GM-CSF therapy inhibits chronic graft-versus-host disease via expansion of regulatory T cells

Regulatory T cells (Tregs), a subset of T cells with suppressive properties, are indispensable to the maintenance of immune tolerance. Although the T-receptor affinity of conventional T cells (Tconvs) against self-antigen is relatively low, they still have an ability to mount autoimmune responses. In addition to limiting T-cell responses against self-antigens, Thus the inhibition of Tconvs by Tregs is an important process to maintain immune tolerance in auto and allogeneic settings, making the in-vivo selective expansion of Tregs seem a promising treatment strategy against graft-versus-host disease.

The maintenance of the peripheral Treg population is achieved by a combination of survival and homeostatic proliferation attained by signaling through the cytokine receptor for interleukin-2 and through the T-cell receptor. Interleukin-2 signaling absence induces a significant reduction of Treg frequency and expansion of activated lymphoid cells, which causes fatal inflammatory disease, while exogenous interleukin-2 administration induces Treg selective expansion and is thus utilized for treatment against various immune diseases. T-cell receptor signaling stimulation through MHC class II, along with costimulatory signals for optimal proliferation of Tregs, is provided by dendritic cells. Antigen presentation by mature or activated dendritic cells leads to protective T-cell immunity, whereas immature dendritic cells promote immunologic tolerance by antigen-specific Tregs.

Granulocyte-macrophage colony-stimulating factor (GM-CSF), Csf-2, is a hematopoietic growth factor that controls the differentiation of the myeloid lineage and is utilized for modulating dendritic cell function, this cytokine is also commonly applied to the generation of dendritic cells from bone marrow and peripheral precursor cells. Notably, the expanded Tregs by GM-CSF are associated with autoimmune disease suppression and alternately conventional dendritic cell development was skewed toward the CD8+ subset in allogeneic bone marrow transplantation. Thus, the authors hypothesized that GM-CSF could expand Tregs and reduce alloantigen-induced inflammatory immune responses through the expansion of CD8- dendritic cells.

Recently, Kansai Medical University scientists: Masaaki Hotta, Hideaki Yoshimura, Dr. Atsushi Satake, Yukie Tsubokura, Professor Tomoki Ito and Professor Shosaku Nomura from the First Department of Internal Medicine in Japan decided to investigate the impact of GM-CSF mediated dendritic cell modulation on Treg maintenance in an allogeneic setting, as well as its effects in protecting against graft-versus-host disease. The work is published in the peer-reviewed journal, European Journal of Immunology.

The authors observed that Tregs and CD4⁺CD8^– dendritic cells are expanded by GM-CSF immune complex injections. This was shown by the observation of maximal Treg expansion in the peripheral blood on day 4, two days following the administration of three daily GM-CSF immune complex injections. In contrast, injection of unmodified GM-CSF induced only a very mild increase in Tregs. Also, it was observed that the administration of GM-CSF expands Tregs and CD4⁺CD8^–DCs during graft-versus-host disease.

Furthermore, the research team discovered that the administration of GM-CSF attenuates chronic graft-versus-host disease. They treated mice with GM-CSF showed significantly less skin graft-versus-host disease compared to phosphate buffered saline (PBS) treated control host mice, although chronic graft-versus-host disease was not prevented completely. Also, their study showed that the frequencies of TH17 and TH1/TH17 cells in graft-versus-host disease are decreased by the administration of GM-CSF.

The study by Kansai Medical University scientists demonstrates that GM-CSF could expand Tregs which were associated with skewed dendritic cell subsets, thereby ameliorating chronic graft-versus-host disease. Notably, Tregs were increased by GM-CSF in the allogeneic setting. Modulation of dendritic cells with GM-CSF may therefore constitute a novel therapeutic strategy for alloimmune inflammatory diseases such as chronic graft-versus-host disease. Further studies examining the involvement of signaling pathways and other factors, including concomitant agents, in GM-CSF mediated immune suppression will be necessary for full therapeutic manipulation of Tregs in graft-versus-host disease using GM-CSF.