Efficacy and immunologic effects of extracorporeal photopheresis plus interleukin-2 in chronic graft-versus-host disease
Efficacy and immunologic effects of extracorporeal photopheresis plus interleukin-2 in chronic graft-versus-host disease
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DOI：
10.1182/bloodadvances.2018029124
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发表时间：
2019-04-09
期刊：
影响因子：
7.5
通讯作者：
Koreth, John
中科院分区：
文献类型：
--
作者：
Belizaire, Roger;Kim, Haesook T.;Koreth, John
慢性移植物抗宿主病（cGVHD）影响50%以上的造血干细胞移植患者。体外光造血（Extracorporeal photopheresis， ECP）是一种免疫调节疗法，可能通过调节性T （T-reg）和自然杀伤（NK）细胞扩增，为类固醇难治性（SR） cGVHD提供临床益处。我们证明了低剂量的白细胞介素-2 （IL2）可以改善SR-cGVHD的临床状况，并刺激T-reg和nk细胞的优先扩增，而对常规T细胞（T-con）的影响最小。在一项前瞻性2期试验中，我们评估了ECP（1 -16周）加IL2 (1 × 10（6) IU/m(2)， 9-16周）对25名成年SR-cGVHD患者的影响。在第8周（单独ECP）和第16周（ECP加IL2），分别有29%和62%的可评估患者出现客观反应。单独使用ECP 8周与CD4(+) T-con （P = 0.03）和CD8(+)T细胞（P = 0.0002）的显著下降有关，T-reg细胞、T-reg:T-con细胞比率或NK细胞的变化最小。添加IL2诱导T-reg细胞（9-16周与8周相比P < 0.05）、T-reg:T（con）细胞比率（9-16周与8周相比P < 0.0001）和NK细胞（9-16周与8周相比P < 0.05）增加。与加入IL2后有反应的患者和无反应的患者相比，单独接受ECP治疗的患者在基线时CD4(+) T-con和CD8(+) T细胞显著减少；t - regg和NK细胞均与单独ECP的反应无关。总之，ECP加IL2对SR-cGVHD患者是安全有效的。ECP和il - 2具有不同的免疫作用，提示不同的治疗机制。
Chronic graft-versus-host disease (cGVHD) affects >50% of hematopoietic stem cell transplant patients. Extracorporeal photopheresis (ECP), an immunomodulatory therapy, provides clinical benefit in steroid-refractory (SR) cGVHD, possibly via regulatory T (T-reg) and natural killer (NK) cell expansion. We demonstrated that low-dose interleukin-2 (IL2) led to clinical improvement in SR-cGVHD and stimulated preferential T-reg and NK-cell expansion with minimal effect on conventional T (T-con) cells. We evaluated the effect of ECP (weeks 1-16) plus IL2 (1 x 10(6) IU/m(2), weeks 9-16) in 25 adult patients with SR-cGVHD in a prospective phase 2 trial. Objective responses occurred in 29% and 62% of evaluable patients at weeks 8 (ECP alone) and 16 (ECP plus IL2), respectively. Eight weeks of ECP alone was associated with a marked decline in CD4(+) T-con, (P = .03) and CD8(+)T cells (P = .0002), with minimal change in T-reg cells, T-reg:T-con cell ratio, or NK cells. Adding IL2 induced an increase in T-reg cells (P < .05 at weeks 9-16 vs week 8), T-reg:T(con )cell ratio (P < .0001 at weeks 9-16 vs week 8), and NK cells (P < .05 at weeks 9-16 vs week 8). Patients responding to ECP alone had significantly fewer CD4(+) T-con, and CD8(+) T cells at baseline compared with patients who responded after IL2 addition and patients who did not respond; neither T-reg nor NK cells were associated with response to ECP alone. Altogether, ECP plus IL2 is safe and effective in patients with SR-cGVHD. ECP and IL2 have distinct immunologic effects, suggesting different therapeutic mechanisms of action.