Oral Complications in Hematopoietic Stem Cell Recipients: The Role of Inflammation

Table 1

Selected inflammatory cytokines involved in graft versus host disease; intervention in cytokine production is an obvious approach to ameliorate GvHD, but because cytokines have complex and pleomorphic effects, this may result in unintended consequences.

Cytokine	Main role in GvHD	References
TNF-α	Activates APCs and enhances alloantigen presentation, recruits effector cells to target organs mediated by inflammatory chemokines and directly causes tissue necrosis.	[66, 105–107]
IL-1α	Higher salivary IL-1α is associated with oral dryness in oral cGvHD.	[108]
IL-1β	Primary activator of chemotactic cytokines and expression of adhesion molecules that facilitate the migration of leucocytes into tissues.	[66, 109]
IL-6	Key factor in CD4+ T cell-dependentaGvHD and inhibition of Tregs. Moreover, an association between IL-6 and the severity of oral cGvHD has been reported.	[108, 110, 111]
IL-2	Critical for T-cell differentiation.	[98]
IL-15	IL-2-like cytokine, enhances T-cell and NK cell proliferation and improves immune reconstitution after allogeneic HSCT.	[98]
IL-12	Pro-inflammatory cytokine involved in the activation of donor T cells. Stimulates T cell and NK cell proliferation and induces maturation of Th1 cells.	[98]
IFN-γ	Complex role in innate and adaptive immune responses. IFN-γ is able to increase chemokine receptors, MHC proteins and adhesions molecules. Renders monocytes and macrophages more sensitive to LPS stimulation, and amplifies GvHD by direct damage to epithelial cells and by NO-mediated immunosuppression. May just reflect the presence of large numbers of activated T cells, and does not necessarily imply a role of this cytokine in the pathogenesis of GvHD.	[66, 112]
IL-17	IL-17 is mainly produced by activated Th-17 cells, stimulates IL-6 and IL-8 secretion and enhances the expression of adhesion molecules. May play a role in either triggering or aggravating aGvHD and cGvHD, but detailed role remains to be elucidated.	[113–115]
IL-18	Affects both Th1 and Th2 mediated responses and is elevated in aGvHD. In mouse models, administration of IL-18 early after allogeneic HSCT attenuated aGvHD by decreasing Th1 cytokine production.	[98]
IL-5	Produced by T cells, mast cells and eosinophils has been associated with aGvHD. Stimulates B cell growth and increases immunoglobulin secretion; is a key mediator in eosinophil activation.	[98, 116]
IL-10	Inhibits secretion of IL-1, TNF, IL-6, IL-8 and IL-12 from monocytes/macrophages and secretion of IFN-γ and IL-2 by T-cells. A protective role for donor-derived IL-10 has been suggested in aGvHD, as it decreases apoptosis. High concentrations of IL-10 in aGvHD may reflect systemic infection and may contribute to immunodeficiency.	[98, 117–120]
IL-21	IL-21 enhances Th1 and Th17 differentiation while inhibiting the conversion of inducible Tregs from naive T cells.	[121]
IL-22	Structurally related to IL-10 and is secreted by Th17 cells and innate immune cells. In line with these findings, IL-22 may act as a protective regulator of tissue sensitivity to GvHD.	[122, 123]
IL-7	Is associated with the development of aGvHD, but mechanism is not well understood.	[98, 124, 125]

GvHD: Graft versus Host Disease, TNF: Tumor Necrosis Factor, APCs: Antigen Presenting Cells, IL: Interleukin, CD4+ T cell: T helper cell expressing surface protein CD4, aGvHD: acute GvHD, Treg: regulatory T cell, NK cell: Natural Killer cell, HSCT: Hematopoietic Stem Cell Transplantation, Th cells: T helper cells, IFN-γ: interferon gamma, MHC: Major Histocompatibility Complex, LPS: lipopolysaccharide, NO: Nitric Oxide, cGvHD: chronic GvHD, GI: Gastro-Intestinal.