53 research outputs found
Enhanced immune reconstitution and function by CD4+CD25+ regulatory T cells following allogeneic hematopoietic cell transplantation
Indirect Impact of PD-1/PD-L1 Blockade on a Murine Model of NK Cell Exhaustion
The induction of exhaustion on effector immune cells is an important limiting factor
for cancer immunotherapy efficacy as these cells undergo a hierarchical loss of
proliferation and cytolytic activity due to chronic stimulation. Targeting PD-1 has shown
unprecedented clinical benefits for many cancers, which have been attributed to the
prevention of immune suppression and exhaustion with enhanced anti-tumor responses.
In this study, we sought to evaluate the role of the PD-1/PD-L1 pathway in murine
natural killer (NK) cell activation, function, and exhaustion. In an in vivo IL-2-dependent
exhaustion mouse model, neutralization of the PD-1/PD-L1 pathway improved NK
cell activation after chronic stimulation when compared to control-treated mice. These
cells displayed higher proliferative capabilities and enhanced granzyme B production.
However, the blockade of these molecules during long-term in vitro IL-2 stimulation did
not alter the progression of NK cell exhaustion (NCE), suggesting an indirect involvement
of PD-1/PD-L1 on NCE. Given the expansion of CD8 T cells and regulatory T cells (Tregs)
observed upon acute and chronic stimulation with IL-2, either of these two populations
could influence NK cell homeostasis after PD-L1/PD-1 therapy. Importantly, CD8 T cell
activation and functional phenotype were indeed enhanced by PD-1/PD-L1 therapy,
particularly with anti-PD-1 treatment that resulted in the highest upregulation of CD25
during chronic stimulation and granted an advantage for IL-2 over NK cells. These
results indicate a competition for resources between NK and CD8 T cells that arguably
delays the onset of NCE rather than improving its activation during chronic stimulation.
Supporting this notion, the depletion of CD8 T cells reversed the benefits of PD-1 therapy
on chronically stimulated NK cells. These data suggest a bystander effect of anti-PD1
on NK cells, resulting from the global competition that exists between NK and CD8 T
cells for IL-2 as a key regulator of these cellsā activation. Thus, achieving an equilibrium
between these immune cells might be important to accomplish long-term efficacy during
anti-PD-1/IL-2 therapy
Equivalence of 2 effective graft-versus-host disease prophylaxis regimens: Results of a prospective double-blind randomized trial
AbstractWe have previously demonstrated a decrease in the incidence of acute graft-versus-host disease (GVHD) with the addition of methotrexate (MTX) to cyclosporine (CSP) and prednisone (PSE) chemotherapy in patients with leukemia. We have now completed a prospective randomized trial comparing the 3-drug regimen (CSP/MTX/PSE, including 3 doses of MTX) to the standard 2-drug regimen (CSP/MTX, including 4 doses of MTX) to investigate the benefit of PSE used up front for the prevention of acute and chronic GVHD. In the trial, 193 patients were randomized and 186 were included in the final analysis. All patients received a bone marrow graft from a fully histocompatible sibling donor. The preparatory regimen consisted of fractionated total-body irradiation (fTBI) and etoposide in all but 13 patients, who received fTBI and cyclophosphamide. The patients were randomized to receive either CSP/MTX/PSE or CSP/MTX. The 2 groups were well balanced with respect to diagnosis, disease stage, age, donor-recipient sex, and parity. In an intent-to-treat analysis, the incidence of acute GVHD was 18% (95% confidence interval [CI] 12-28) for the CSP/MTX/PSE group compared with 20% (CI 10-26) for the CSP/,MTX group (P = .60), with a median follow up of 2.2 years. Overall survival was 65% for those receiving CSP/MTX/PSE and 72% for those receiving CSP/MTX (P = .10); the relapse rate was 15% for the CSP/MTX/PSE group and 12% for the CSP/MTX group (P = .83). The incidence of chronic GVHD was similar (46% versus 52%; P = .38), with a follow-up of 0.7 to 6.0 years. Of interest, 21 patients went off study due to GVHD (5 in the CSP/MTX/PSE group and 16 in the CSP/MITX group [P = .02]), and 11 patients went off study because of alveolar hemorrhage (3 in the CSP/MTX/PSE group and 8 in the CSP/MTX group [P = .22]). The addition of PSE did not result in a higher incidence of infectious complications, bacterial (66% versus 58%), viral (77% versus 66%), or fungal (20% versus 20%), in those receiving CSP/MTX/PSE versus CSP/MTX, respectively. These data suggest that the addition of PSE was associated with a somewhat lower incidence of early posttransplantation complications but did not have a positive impact on the incidence of acute or chronic GVHD or event-free or overall survival.Biol Blood Marrow Transplant 2000;6(3):254-61
Development of a minimally invasive bone marrow harvest device and method for the rapid extraction of bone marrow for use in bone marrow transplantation and stem cell therapy
Silica-Induced Impairment of Macrophage Function Reduces GVHD Severity and Improves Survival
Early treatment with CD4+CD25+ regulatory T cells provides prolonged suppressive effects which control evolving but not established graft-versus-host-disease
Primary Human Acute Myeloid Leukemia Stem Cells Show Reduced Sensitivity To Natural Killer Cell-Mediated Killing
Isolation and characterization of human CD4+CD25+ T regulatory cells for early phase clinical trials in hematopoietic cell transplantation
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