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
View: Text | PDF
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

×

Figure 1

Glucocorticoids attenuate GVHD and permit effective GVL responses.

Options: View larger image (or click on image) Download as PowerPoint
Glucocorticoids attenuate GVHD and permit effective GVL responses. B6C3F...
B6C3F1 mice were transplanted with 5 × 106 BM and 2 × 107 splenocytes from B6D2F1 with or without glucocorticoid (GC) treatment. B6C3F1 background MLL/AF9-transduced leukemia cells were transplanted with T cell replete grafts (not TCD). (A) Haploidentical BMT model. (B and C) Overall survival by Kaplan-Meier analysis and clinical GVHD scores (compared by Student’s t test at the indicated time points) of the T cell replete groups. Results are combined from 2–3 experiments, 6–20 mice per group. (D) Competing risk analysis of GVHD versus leukemia death. (E) Representative H&E-stained sections (scale bars: 100 μm, upper panels) and immunofluorescent staining (scale bars: 50 μm, lower panels) of colon at day 14. (F) GVHD histopathology scores in the small intestine and colon. Results combined from 2 experiments (n = 5–9 per group). Multiple comparison by 1-way Welch ANOVA (colon) or Kruskal-Wallis test (small intestine). (G) Kinetics of donor CD4+ and CD8+ T cell numbers in the mLN (upper) and BM (lower panels) at day 4, 7 and 14 after allogeneic BMT (n = 6 per group from 3 experiments). Comparisons by Student’s t test with Welch’s modification. (H) Leukemia cell (LC) numbers per 2 recipient femurs at day 14 (n = 4–8 per group from 2 experiments). Multiple comparison by Kruskal-Wallis test. (I) Representative histogram of granzyme B expression (blue, vehicle; red, GC-treated) in donor CD44+CD8+ T cells at day 10 BM from vehicle- or GC-treated recipients (IgG isotype control in gray). Pooled donor-type H-2Kd+CD44+CD8+ T cells were sorted by FACS at day 10 and cocultured with luciferase-expressing leukemic cells with or without soluble anti-CD3ε. Lytic activity as described in Methods. Data combined from 2 experiments. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01; ***P < 0.001.