Indoleamine 2,3-dioxygenase in human hematopoietic stem cell transplantation

Abstract

In recent years tryptophan metabolism and its rate limiting enzyme indoleamine 2,3-dioxygenase (IDO) have attracted increasing attention for their potential to modulate immune responses including the regulation of transplantation tolerance. The focus of this review is to discuss some features of IDO activity which particularly relate to hematopoietic stem cell transplantation (HSCT). HSCT invariably involves the establishment of some degree of a donor-derived immune system in the recipient. Thus, the outstanding feature of tolerance in HSCT is that in this type of transplantation it is not rejection, which causes the most severe problems to HSCT recipients, but the reverse, graft-versus-host (GvH) directed immune responses. We will discuss the peculiar role of IDO activity and accelerated tryptophan metabolism at the interface between immune activation and immune suppression and delineate from theoretical and experimental evidence the potential significance of IDO in mediating tolerance in HSCT. Finally, we will examine therapeutic options for exploitation of IDO activity in the generation of allo-antigen-specific tolerance, i.e. avoiding allo-reactivity while maintaining immunocompetence, in HSCT.

Keywords: HSCT; IDO; hematopoietic stem cell transplantation; indoleamine 2,3-dioxygenase; tryptophan metabolism.

Figure 1.

Immunodeficiency after HSCT. The figure comprises some important factors that invariably contribute to the immune deficiency after HSCT. The numbers of the scale indicate days after transplant. Immediately after transplantation the number of immune cells is diminishing, and the appearance of donor-derived immunocompetent cells requires some time. Therefore, the risk for GvHD increases as donor-derived immune cells reappear in the recipient.

Figure 2.

Allo-antigen-specific tolerance. The post-transplant immune system, which will contain some degree of donor-chimerism (see text), is required to specifically be devoid of allo-reactivity in both directions, HvG and GvH, but to protect from microbial infections and provide immune reactivity against neoplastic cells (graft-versus-leukemia, GvL, and graft-versus-tumor, GvT).

Figure 3.

Hypothetical model of IDO activity in the regulation of immune responses. It is presumed that the main effects of IDO-mediated tryptophan breakdown, tryptophan depletion and kynurenine accumulation, act in concert to modulate T cell responses. Note, that according to the model T cells that are not responsive to the antigen presented are considered to remain largely unaffected by the effect of IDO.

Figure 4.

Exploitation of IDO activity to generate allo-antigen-specific tolerized T cells. After an ex vivo mixed leukocyte reaction of recipient IDO competent APCs and donor T cells the recovered T cells are supposed to be unable to mount allo-responses in the GvH direction due to the effects of IDO but retain the immune competence against microbial pathogens. These T cells should therefore be suitable for being adoptively transferred to the recipient to provide transient immunocompetence but avoid GvHD induction.