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SOCS3 regulates graft-versus-host disease

Geoffrey R Hill1, Rachel D Kuns, Neil C Raffelt

  • 1The Queensland Institute of Medical Research, 300 Herston Rd., Brisbane, Queensland 4006, Australia.

Blood
|May 4, 2010
PubMed

Insights

Suppressor of cytokine signaling-3 (SOCS3) deficiency in donor T cells exacerbates graft-versus-host disease (GVHD) after stem cell transplantation. Targeting SOCS3 may inhibit both acute and chronic GVHD.

Area of Science:

  • Immunology
  • Hematology
  • Transplantation Biology

Background:

  • Suppressor of cytokine signaling-3 (SOCS3) regulates granulocyte colony-stimulating factor signaling.
  • Graft-versus-host disease (GVHD) is a major complication of allogeneic stem cell transplantation (SCT).

Purpose of the Study:

  • To investigate the role of SOCS3 in regulating GVHD after SCT.
  • To determine the specific cell lineages in which SOCS3 deficiency impacts GVHD.

Main Methods:

  • Utilized genetically modified donor mice with SOCS3 deficiency restricted to specific hematopoietic compartments (hematopoietic, myeloid, T-cell).
  • Assessed GVHD induction, mortality, and histopathology following allogeneic SCT.
  • Analyzed T-cell proliferation and cytokine production (IL-10, IL-17, IFNγ).

Main Results:

  • SOCS3 deficiency in donor T cells (SOCS3(-/Deltalck)) significantly augmented acute GVHD mortality and gastrointestinal histopathology.
  • SOCS3-deficient T cells exhibited enhanced alloantigen-dependent proliferation and increased production of IL-10, IL-17, and IFNγ.
  • IFNγ was critical for the enhanced GVHD induced by SOCS3-deficient T cells, while IL-10 and IL-17 were not.
  • SOCS3-deficient T cells also induced severe sclerodermatous (chronic) GVHD dependent on TGF-β and IFNγ.

Conclusions:

  • SOCS3 deficiency in donor T cells is a key driver of both acute and chronic GVHD.
  • Targeting SOCS3, potentially with small molecule mimetics, could be a therapeutic strategy for inhibiting GVHD after SCT.

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