Demystifying Tolerance

Although tolerance to transplanted organs has fascinated clinicians and scientists for decades, it is only recently that inducing tolerance in selected clinical settings has been possible. 1 Sykes M. Chandran S. Kawai T. et al. Meeting report: the fifth International Samuel Strober Workshop on clinical immune tolerance. Transplantation. 2023; 107: 564-569https://doi.org/10.1097/TP.0000000000004473 Crossref PubMed Scopus (1) Google Scholar A major barrier to the development of tolerance strategies is our incomplete knowledge of the mechanisms underlying the tolerant state. This lack of mechanistic understanding limits both enthusiasm for established tolerance-inducing strategies and the development of new strategies to induce operational tolerance (OT). In this issue of the American Journal of Transplantation, Azim et al 2 Azim S. Zubair H. Rousselle T. et al. Single-cell RNA sequencing reveals peripheral blood mononuclear immune cell landscape associated with operational tolerance in a kidney transplant recipient. Am J Transplant. 2023 May 16; (S1600-6135(23)00466-5. Online ahead of print)https://doi.org/10.1016/j.ajt.2023.04.035 Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar report the use of a powerful new approach to compare gene expression profiles at the single-cell level in peripheral blood mononuclear cells (PBMCs) from an OT kidney transplant recipient to those of 2 healthy controls and a transplant recipient receiving standard of care immunosuppression (SOC). Using single-cell RNA sequencing (scRNA-Seq) technology, they report that the proportion of TCL1A+ naïve B cells and LSGAL1+ regulatory T cells (Tregs) was increased in the OT recipient as compared to a recipient receiving SOC and more closely resembled that of 2 healthy control subjects. Analysis of ligand-receptor interactions revealed interactions between B cells and Tregs, which enhance the proliferation and suppressive function of Tregs. Similar interactions were not observed in the subject receiving SOC. The predominance of genes associated with naïve B cells as well as interactions between B and T cells leading to an increased frequency of Tregs such as those described by Azim et al are consistent with reports from other groups as well as a recently developed immunosuppression-independent consensus gene expression signature of OT kidney transplant recipients. 3 Christakoudi S. Runglall M. Mobillo P. et al. Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy. EBioMedicine. 2020; 58:102899https://doi.org/10.1016/j.ebiom.2020.102899 Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Single-cell RNA sequencing reveals peripheral blood mononuclear immune cell landscape associated with operational tolerance in a kidney transplant recipientAmerican Journal of TransplantationVol. 23Issue 9PreviewOperational tolerance (OT) after kidney transplantation is defined as stable graft acceptance without the need for immunosuppression therapy. However, it is not clear which cellular and molecular pathways are driving tolerance in these patients. In this first-of-its-kind pilot study, we assessed the immune landscape associated with OT using single-cell analyses. Peripheral mononuclear cells from a kidney transplant recipient with OT (Tol), 2 healthy individuals (HC), and a kidney transplant recipient with normal kidney function on standard-of-care immunosuppression (SOC) were evaluated. Full-Text PDF