engleski

Host Langerhans Cells (LCs) Can Be Therapeutically Manipulated In Vivo with Imiquimod (TLR7 Agonist) to Augment DLI-Mediated GVH and GVL Reactivity

We recently found in murine models that after MHC-matched allografting, the residual host LCs, the major dendritic cells (DCs) of the skin, survive in epidermis despite the presence of large numbers of peripheral donor T cells in the graft and conversion to the full donor DC chimerism in blood. This observation led us to hypothesized that in vivo manipulation of residual host LCs, which persist in complete donor chimeras after MHC-matched allografting, may have a central role in augmenting DLI-mediated alloimmune responses. We tested our hypothesis in two murine models of MHC-matched allografting. To manipulate T cell-LC interaction in vivo we used Toll-like receptor 7 (TLR7) ligand imiquimod. Topical application of imiquimod is known to augment in situ maturation of the LCs and enhance their emigration from the skin to the skin-draining lymph nodes (LNs). We first tracked the in vivo fate of DLI-derived T cells after their administration to the 8 weeks-old B6.SJLC3H.SW complete donor chimeras that were pretreated with vehicle or imiquimod. As DLI, we used purified donor T cells from the B6.PL-Thy1a mice that differ in the expression of Thy 1.1 allele. In imiquimod treated group, the expansion of DLI-derived Thy 1.1+ T cells in LNs and spleen was significantly better than that of the vehicle-treated group. This augmented DLI-mediated GVH response was also reflected by higher number of DLI-derived CD8+ INF- secreting T cells and by increase in donor-derived LC chimerism in the imiquimod-treated group. Next, we tested the effect of imiquimod on the GVL reactivity of DLI. Four weeks old C3H.SWC57/BL6 chimeras constructed after lethal conditioning were pretreated with imiquimod prior to DLI administration and lethal challenge with C1498 leukemia cells. Chimeras that received imiquimod and DLI had superior leukemia-free survival in comparison to animals that received DLI plus vehicle (p<0.01) or imiquimod alone (p<0.02). The superior leukemia-free survival in group that received DLI plus imiquimod correlated also with faster conversion to full donor CD8+ T cell chimerism in comparison to DLI plus vehicle group (p<0.01). In both models, we have not observed any significant clinical signs of GVHD. These results indicate that imiquimod, through its action on LCs, can be used to enhance the DLI-mediated alloimune responses including their GVL reactivity without exacerbating GVHD.

Alogeneic transplantation; Langerhans cells

nije evidentirano