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. 2016 Mar 22;8(3):85. doi: 10.3390/v8030085

Table 1.

Mediators of acute graft-versus-host disease.

Mediators of aGVHD Examples Functions in the Context of aGVHD Ref.
T cell co-receptors for MHC class I and class II CD4+ (MHC-class II) and CD8+ (MHC class I) T cells.
  • -

    In the majority of HLA matched HCT, CD4+ or CD8+ or both are induced in response to mHAs.

 [81]
Naïve and memory T cells CD62L+ CD44− (naïve T cells); CD62L+ CD44+ (central memory T cells); CD62L− CD44− (terminally differentiated effector/effector memory).
  • -

    Donor naïve CD62L+ are the primary alloreactive cells that enhance the GVHD

  • -

    Induction of anergy of alloreactive naïve T cells is possible with co-stimulation blockade, deletion via cytokine modulation among others.

  • -

    While memory and alloreactive T cells can cause severe GVHD, memory T cells that are not alloreactive do not cause GVHD, yet transfer functional memory that mediates GVL effects

 [82,83,84,85,86]
Th1 subset IFN-γ, IL-2 and TNF-α.
  • -

    IL-2 production by donor T cells is the main target of prophylactic approaches and treatment of GVHD.

  • -

    The role of Th1 cytokines is complex. In fact, they can be regulators or inducers of GVHD.

 [87,88]
Th2 subset IL-4, and IL-10, G-CSF, IL-4 and IL-18.
  • -

    Lack of secretion of Th2 cytokines by donor T cells is reflected in an increase in the severity of GVHD.

  • -

    Some studies have demonstrated that polarization of donor T cells toward the production of Th2 cytokines reduces Th1 production and the severity of aGVHD. However, other studies have failed to demonstrate the beneficial effect of Th2 polarization in aGVHD

  • -

    IL-18 pre-treatment has been associated with reduced IFN-γ and higher IL-4 secretion.

 [34,59,89,90,91]
Th17 subset IL-17
  • -

    The role of IL17 in GVHD remains unclear. In fact, some studies have shown IL-17 contributes to the early development of GVHD by promoting the induction of inflammatory cytokines. In contrast, other studies have shown that absence of IL-17 in donor T cells increases Th1 differentiation, IFN-γ production and exacerbates aGVHD in allogeneic recipients.

 [34,92,93]
Regulatory T cells (Tregs) CD4+CD25+Foxp3+ (nTregs)
  • -

    nTregs suppress the proliferation of effector allo-reactive donor T cells resulting in the prevention aGVHD.

  • -

    Also, after allo-HSCT viral immunity is preserved in the presence of Tregs.

  • -

    However, Tregs can prevent GVL depending on the ratio of effector T cells to Tregs.

 [94,95,96]

GVHD: graft-versus-host disease; aGVHD: acute graft-versus-host disease; allo-HSCT: allogeneic hematopoietic stem cell transplantation; G-CSF: granulocyte colony-stimulating factor; GVL: graft-versus-leukemia; IFN: interferon; HCT: hematopoietic cell transplant; HLA: human leukocyte antigen; MHC: major histocompatibility complex; mHa: minor histocompatibility antigen; IL: interleukin; Ref: reference; nTregs: naturally occurring Tregs.