Sonia Norris

Biomarkers of Tolerance in Kidney Transplantation: Are We Predicting Tolerance or Response to Immunosuppressive Treatment?

We and others have previously described signatures of tolerance in kidney transplantation showing the differential expression of B cell–related genes and the relative expansions of B cell subsets. However, in all of these studies, the index group—namely, the tolerant recipients—were not receiving immunosuppression (IS) treatment, unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS‐independent signature of tolerance. Analyzing gene expression in three independent kidney transplant patient cohorts (232 recipients and 14 tolerant patients), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B cells. We have defined and validated a new gene expression signature that is independent of drug effects and also differentiates tolerant patients from healthy controls (cross‐validated area under the receiver operating characteristic curve [AUC] = 0.81). In a prospective cohort, we have demonstrated that the new signature remained stable before and after steroid withdrawal. In addition, we report on a validated and highly accurate gene expression signature that can be reliably used to identify patients suitable for IS reduction (approximately 12% of stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS minimization safe and hence allow critical improvements in kidney posttransplant management.

Reduced Tcr Signaling Contributes to Impaired Th17 Responses in Tolerant Kidney Transplant Recipients

Background The development of spontaneous kidney transplant tolerance has been associated with numerous B cell–related immune alterations. We have previously shown that tolerant recipients exhibit reduced B-cell receptor signalling and higher IL-10 production than healthy volunteers. However, it is unclear whether cluster of differentiation (CD)4+ T cells from tolerant recipients also display an anti-inflammatory profile that could contribute to graft maintenance. Methods CD4+ T cells were isolated from kidney transplant recipients who were identified as being tolerant recipients, patients with chronic rejection or healthy volunteers. CD4+ T cells from the 3 groups were compared in terms of their gene expression profile, phenotype, and functionally upon activation. Results Gene expression analysis of transcription factors and signalling proteins, in addition to surface proteins expression and cytokine production, revealed that tolerant recipients possessed fewer Th17 cells and exhibited reduced Th17 responses, relative to patients with chronic rejection or healthy volunteers. Furthermore, impaired T-cell receptor signalling and altered cytokine cooperation by monocytes contributed to the development of Th17 cells in tolerant recipients. Conclusions These data suggest that defective proinflammatory Th17 responses may contribute to the prolonged graft survival and stable graft function, which is observed in tolerant recipients in the absence of immunosuppressive agents.

Absence of Anti-Donor Specific Antibodies in Drug-Free Tolerant Kidney Transplant Recipients: 1920

Mobillo P.1, Norris S.1, Rebollo-Mesa I.1, Nova-Lamperti E.1, Kamra Y.2,3, Lord G.2,3,4, Vaughan R.2,5, Lechler R.2,4, Hernandez-Fuentes M.1,3, GAMBIT Consortium; Immune Tolerance Network; Indices of Tolerance Consortium 1King‘s College London, MRC Centre for Transplantation, London, United Kingdom, 2King‘s College London, London, United Kingdom, 3NIHR Comprehensive Biomedical Research Centre at Guy‘s and St Thomas‘s Hospital. NHS Foundation Trust in partnership with King‘s College London and King‘s College Hospital, London, United Kingdom, 4King‘s Health Partners, London, United Kingdom, 5Guy‘s and St Thomas‘ NHS foundation Trust, Clinical Transplantation laboratory, London, United Kingdom