细胞形成，同时部分保留IL-10以及B细胞的GrB产生。因此，FTI可能具有免疫抑制能力，鼓励进一步研究以研究该药物的潜在免疫调节价值。
■为此，从健康对照和肾移植患者的外周血中分离B细胞。在存在或不存在FTI的情况下,通过Toll样受体9(TLR-9)刺激纯化的B细胞。监管职能,如IL-10和颗粒酶B（GrB）的分泌，通过流式细胞术进行评估。此外,效应B细胞功能，如浆细胞形成和IgG分泌，被研究过。
■两种FTILonafarnib和替比法尼均抑制TLR-9诱导的B细胞增殖。高浓度的FTI抑制了产生IL-10的B细胞的成熟以及GrB分泌B细胞的诱导。FTI有效抑制了血浆母细胞的形成和IgG的分泌。此外，来自免疫抑制的肾移植患者的纯化B细胞也容易受到FTI诱导的效应子功能抑制，由减少的IgG分泌证明。
■FTI抑制体外B细胞增殖和浆细胞形成，同时部分保留IL-10以及B细胞的GrB产生。因此，FTI可能具有免疫抑制能力，鼓励进一步研究以研究该药物的潜在免疫调节价值。
