Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) has curative potential for hematological malignancies, but is often associated with life-threatening complications including graft-versus-host disease (GVHD). The graft-versus-leukemia (GVL) activity which accompanies HSCT is responsible for eradication of tumor cells and prevention of relapse. GVHD and GVL are usually associated with each other and the separation of the two activities occurs in limited circumstances. In this study, we aimed to mitigate GVHD but retain GVL through transplantation of allogeneic T cells encapsulated with bio-degradable nanoparticle materials.
For the above purpose, donor T cells were encapsulated with chitosan and alginate through layer-by-layer coating using electrostatic deposition. Encapsulated donor T cells were characterized in vitro, and their ability to inhibit GVHD and retain GVL was determined in vivo after being transplanted together with non-encapsulated donor bone marrow (BM) cells in a C57BL/6 → BALB/c HSCT mouse model.
We found 85.7% of donor T cells were successfully encapsulated by the above method (Fig 1A). In vitro studies showed that the encapsulation did not change the phenotype of T cells as defined through the following parameters: size, viability, proliferation, antibody binding, cytokine secretion, and cytotoxicity of T cells (Fig. 1B and data not shown). Mice transplanted with encapsulated allogeneic T cells exhibited less severe acute GVHD and prolonged survival (Fig. 1 C-E). The mice showed a lower GVHD score, less liver damage, a smaller CD8/CD4 T cell ratio, and a higher number of donor BM-derived cells following transplantation with encapsulated donor T cells (Fig. 1 C-E and data not shown). When this GVHD model was combined with implantation of A20 lymphoma cells, GVL of encapsulated T cells was not compromised, while GVHD was still suppressed and the mouse survival also prolonged (Figure 2).
In summary, nanoencapsulation of T cells with bio-degradable materials attenuated the severity of GVHD but retained GVL, presenting a novel and potentially safer and effective approach of allogeneic HSCT for future clinical application.
Figure 1 Figure 1. Figure 2 Figure 2.
Disclosures
No relevant conflicts of interest to declare.
IL-22 deficiency in donor T cells attenuates murine acute graft-versus-host disease mortality while sparing the graft-versus-leukemia effect
