Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1337-1352 |
| Number of pages | 16 |
| Journal | Blood |
| Volume | 141 |
| Issue number | 11 |
| DOIs | |
| State | Published - Mar 16 2023 |
Bibliographical note
Funding Information:This work was supported by grants from the National Institute of Allergy and Infectious Diseases , National Institutes of Health (NIH) and National Heart, Lung, and Blood Institute (NHLBI) , NIH (grant numbers NIH R01 56067 , R37 AI34495 , R01 HL11879 , R01 HL155114 , P01 AI056299 , T32 AI007313 , and F30HL156312 ). This work was supported by grants from the NIH, NHLBI ( P01 HL075462 ) (R.S.N.). Flow cytometry analysis and sorting were performed on instruments in the Stanford Shared FACS Facility purchased using a NIH S10 Shared Instrumentation Grant ( S10RR027431-01 ).
Funding Information:
The authors thank Xuhuai Ji at the Stanford Functional Genomics Facility for their excellent technical assistance in the genomic analysis. This work was supported by grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) and National Heart, Lung, and Blood Institute (NHLBI), NIH (grant numbers NIH R01 56067, R37 AI34495, R01 HL11879, R01 HL155114, P01 AI056299, T32 AI007313, and F30HL156312). This work was supported by grants from the NIH, NHLBI (P01 HL075462) (R.S.N.). Flow cytometry analysis and sorting were performed on instruments in the Stanford Shared FACS Facility purchased using a NIH S10 Shared Instrumentation Grant (S10RR027431-01). Contribution: T.L.R. and S.B.-W. conceived and designed the research studies and wrote the manuscript; S.B.-W. T.L.R. S.J. G.T. F.S. T.H. and P.-Y.L. conducted experiments; T.L.R. F.S. J.K.L. and A.S. analyzed data; B.K. L.L.S. and L.K.P. developed methodology and analyzed data; J.B. developed methodology and provided essential reagents; J.K.L. M.R. C.E. J.T. A.P.-M. J.E.W. and K.C.G. provided essential tools and intellectual input; and R.S.N. and B.R.B. supervised the research.
Publisher Copyright:
© 2023 The American Society of Hematology
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural