Factors governing the activation of adoptively transferred donor T cells infused after allogeneic bone marrow transplantation in the mouse

Abstract

Murine models of bone marrow transplantation were used to study the mechanisms governing the activation of donor lymphocyte infusions (DLIs) manifesting as lymphohematopoietic graft-versushost (LH-GVH) and graft-versus-leukemia (GVL) reactivities. We demonstrate here that established mixed chimerism influences the potency of DLI-mediated alloreactivity only in the MHC-mismatched but not MHC-matched setting. In the MHCmatched setting, high levels (> 40%) of residual host chimerism correlated negatively with DLI-mediated alloreactivity irrespective of the timing of their administration, the donor's previous sensitization to host antigens, or the level of residual host APCs. In vivo administration of Tolllike receptor (TLR) ligands was required to maximize DLI-mediated LH-GVH and GVL reactivities in chimeras with low levels (< 15%) of residual host chimerism. In contrast, coadministration of DLI with antigen-presenting cell (

Effective posttransplant antitumor immunity is associated with TLR-stimulating nucleic acid–immunoglobulin complexes in humans

“…Our results mirror recent findings in murine models that efficacy of DLI-induced antitumor responses are improved with the coadministration of TLR ligands (26). In contrast, administration of TLR agonists concurrent with conditioning chemoradiation and stem cell infusion appears to aggravate graft rejection and GvHD (27) and underscore the critical importance of timing of adjuvant exposure together with its interaction with other immune-activating stimuli to determine the direction of clinical outcome (28).…”

Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice

“…Using donor transgenic strains enabling selective ablation of CD4 Bone marrow transplantation, GVHD monitoring, flow cytometry, sorting, in vitro suppression assays, in vivo bioluminescent imaging (BLI), histopathology and statistical analyses were performed as previously described 19,20 and are detailed in the supplemental Methods (available on the Blood Web site). PTCy was administered IP in previously published doses, [21][22][23] as described in the figure legends.…”

New strategies of DLI in the management of relapse of hematological malignancies after allogeneic hematopoietic SCT

“…70,81 However, some clinical studies suggested that only one-third of evaluable patients were converted from mixed to FDC on DLI administration after HLA-matched nonmyeloablative BMT, and patients with donor T-cell chimerism below 50% rarely responded. 82,83 Durakovic et al 84 demonstrated that in vivo administration of Toll-like receptor (TLR) ligands was able to maximize DLI-mediated lymphohematopoietic graft-vs-host and GVL reactivity in chimeras with low levels (⩽15%) of residual host chimerism. In this study, it was also shown that, in the absence of tissue damage, TLR ligands could augment the GVL effect of MHC-matched DLI mediated by anti-mHAg responses without inducing lethal GVHD, which is highly associated with conversion to complete donor T-cell chimerism after HLA-matched nonmyeloablative allografting.…”