Prevention of acute GVHD using an orthogonal IL-2/IL-2Rβ system to selectively expand regulatory T cells in vivo

被引：23

作者：

Ramos, Teresa L. ^{[1
]}

Bolivar-Wagers, Sara ^{[2
,3
]}

Jin, Sujeong ^{[2
,3
]}

Thangavelu, Govindarajan ^{[2
,3
]}

Simonetta, Federico ^{[1
,4
]}

Lin, Po-Yu ^{[1
]}

Hirai, Toshihito ^{[1
,5
]}

Saha, Asim ^{[2
,3
]}

Koehn, Brent ^{[2
,3
]}

Su, Leon L. ^{[6
]}

Picton, Lora K. ^{[6
]}

Baker, Jeanette ^{[1
]}

Lohmeyer, Juliane K. ^{[1
]}

Riddle, Megan ^{[2
,3
]}

Eide, Cindy ^{[2
,3
]}

Tolar, Jakub ^{[2
,3
]}

Panoskaltsis-Mortari, Angela ^{[2
,3
]}

Wagner, John E. ^{[2
,3
]}

Garcia, K. Christopher ^{[6
]}

Nogrin, Robert S. ^{[1
]}

Blazar, Bruce R. ^{[2
,3
]}

机构：

[1] Stanford Univ, Dept Med, Div Blood & Marrow Transplantat & Cellular Therapy, 269 W Campus Dr,Room 2205, Stanford, CA 94305 USA

[2] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplant & Cellular Therapy, Minneapolis, MN 55455 USA

[3] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA

[4] Univ Geneva, Fac Med, Translat Res Ctr Oncohematol, Dept Internal Med Specialties, Geneva, Switzerland

[5] Tokyo Womens Med Univ, Dept Urol, Tokyo, Japan

[6] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Dept Struct Biol, Stanford, CA 94305 USA

来源：

BLOOD | 2023年 / 141卷 / 11期

基金：

美国国家卫生研究院;

关键词：

VERSUS-HOST-DISEASE; ALLOGENEIC BONE-MARROW; LOW-DOSE INTERLEUKIN-2; ENGRAFTMENT; THERAPIES; INFUSION; PROFILE; MICE;

D O I：

10.1182/blood.2022018440

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with hematological disorders and bone marrow (BM) failure syndromes. Graft-versus-host disease (GVHD) remains a leading cause of morbidity posttransplant. Regulatory T cell (Treg) therapies are efficacious in ameliorating GVHD but limited by variable suppressive capacities and the need for a high therapeutic dose. Here, we sought to expand Treg in vivo by expressing an orthogonal interleukin 2 receptor beta (oIL-2R beta) that would selectively interact with oIL-2 cytokine and not wild-type (WT) IL-2. To test whether the orthogonal system would preferentially drive donor Treg expansion, we used a murine major histocompatibility complex-disparate GVHD model of lethally irradiated BALB/c mice given T cell-depleted BM from C57BL/6 (B6) mice alone or together with B6(Foxp3+GFP+) Treg or oIL-2R beta-transduced Treg at low cell numbers that typically do not control GVHD with WT Treg. On day 2, B6 activated T cells (Tcons) were injected to induce GVHD. Recipients were treated with phosphate-buffered saline (PBS) or oIL-2 daily for 14 days, then 3 times weekly for an additional 14 days. Mice treated with oIL-2R beta Treg and oIL-2 compared with those treated with PBS had enhanced GVHD survival, in vivo selective expansion of Tregs, and greater suppression of Tcon expansion in secondary lymphoid organs and intestines. Importantly, oIL-2R beta Treg maintained graft-versus-tumor (GVT) responses in 2 distinct tumor models (A20 and MLL-AF9). These data demonstrate a novel approach to enhance the efficacy of Treg therapy in allo-HSCT using an oIL-2/oIL-2R beta system that allows for selective in vivo expansion of Treg leading to GVHD protection and GVT maintenance.

引用

页码：1337 / 1352

页数：16

共 52 条

[51] Acute Graft-versus-Host Disease - Biologic Process, Prevention, and Therapy [J].