Interleukin-2 and regulatory T cells in graft-versus-host disease.
Interleukin-2 and regulatory T cells in graft-versus-host disease.
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DOI：
10.1056/nejmoa1108188
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发表时间：
2011-12-01
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影响因子：
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通讯作者：
Soiffer RJ
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作者：
Koreth J;Matsuoka K;Kim HT;McDonough SM;Bindra B;Alyea EP 3rd;Armand P;Cutler C;Ho VT;Treister NS;Bienfang DC;Prasad S;Tzachanis D;Joyce RM;Avigan DE;Antin JH;Ritz J;Soiffer RJ
调节性T（Treg）细胞的功能障碍已在多种炎性疾病中检测到，包括慢性移植物抗宿主病（GVHD）。白细胞介素-2对于Treg细胞生长、存活和活性至关重要。我们假设低剂量白细胞介素2可以优先增强体内Treg细胞并抑制慢性GVHD的临床表现。在这项观察性队列研究中，糖皮质激素治疗无效的慢性GVHD患者接受每日低剂量皮下注射白细胞介素-2（0.3×106、1×106或3×106 IU/m2体表面积），持续8周。终点是安全性、临床和免疫应答。经过4周的间歇期，有反应的患者可以接受白细胞介素-2治疗一段时间。共入组29例患者。无慢性GVHD进展或血液系统癌症复发。白细胞介素-2的最大耐受剂量为1×106 IU/m2。最高剂量水平诱导了不可接受的全身症状。在23例可评价缓解的患者中，12例发生了涉及多个部位的主要缓解。所有患者的CD 4 + Treg细胞数量均优先增加，在4周时达到峰值中位数，是基线值的8倍以上（P<0.001），而不影响CD 4+常规T（Tcon）细胞。Treg：Tcon比率增加到基线值的五倍以上的中值（P<0.001）。Treg细胞计数和Treg：Tcon比率在8周时保持升高（与基线值相比均P<0.001），然后在患者未接受白细胞介素-2时下降。Treg细胞数量的增加表达转录因子叉头盒P3（FOXP 3），并可抑制自体Tcon细胞。长期接受白细胞介素-2治疗的患者可维持免疫和临床反应，从而使糖皮质激素剂量平均减少60%（范围为25至100）。每日低剂量白细胞介素-2可安全用于糖皮质激素治疗无效的慢性GVHD患者。给药与体内Treg细胞的优先、持续扩增和相当大比例患者慢性GVHD表现的改善相关。（由丹娜法伯邓肯甜甜圈上升星星奖和其他人资助; ClinicalTrials.gov编号，NCT 00529035。）
Dysfunction of regulatory T (Treg) cells has been detected in diverse inflammatory disorders, including chronic graft-versus-host disease (GVHD). Interleukin-2 is critical for Treg cell growth, survival, and activity. We hypothesized that low-dose interleukin-2 could preferentially enhance Treg cells in vivo and suppress clinical manifestations of chronic GVHD. In this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous interleukin-2 (0.3×106, 1×106, or 3×106 IU per square meter of body-surface area) for 8 weeks. The end points were safety and clinical and immunologic response. After a 4-week hiatus, patients with a response could receive interleukin-2 for an extended period. A total of 29 patients were enrolled. None had progression of chronic GVHD or relapse of a hematologic cancer. The maximum tolerated dose of interleukin-2 was 1×106 IU per square meter. The highest dose level induced unacceptable constitutional symptoms. Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites. The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than eight times the baseline value (P<0.001), without affecting CD4+ conventional T (Tcon) cells. The Treg:Tcon ratio increased to a median of more than five times the baseline value (P<0.001). The Treg cell count and Treg:Tcon ratio remained elevated at 8 weeks (P<0.001 for both comparisons with baseline values), then declined when the patients were not receiving interleukin-2. The increased numbers of Treg cells expressed the transcription factor forkhead box P3 (FOXP3) and could inhibit autologous Tcon cells. Immunologic and clinical responses were sustained in patients who received interleukin-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60% (range, 25 to 100). Daily low-dose interleukin-2 was safely administered in patients with active chronic GVHD that was refractory to glucocorticoid therapy. Administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic GVHD in a substantial proportion of patients. (Funded by a Dana–Farber Dunkin' Donuts Rising Star award and others; ClinicalTrials.gov number, NCT00529035.)