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

Ramos, Teresa L. ; Bolivar-Wagers, Sara ; Jin, Sujeong ; Thangavelu, Govindarajan ; Simonetta, Federico ; Lin, Po-Yu ; Hirai, Toshihito ; Saha, Asim ; Koehn, Brent ; Su, Leon L. ; Picton, Lora K. ; Baker, Jeanette ; Lohmeyer, Juliane K. ; Riddle, Megan ; Eide, Cindy ; Tolar, Jakub ; Panoskaltsis-Mortari, Angela ; Wagner, John E. ; Garcia, K. Christopher ; Negrin, Robert S. ; Blazar, Bruce R.

Blood, 2023-03, Vol.141 (11), p.1337-1352 [Periódico revisado por pares]

United States: Elsevier Inc

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  • Título:
    Prevention of acute GVHD using an orthogonal IL-2/IL-2Rβ system to selectively expand regulatory T cells in vivo
  • Autor: Ramos, Teresa L. ; Bolivar-Wagers, Sara ; Jin, Sujeong ; Thangavelu, Govindarajan ; Simonetta, Federico ; Lin, Po-Yu ; Hirai, Toshihito ; Saha, Asim ; Koehn, Brent ; Su, Leon L. ; Picton, Lora K. ; Baker, Jeanette ; Lohmeyer, Juliane K. ; Riddle, Megan ; Eide, Cindy ; Tolar, Jakub ; Panoskaltsis-Mortari, Angela ; Wagner, John E. ; Garcia, K. Christopher ; Negrin, Robert S. ; Blazar, Bruce R.
  • Assuntos: Animals ; Bone Marrow Transplantation ; Cytokines ; Graft vs Host Disease - prevention & control ; Interleukin-2 - pharmacology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neoplasms ; T-Lymphocytes, Regulatory
  • É parte de: Blood, 2023-03, Vol.141 (11), p.1337-1352
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
  • Descrição: •oIL-2Rβ Tregs can be selectively expanded in vivo with oIL-2 administered after allo-HSCT.•Smaller numbers of oIL-2Rβ Tregs–oIL-2 are needed to reduce clinical scores, improve GVHD survival, and maintain GVT responses. [Display omitted] 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 β (oIL-2Rβ) 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 B6Foxp3+GFP+ Treg or oIL-2Rβ–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-2Rβ 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-2Rβ 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-2Rβ system that allows for selective in vivo expansion of Treg leading to GVHD protection and GVT maintenance.
  • Editor: United States: Elsevier Inc
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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