Kennedy-Nasser Alana A, Ku Stephanie, Castillo-Caro Paul, Hazrat Yasmin, Wu Meng-Fen, Liu Hao, Melenhorst Jos, Barrett A John, Ito Sawa, Foster Aaron, Savoldo Barbara, Yvon Eric, Carrum George, Ramos Carlos A, Krance Robert A, Leung Kathryn, Heslop Helen E, Brenner Malcolm K, Bollard Catherine M
Authors' Affiliations: Center for Cell and Gene Therapy, Dan L. Duncan Cancer Center, Baylor College of Medicine; The Methodist Hospital, Houston, Texas; and National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
Clin Cancer Res. 2014 Apr 15;20(8):2215-25. doi: 10.1158/1078-0432.CCR-13-3205. Epub 2014 Feb 26.
GVHD after allogeneic hematopoietic stem cell transplantation (alloSCT) has been associated with low numbers of circulating CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs). Because Tregs express high levels of the interleukin (IL)-2 receptor, they may selectively expand in vivo in response to doses of IL-2 insufficient to stimulate T effector T-cell populations, thereby preventing GVHD.
We prospectively evaluated the effects of ultra low-dose (ULD) IL-2 injections on Treg recovery in pediatric patients after alloSCT and compared this recovery with Treg reconstitution post alloSCT in patients without IL-2. Sixteen recipients of related (n = 12) or unrelated (n = 4) donor grafts received ULD IL-2 post hematopoietic stem cell transplantation (HSCT; 100,000-200,000 IU/m(2) ×3 per week), starting <day 30 and continuing for 6 to 12 weeks.
No grade 3/4 toxicities were associated with ULD IL-2. CD4(+)CD25(+)FoxP3(+) Tregs increased from a mean of 4.8% (range, 0%-11.0%) pre IL-2 to 11.1% (range, 1.2%-31.1%) following therapy, with the greatest change occurring in the recipients of matched related donor (MRD) transplants. No IL-2 patients developed grade 2-4 acute GVHD (aGVHD), compared with 4 of 33 (12%) of the comparator group who did not receive IL-2. IL-2 recipients retained T cells reactive to viral and leukemia antigens, and in the MRD recipients, only 2 of 13 (15%) of the IL-2 patients developed viral infections versus 63% of the comparator group (P = 0.022).
Hence, ULD IL-2 is well tolerated, expands a Treg population in vivo, and may be associated with a lower incidence of viral infections and GVHD.
异基因造血干细胞移植（alloSCT）后的移植物抗宿主病（GVHD）与循环中CD4(+)CD25(+)FoxP3(+)调节性T细胞（Tregs）数量减少有关。由于Tregs表达高水平的白细胞介素（IL）-2受体，它们可能在体内对不足以刺激效应T细胞群体的IL-2剂量作出反应而选择性扩增，从而预防GVHD。
我们前瞻性评估了超低剂量（ULD）IL-2注射对alloSCT后儿科患者Treg恢复的影响，并将这种恢复与未接受IL-2的alloSCT患者的Treg重建情况进行比较。16例接受相关（n = 12）或无关（n = 4）供体移植物的受者在造血干细胞移植（HSCT）后接受ULD IL-2（100,000 - 200,000 IU/m(2)×每周3次），在第30天之前开始并持续6至12周。
ULD IL-2未出现3/4级毒性反应。CD4(+)CD25(+)FoxP3(+) Tregs从IL-2治疗前的平均4.8%（范围0% - 11.0%）增加到治疗后的11.1%（范围1.2% - 31.1%），最大变化发生在接受匹配相关供体（MRD）移植的受者中。未接受IL-2的患者未发生2 - 4级急性GVHD（aGVHD），而未接受IL-2的对照组33例中有4例（12%）发生。接受IL-2的受者保留了对病毒和白血病抗原具有反应性的T细胞，在MRD受者中，13例接受IL-2的患者中只有2例（15%）发生病毒感染，而对照组为63%（P = 0.022）。
因此，ULD IL-2耐受性良好，可在体内扩增Treg群体，并且可能与较低的病毒感染和GVHD发生率相关。
