scholarly journals Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD4+25+ T cells to allow an effective graft-versus-leukemia response

2003 ◽  
Vol 9 (4) ◽  
pp. 243-256 ◽  
Author(s):  
Stephen C. Jones ◽  
George F. Murphy ◽  
Robert Korngold
Keyword(s):  
T Cells ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia

Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease

2022 ◽  
Author(s):  
Marie Bleakley ◽  
Alison Sehgal ◽  
Stuart Seropian ◽  
Melinda A. Biernacki ◽  
Elizabeth F. Krakow ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Iii

PURPOSE Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (TN) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of TN-depletion of peripheral blood stem-cell (PBSC) grafts. METHODS One hundred thirty-eight patients with acute leukemia received TN-depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of TN. Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD. RESULTS cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years. CONCLUSION Depletion of TN from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches.

SMAD3 prevents graft-versus-host disease by restraining Th1 differentiation and granulocyte-mediated tissue damage

Blood ◽  
2011 ◽  
Vol 117 (5) ◽  
pp. 1734-1744 ◽  
Author(s):  
Martin Giroux ◽  
Jean-Sébastien Delisle ◽  
Simon-David Gauthier ◽  
Krista M. Heinonen ◽  
Julie Hinsinger ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Tissue Damage ◽  
Hematopoietic Cell Transplantation ◽  
Transforming Growth Factor ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Host Disease ◽  
Graft Versus Host

Abstract Gene expression profiling of human donor T cells before allogeneic hematopoietic cell transplantation revealed that expression of selected genes correlated with the occurrence of graft-versus-host disease (GVHD) in recipients. The gene with the best GVHD predictive accuracy was SMAD3, a core component of the transforming growth factor-β signaling pathway, whose expression levels vary more than a 6-fold range in humans. The putative role of SMAD3 in the establishment of graft-host tolerance remained elusive. We report that SMAD3-KO mice present ostensibly normal lymphoid and myeloid cell subsets. However, the lack of SMAD3 dramatically increased the frequency and severity of GVHD after allogeneic hematopoietic cell transplantation into major histocompatibility complex-identical recipients. Lethal GVHD induced by SMAD3-KO donors affected mainly the intestine and resulted from massive tissue infiltration by T-bet+ CD4 T cells and granulocytes that caused tissue damage by in situ release of Th1 cytokines and oxidative-nitrosative mediators, respectively. Our report reveals the nonredundant roles of SMAD3 in the development of tolerance to the host. Furthermore, our data support the concept that SMAD3 levels in donor cells dictate the risk of GVHD and that SMAD3 agonists would be attractive for prevention of GVHD.

scholarly journals Blockade of TIM-1 on the donor graft ameliorates graft-versus-host disease following hematopoietic cell transplantation

2019 ◽  
Vol 3 (21) ◽  
pp. 3419-3431
Author(s):  
Bettina P. Iliopoulou ◽  
Katie Hsu ◽  
Magdiel Pérez-Cruz ◽  
Sai-Wen Tang ◽  
Wendy W. Pang ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Key Points ◽  
Donor Graft

Key Points Administration of anti–TIM-1 blocking mAb ameliorates acute GVHD while preserving graft-versus-tumor effects. Treatment with anti–TIM-1 blocking mAb does not affect proliferation of donor allogeneic T cells.

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