title: 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-versus-host (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 MHC-matched setting, high levels (>or= 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 Toll-like receptor (TLR) ligands was required to maximize DLI-mediated LH-GVH and GVL reactivities in chimeras with low levels (<or= 15%) of residual host chimerism. In contrast, coadministration of DLI with antigen-presenting cell (APC) activators was insufficient to augment their LH-GVH response in the presence of high levels of host chimerism unless the host's T cells were transiently depleted. Together, these results show the cardinal influence of donor-host incompatibility on DLI-mediated GVH responses and suggest that in MHC-matched chimeras, the induction of optimal alloreactivity requires not only donor T cells and host APCs but also TLR ligands and in the presence of high levels of host chimerism depletion of host T cells.
authors.affiliation: Divisions of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Nadira
authors.initials: N
authors.lastname: Durakovic
authors.forename: Vedran
authors.initials: V
authors.lastname: Radojcic
authors.forename: Mario
authors.initials: M
authors.lastname: Skarica
authors.forename: Karl B
authors.initials: KB
authors.lastname: Bezak
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Powell
authors.forename: Ephraim J
authors.initials: EJ
authors.lastname: Fuchs
authors.forename: Leo
authors.initials: L
authors.lastname: Luznik
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D006087:Graft vs Host Reaction; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000378:metabolism* / Q000637:transplantation*; D014019:Tissue Donors; D018183:Transplantation Chimera / Q000276:immunology; D014184:Transplantation, Homologous