Biomarkers to Discern Transplantation Tolerance after Allogeneic Hematopoietic Cell Transplantation

Although it is commonly accepted that allogeneic hematopoietic cell transplant (HCT) recipients develop transplantation tolerance and can quickly discontinue all immunosuppressive drugs, existing data does not support this concept. Most patients will require a prolonged duration of immunosuppression, lasting commonly several years. This has even greater importance, as the majority of transplants are now performed utilizing peripheral blood mobilized stem cells, which are associated with an increased risk of chronic graft-versus-host disease (cGVHD) and prolonged duration of immunosuppression. Despite these challenges, the approach to liberation from immunosuppression after HCT is empiric, and biomarkers of operational tolerance after HCT are lacking. Conversely, investigators in solid organ allografting have begun to examine tolerance associated gene expression in renal and hepatic allograft recipients. Significant challenges in the design and interpretation of these studies potentially limit comparisons. However, a relatively unified model is beginning to emerge, which largely recapitulates previously established mechanisms of immune tolerance. This evidence supports a state of immune quiescence with reduced expression of costimulation and immune response genes, and upregulation of cell cycle control genes. Data indirectly supports the importance of tumor growth factor (TGF)-β, supports the role of CD4+CD25+ regulatory T cells, and offers new insights into the role of natural killer (NK) cells. Distinct in hepatic allograft tolerance, emerging evidence highlights the importance of γδT cells, and selection of the Vγδ1+ subtype among the γδT cell population. The deficiencies in the current understanding of transplantation tolerance after HCT, as well as the inadequacies evident in the current empiric approach to immunosuppressive medication (IS) management after HCT make clear the rationale for investigation aimed at elucidating tolerance associated biomarkers after HCT.