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Abstract: S126

Type: Oral Presentation

Presentation during EHA21: On Friday, June 10, 2016 from 12:15 - 12:30

Location: Hall C13

Background
Graft-versus-host disease (GVHD) still represents the major complication after allogeneic bone marrow transplantation (BMT) since allogeneic transplant-derived T cells attack and destroy recipient tissues. Therefore, a prerequisite for GVHD prevention is the interference with T cell activation, proliferation and functions. Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells, which inhibit T cell functions by versatile mechanisms.

Aims
Therefore, we tested whether co-transplantation of in vitro-generated MDSCs prevents GVHD and elucidated the influence of GVHD conditions on the differentiation of MDSCs.

Methods
MDSCs were generated in vitro by culturing BM cells in the presence of GM-CSF and G-CSF. After 4 days more than 90% exhibited a Gr-1⁺CD11b⁺ MDSC phenotype. To test whether and how MDSCs prevent allogeneic T cell functions, we co-transplanted MDSCs into lethally irradiated recipient mice together with allogeneic BM and spleen cells or we cultivated MDSCs in medium containing serum derived from GVHD developing mice.

Results
In vitro-generated MDSCs efficiently prevented T cell proliferation in vitro. If co-transplanted with allogeneic BM and spleen cells, MDSCs inhibited clinical GVHD and GVHD-associated death and attenuated histological GVHD. Interestingly, MDSCs did not predominantly reduce the numbers of allogeneic T cells but induced type 2 allogeneic T cells characterized by the expression of Th2 specific cytokines and transcription factors. In vitro-generated MDSCs represent a mixed population of CD11b⁺CD11c^- and CD11b⁺CD11c⁺ cells. To further investigate the Th2-inducing capacity of MDSCs, we cultured MDSCs in medium supplemented with GVHD serum, which induced an expansion of CD11b⁺CD11c⁺ cells. CD11b⁺CD11c⁺ cells expressed MHC class II^high, Gr-1^med, CD301b^pos while CD11b⁺CD11c^- cells were MHC class II^low, Gr-1^high and CD301b^neg. CD301 expression is associated with a Th2 inducing phenotype in dendritic cells just as the presence of transcription factors IRF4 and Klf4, whose expression was also higher in CD11b⁺CD11c⁺ cells. Similarly, MDSCs co-injected with the allogeneic transplant exhibited an expansion of CD11b⁺CD11c⁺ cells in spleen and GVHD target organs preferentially in mice developing GVHD. Comparable to the in vitro conditions, these CD11b⁺CD11c⁺ cells acquired a phenotype similar to antigen-presenting cells characterized by CD80, CD86, CD40, and MHC class II expression. Isolation of the different MDSC subpopulations in vitro and subsequent incubation with allogeneic spleen cells showed that CD11b⁺CD1c⁺ MDSCs induce the secretion of Th2 cytokine IL-5, while CD11b⁺CD11c^- cells provoked only a weak Th2 response.

Conclusion
In summary, we could show that transplantation of MDSCs prevents GVHD after allogeneic BMT by inducing type 2 T cells. Th2 inducing capacity, however, was preferentially mediated by a subpopulation of MDSCs. Further studies will elucidate the molecular mechanisms of Th2 induction and will clarify whether MDSC differentiation and functions are dependent on the type of inflammatory environment.

Session topic: Stem cell transplantation - Experimental

Keyword(s): Allogeneic bone marrow transplant, Graft-versus-host disease (GVHD), Immunomodulation, T cell response