GM-CSF mitigates chronic GVHD via proliferation of regulatory T cells.

Abstract

Regulatory T cells (Tregs) possess the ability to suppress chronic graft-versus-host disease (cGVHD). Hence, the in vivo expansion of Tregs can be used as therapy against cGvHD. In addition to IL-2, Tregs require TCR and costimulatory signals from antigen presenting cells such as dendritic cells (DCs) for their optimal proliferation.

Both fms-like tyrosine kinase 3 ligand (FLT3-L) and granulocyte macrophage colony stimulation factor (GM-CSF) induce the development of DCs and promote the proliferation of Tregs in a DC-dependent manner. GM-CSF preferentially increases CD8α- DCs, whereas FLT3L more equally supports the development of many DC subsets. However, it is unknown whether GM-CSF-mediated CD8α- DC expansion leads to the proliferation of Tregs and contributes to the inhibition of allo-immune responses against host antigens.

To test whether the injection of GM-CSF augments Tregs and ameliorates cGVHD, we used a MHC-matched mouse cGVHD model (B10.D2 → BALB/c). BALB/c mice were lethally irradiated and transplanted with T cell-depleted bone marrow cells and CD4+ T cells from either syngeneic or B10.D2 mice. Host mice were treated with vehicle or GM-CSF for 3 days and monitored for skin GVHD.

The administration of GM-CSF to allogeneic host mice significantly protected against GVHD-induced skin diseases. GM-CSF increased Tregs in peripheral lymph node and peripheral blood. This results indicate that GM-CSF mitigates cGVHD via proliferation of Tregs.