Vaccination with Host Dendritic Cells Induces Graft-Versus-Leukemia Responses without Severe Graft-Versus-Host Disease in a Preclinical Mouse Model for Allogeneic Stem Cell Transplantation.

Allogeneic stem cell transplantation is a potent treatment for patients with leukemia. This therapeutic effectiveness is largely attributed to the graft-versus-leukemia (GVL) response during which alloreactive donor CD8⁺ T cells eradicate minor histocompatibility antigens (MiHA)-expressing leukemic cells. Unfortunately, recognition of MiHA expressed in healthy tissues, including the liver, skin and gut, often results in morbidity and even mortality due to the development of graft-versus-host disease (GVHD). Antigen presenting cells (APC) play an essential role in the activation of alloreactive T cells and thus in the induction of GVL responses and GVHD. Using several in vivo models it has been suggested that host APC, which present endogenous MiHA to donor CD8⁺ T cells, are more potent inducers of alloreactive responses than donor APC. Here, we compared the ability of host APC versus donor APC to activate alloreactive T cells in vitro and to induce alloreactions in vivo. For this purpose, we isolated T cells and cultured bone marrow-derived dendritic cells (DC), the most potent APC, from B6.SJL ‘host’ mice and MHC (H-2b)-matched but MiHA-mismatched C3.SW ‘donor’ mice. Following their activation by the TLR4 ligand lipopolysaccharide for no longer than 5 hours, both host and donor DC showed a fully mature phenotype (MHCI^high MHCII^high CD40⁺ CD80^high CD86^high), and comparable migratory behavior towards lymph node-specific chemokines. In primary mixed leukocyte reactions host DC were 2–3 times more potent than donor DC in inducing donor CD8⁺ T cell proliferation. To determine the role of host and donor DC in the development of GVL and GVHD, we established a preclinical mouse model (C3>B6) for allogeneic stem cell transplantation. Repopulation analyses demonstrated that T cells, B cells and myeloid cells from blood and spleen of transplanted mice were for more than 95% of donor origin. Transplanted mice were subsequently vaccinated intravenously with 3 weekly doses of 3 × 10⁵ host or donor DC. DC vaccination, which did not lead to significant GVHD, was followed by an intravenous challenge with 10⁶ GFP-expressing mouse AML (C1498) cells. While sham-vaccinated mice died quickly due to leukemia progression, vaccination with both host and donor DC resulted in diminished leukemia growth. However, only vaccination with host DC, and not donor DC, resulted in a (partial) rescue from challenge. These results suggest that host DC are the most potent inducers of GVL reactions without causing significant GVHD. We believe that these data will be instrumental in designing appropriate DC-based immunotherapies in transplanted leukemia patients.