Implications of IFN-γ-Mediated Tryptophan Catabolism on Solid Organ Transplantation

Abstract

The Th1-type cytokine interferon-gamma (IFN-gamma) is known as one of the most versatile players of the immune system. In transplantation immunology IFN-gamma has been shown to have contradictory effects on allograft survival via effects on both, the immune system and on the graft itself. The immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO), widely distributed in mammals, is induced preferentially by IFN-gamma. IDO degrades the essential amino acid tryptophan to form N-formyl kynurenine which is subsequently converted to niacin. Recently, it has been proposed that IFN-gamma-mediated activation of IDO is critically involved in the regulation of immune responses, to establish immune-tolerance in pregnant mice upon their fetuses, or to induce T-cell unresponsiveness. Proliferation of alloreactive T-cells is thereby arrested via local tryptophan deprivation and the accumulation of toxic tryptophan catabolites. Despite growing recognition of the molecular T-cell regulatory mechanisms, the physiologic role of IDO in solid organ transplantation, however, remains unclear. Available experimental data indicate that IDO is involved in the mechanism of spontaneous donor-specific tolerance of liver grafts, and that genetic manipulation by introduction of the IDO gene into allografts is associated with prolonged survival. Furthermore, antigen-presenting cells, such as dendritic cells, can increase their expression of IDO, thus regulating immune responses. Based on these findings, the concept that cells expressing IDO can inhibit T-cell responses and hence induce tolerance has emerged as a new paradigm in immunology. Here we review the current literature on IDO in the context of transplantation and outline its potential implication as a target for tolerance induction.

Indoleamine 2,3-dioxygenase (IDO) expression in lung cancer

“…Concerning the IDO expression by the neighboring to the tumor non-malignant lung tissue, it could be attributed to a degree of infiltration by the same as above cell types. Moreover, tumor-derived soluble factors, like interferon, 16,17 a known inducer of IDO, 18 could to a greater extent be responsible, by perfusing the surrounding pulmonary tissue and stimulating in this way even normal cellular elements (e.g., macrophages) to produce IDO. Finally, chronic pulmonary inflammation, usually coexisting in lung cancer, could by itself induce IDO expression in the non affected peri-tumoral lung areas.…”

IFN-γ, as Secreted during an Alloresponse, Induces Differentiation of Monocytes into Tolerogenic Dendritic Cells, Resulting in FoxP3+ Regulatory T Cell Promotion

“…؉ Regulatory T Cell Promotion I nterferon-␥ has recently been implicated in tolerance induction either 1) by acting as an inducer of Th2 responses, which counteracts the activity of Th1, or 2) by allowing regulatory T cell (Treg) 3 function and/or expansion, or 3) by inducing the tolerogenic activity of APC, notably through increased expression of inducible NO synthase and/or induction of the immunomodulatory IDO enzyme activity (1)(2)(3)(4). Moreover, the positive effect of IFN-␥ on tolerance induction has also been demonstrated in vivo by using animal models.…”

Mechanisms of Murine Spontaneous Liver Transplant Tolerance

“…4,24 In addition, overexpression of indoleamine 2,3-dioxygenase within the liver allograft or antigen presenting cells causes suppression of activated CD4 or CD8 T-cells and promotes T cell apoptosis. 25 Expression of indoleamine 2,3-dioxygenase is higher in spontaneously tolerated murine liver grafts, and 1-methyltryptophan, which blocks indoleamine 2,3-dioxygenase activity, can abolish liver tolerance. 26 Therefore, liver nonparenchymal cells, cytotoxic T lymphocyte antigen 4, indoleamine 2,3-dioxygenase, activated T-cell apoptosis, and CD4+ CD25+ Foxp3+ Treg cells all affect the induction and maintenance of liver tolerance (Figure 2).…”

“…70 The Treg cells modulate tryptophan catabolism by inducing indoleamine 2,3-dioxygenase production; this is done by a mechanism that is dependent on cytotoxic T lymphocyte antigen 4 and that suppresses downstream T-cell activation. 25 Therefore, indoleamine 2,3-dioxygenase may be down-stream of Treg cell-mediated immunosuppression.…”