Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall antigen
Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall antigen
复制标题
DOI：
10.1182/blood-2011-06-363408
复制
发表时间：
2011-11-10
期刊：
影响因子：
20.3
通讯作者：
Young, James W.
中科院分区：
文献类型：
--
作者：
Betts, Brian C.;Abdel-Wahab, Omar;Young, James W.
Janus激酶 - 2（JAK2）通过对信号转导和转录激活因子3（STAT3）的磷酸化，传递包括白细胞介素 - 6（IL - 6）在内的几种炎性细胞因子的受体结合信号。我们证实，在人T细胞与同种异体单核细胞衍生的树突状细胞初次接触过程中，TG101348对JAK2的选择性抑制作用，会在再次接触相同同种抗原时诱导持久、显著且特异性的T细胞耐受。非同种反应性T细胞对致病性普通抗原从头刺激的后续反应保持完整。当TG101348仅在同种抗原再刺激期间存在时，它也会抑制已致敏T细胞的反应。TG101348消除IL - 6 / JAK2介导的STAT3磷酸化，但对IL - 2或IL - 15 / JAK3 / pSTAT5依赖性信号传导无脱靶效应，这些信号传导维持调节性T细胞（Tregs）和其他效应T细胞的反应。JAK2抑制可保持Treg数量，从而提高CD4(+)Tregs与CD8(+)CD25(+)效应T细胞的比例，有利于Tregs。JAK2抑制还可减少同种异体混合淋巴细胞反应（MLRs）中IL - 6和肿瘤坏死因子 - α的产生，削弱中枢记忆T细胞和效应记忆T细胞的活化以及应答性Th1和Th17细胞的扩增。虽然我们已经报道了单独抑制白细胞介素 - 6受体 - α对树突状细胞刺激的同种异体反应性的局限性，但我们在此证明JAK2是一个控制移植物抗宿主病（GVHD）或同种异体移植排斥反应且无更广泛免疫损伤的相关生物学靶点。（《血液》2011年；118(19)：5330 - 5339）
Janus kinase-2 (JAK2) conveys receptor-binding signals by several inflammatory cytokines, including IL-6, via phosphorylation of signal transducer and activator of transcription 3 (STAT3). We demonstrate that selective JAK2 inhibition by TG101348 during initial encounters between human T cells and allogeneic monocyte-derived dendritic cells induces durable, profound, and specific T-cell tolerance upon reexposure to the same alloantigens. Subsequent responses by nonalloreactive T cells to stimulation de novo by a pathogenic nominal antigen remain intact. TG101348 also suppresses primed T-cell responses when present only during alloantigen restimulation. TG101348 ablates IL-6/JAK2-mediated phosphorylation of STAT3, but has no off-target effects on IL-2 or IL-15/JAK3/pSTAT5-dependent signaling, which sustain the responses of regulatory T cells ( Tregs) and other effector T cells. JAK2 inhibition preserves Treg numbers and thereby enhances the ratio of CD4(+) Tregs to CD8(+)CD25(+) effector T cells in favor of Tregs. JAK2 inhibition also reduces the production of IL-6 and TNF-alpha in allogeneic MLRs, impairing the activation of central and effector memory T cells as well as the expansion of responder Th1 and Th17 cells. While we have reported the limitations of isolated IL-6R-alpha inhibition on dendritic cell-stimulated alloreactivity, we demonstrate here that JAK2 represents a relevant biologic target for controlling GVHD or allograft rejection without broader immune impairment. (Blood. 2011; 118(19): 5330-5339)