Monocyte-mediated T-cell suppression and augmented monocyte tryptophan catabolism after human hematopoietic stem-cell transplantation

• Published in: Blood 2005-05, Vol.105 (10), p.4127-4134
• Main Authors: Hainz, Ursula, Obexer, Petra, Winkler, Christiana, Sedlmayr, Peter, Takikawa, Osamu, Greinix, Hildegard, Lawitschka, Anita, Pütschger, Ulrike, Fuchs, Dietmar, Ladisch, Stephan, Heitger, Andreas
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Apoptosis; Biological and medical sciences; Bone marrow, stem cells transplantation. Graft versus host reaction; Cell Proliferation; Cells, Cultured; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Humans; Kynurenine - metabolism; Male; Medical sciences; Middle Aged; Monocytes - metabolism; Monocytes - physiology; T-Lymphocytes - cytology; T-Lymphocytes - metabolism; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; Tryptophan - metabolism; Tryptophan Oxygenase - antagonists & inhibitors; Tryptophan Oxygenase - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-05-1726

T-cell dysfunction after human hematopoietic stem-cell transplantation (HSCT) is generally attributed to intrinsic T-cell defects. Here we show that the characteristic impaired proliferative responses to polyclonal stimulation of post-HSCT peripheral blood mononuclear cells (PB-MCs) were markedly (4-fold) improved by T-cell enrichment. Conversely, addback of post-HSCT monocytes to these enriched T cells dampened their proliferative responses, suggesting that post-HSCT monocytes effectively mediate T-cell suppression. As a mechanism possibly contributing to monocyte-mediated T-cell suppression, we investigated monocyte tryptophan catabolism by indoleamine 2,3-dioxygenase into kynurenine, which has been implicated in regulating T-cell responses. Compared with controls, all post-HSCT monocyte-containing cell cultures (total PBMCs, monocytes, and monocyte/T-cell cocultures), but not monocyte-depleted populations, secreted elevated amounts of kynurenine. Blockade of tryptophan catabolism improved the proliferative responses. The slightly increased kynurenine release and substantial release of neopterin by unstimulated post-HSCT monocytes suggests that they were in a state of continuous activation. Superimposed on this state, stimulation of these cells caused a striking, additional increase (10-fold) in kynurenine release, and they triggered marked apoptosis of autologous post-HSCT T cells. We conclude that the amplified kynurenine release by post-HSCT monocytes, particularly induced upon stimulation, may underlie their suppressor activity, which in turn may contribute to the depressed T-cell immune responses after HSCT.