Peritransplant glucocorticoids redistribute donor T cells to the bone marrow and prevent relapse after haploidentical SCT
Takayuki Inoue, Motoko Koyama, Katsuji Kaida, Kazuhiro Ikegame, Kathleen S. Ensbey, Luke Samson, Shuichiro Takahashi, Ping Zhang, Simone A. Minnie, Satoshi Maruyama, Shinichi Ishii, Takashi Daimon, Takahiro Fukuda, Hirohisa Nakamae, Takahide Ara, Yumiko Maruyama, Ken Ishiyama, Tatsuo Ichinohe, Yoshiko Atsuta, Bruce R. Blazar, Scott N. Furlan, Hiroyasu Ogawa, Geoffrey R. Hill
Takayuki Inoue, Motoko Koyama, Katsuji Kaida, Kazuhiro Ikegame, Kathleen S. Ensbey, Luke Samson, Shuichiro Takahashi, Ping Zhang, Simone A. Minnie, Satoshi Maruyama, Shinichi Ishii, Takashi Daimon, Takahiro Fukuda, Hirohisa Nakamae, Takahide Ara, Yumiko Maruyama, Ken Ishiyama, Tatsuo Ichinohe, Yoshiko Atsuta, Bruce R. Blazar, Scott N. Furlan, Hiroyasu Ogawa, Geoffrey R. Hill
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Research Article Transplantation

Peritransplant glucocorticoids redistribute donor T cells to the bone marrow and prevent relapse after haploidentical SCT

Abstract

Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes, with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities, but it typically requires intensive immunosuppression with posttransplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here, we demonstrate in preclinical models that glucocorticoid administration from days –1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the BM, promoting donor T cell residency. This results in significant reductions in GVHD while promoting potent GVL effects; relapse in recipients receiving glucocorticoids, vehicle, or PT-Cy was 12%, 56%, and 100%, respectively. Intriguingly, patients with acute myeloid leukemia not in remission who received unmanipulated haplo-SCT and peritransplant glucocorticoids also had an unexpectedly low relapse rate at 1 year (32%; 95% CI, 18%–47%) with high overall survival at 3 years (58%; 95% CI, 38%–74%). These data highlight a potentially simple and effective approach to prevent relapse in patients with otherwise incurable leukemia that could be studied in prospective randomized trials.

Authors

Takayuki Inoue, Motoko Koyama, Katsuji Kaida, Kazuhiro Ikegame, Kathleen S. Ensbey, Luke Samson, Shuichiro Takahashi, Ping Zhang, Simone A. Minnie, Satoshi Maruyama, Shinichi Ishii, Takashi Daimon, Takahiro Fukuda, Hirohisa Nakamae, Takahide Ara, Yumiko Maruyama, Ken Ishiyama, Tatsuo Ichinohe, Yoshiko Atsuta, Bruce R. Blazar, Scott N. Furlan, Hiroyasu Ogawa, Geoffrey R. Hill

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Figure 3

Glucocorticoid treatment has minimal effects on T cell proliferation of apoptosis in the mLN.

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Glucocorticoid treatment has minimal effects on T cell proliferation of ...
(A, B, and E) B6D2F1 mice were transplanted with 5 × 106 BM and 2 × 106 from B6 mice with or without GC treatment. (A) Representative histograms and quantification of cell tracking violet dye–labeled CD4+ and CD8+ T cells in the mLN at day 3 (n = 4–5 per group from 2 experiments). (B) Cell cycle analysis of donor CD4+ and CD8+ T cells in the mLN are shown as evaluated by Ki-67 expression versus Hoechst dye staining at day 5 (n = 6 per group from 2 experiments). (C and D) A total of 4 × 103 alloantigen-specific TEa.Rag1–/– T cells (TEa) combined with congenic polyclonal 2 × 106 WT B6 CD3+ T cells were transplanted with 5 × 106 WT B6 BM into B6D2F1 mice. Cleaved caspase-3 expression of polyclonal donor CD4+ and CD8+ T cells (C) and TEa.Rag1–/– cells (D, left) in the mLN at day 5. The ratios of caspase-3 expression in the TEa.Rag1–/– and polyclonal CD4+ T cells from the GC-treated group (relative to vehicle-treated control) are shown (D, right). ***P < 0.001, n = 8 per group from 2 experiments. (E) Representative histogram plots (left) and quantified data (right) of integrin α4β7 expression on donor T cells in the vehicle- and GC-treated mLN at day 5. **P < 0.01, n = 11 per group from 3 experiments. Data are presented as mean ± SEM. Student’s t test with Welch’s modification.