Predominant immature CD8α⁺ dendritic cells prevent graft‐vs.‐host disease but do not increase the risk of leukemia recurrence

Abstract

Graft-vs.-host disease (GVHD) remains the major limitation of allogeneic bone marrow transplantation (BMT) and stem cell transplantation, and leukemia recurrence is another important complication in leukemia treatment. Immature CD8alpha+ dendritic cells (DC) have good potential in GVHD treatment and immunological tolerance studies. To find a new way to prevent GVHD, not increasing the risk of leukemia recurrence, in this study, predominant CD8alpha+ immature DC were induced from murine bone marrow (BM) cells by 5 ng/mL granulocyte-macrophage colony stimulating factor (GM-CSF) plus 20-ng/mL interleukin (IL)-4, 100-ng/mL stem cell factor (SCF) and 25-ng/mL Flt3L, and 97.09 of prepared DC were CD8alpha+ on day 3. These DC were identified as morphologically and phenotypically immature CD8alpha+ DC. The suppressive function was observed in vitro, and then in vivo on allo-BMT leukemia model. The prepared predominant immature CD8alpha+ DC were weak syngeneic lymphocyte stimulators and could suppress mixed leukocyte reaction in vitro. In vivo, they prevented the pathological changes of GVHD and prolonged the surviving time of allo-BMT leukemia mice. The effect showed a dose-effect relationship. 86.7% of allo-BMT plus 1 million predominant CD8alpha+ DC leukemia mice reached long-term survival. Although predominant immature CD8alpha+ DC had the function of GVHD suppression, they did not increase leukemia recurrence. The method and findings may have important potency for GVHD treatment in clinical application.

Generation and characteriztion of regulatory dendritic cells for the amelioration of acute graft versus host disease

“…In a murine model of GVHD, a single treatment with age-matched, syngeneic DCreg attenuated allogeneic-BMT induced GVHD, while maintaining the GVT response [89,91,241,265]. Importantly, our studies also demonstrated amelioration of GVHD in older mice following allogeneic BMT (Chapter II).…”

“…In a murine model of GVHD, a single treatment with age-matched, syngeneic DCreg attenuated complete MHC mismatched allogeneic-BMT induced GVHD, while maintaining the GVT response [89,91,241,265].…”

Tumor antigen-pulsed CD8α+ dendritic cells induce T cell-mediated graft-versus-tumor effect in vitro

“…Some DC subsets are also proved to induce immunotolerance [4,[21][22][23] . It has been reported that CD8α + DCs could induce tolerance [9,16,22] , but there has not been reported whether tumor antigen-pulsed CD8α + DCs can induce GVT/GVL. EL9611 is a leukemia cell line established in China [12] , and there has not been any report on its antigenicity and its application in GVL research by now.…”

“…However, after CD8α + DCs were pulsed by tumor antigen, T cell proliferation was significantly enhanced with the CD8α + DC/T ratio. Our previous studies found that non-antigen-pulsed immature CD8α + DCs expressed low level of MHC and Ⅱ costimulatory molecules on the surface, could not stimulated T cell proliferation effectively, and could prevent GVHD [6,7,9,11] . In this study, we found that tumor antigen-pulsed immature CD8α + DCs could present antigens and stimulate T cell proliferation.…”

“…Mature DCs mainly stimulate T cells and induce immune responses, while immature DCs can induce immunotolerance [3][4][5] . In our previous studies [6][7][8] , we examined and improved the methods to prepare immature CD8α + DCs, and by in vitro and in vivo experiments, proved their function to prevent GVHD while not to increase the risk of leukemia recurrence at the same time [9][10][11] . We hypothesized that there may exist GVL/GVT effect induced by CD8α + DCs.…”