Host Indoleamine 2,3-Dioxygenase Is a Critical Regulator of Acute GVHD Lethality.

Abstract

Graft versus host disease (GVHD), the major cause of morbidity and mortality after bone marrow transplant (BMT), is initiated following activation of donor T cells by host antigen presenting cells (APCs). The immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) is expressed by APCs and parenchymal cells and is further inducible by inflammation. We investigated whether lethal conditioning and GVHD induce IDO and if IDO prevents tissue injury by suppressing immune responses at the induction site. Using a fully MHC-mismatched murine GVHD model, we determined that IDO is a critical regulator of GVHD, most strikingly in the colon, where epithelial cells dramatically upregulated IDO expression during GVHD. No IDO upregulation was detected in mice that received irradiation only or irradiation and T cell-depleted BM without added alloreactive T cells. When mice with a genetic ablation of the IDO gene (IDO−/−) were used as recipients of BM and T cells, they suffered accelerated GVHD lethality compared to wild-type recipients, displaying increased colonic inflammation and T cell infiltration. This was true using grafts of either CD4+ T cells or combined CD4+ and CD8+ T cells. In addition, the IDO inhibitor 1-methyltryptophan caused accelerated GVHD in wild-type recipients. Lethality was not due to increased radiation sensitivity, as sublethally irradiated IDO−/− recipients showed no morbidity, and syngeneic BM was capable of rescuing lethally irradiated IDO−/− recipients. GVHD protection was not mediated by early control of T cell proliferation or apoptosis in lymph nodes or spleen. Furthermore, IDO did not affect expression of T cell effector molecules in lymphoid organs. Though studies have suggested a link between IDO and T regulatory cell (Treg) function, Treg depletion of donor grafts did not abrogate the IDO effect, indicating donor Tregs are not required for the suppressive function of IDO. Conversely, cultured Tregs added to the graft delayed GVHD in IDO−/− recipients, proving Tregs do not require host IDO for their function in this model. Instead, colons from IDO−/− hosts contained more proliferating CD4+ cells than wild-type colons after transplant. Together, this evidence suggests that in GVHD IDO acts primarily at the site of its expression to decrease effector T cell proliferation, diminish colonic inflammation, and reduce disease severity. These studies are the first to identify a function for IDO in GVHD lethality and suggest that modulation of the IDO pathway may be an effective strategy for treatment of this disease.