Biomarkers of clinical transplantation tolerance
Lead Research Organisation:
King's College London
Department Name: Immunology Infection and Inflam Diseases
Abstract
Kidney transplant recipients need to be treated with drugs that hold down the immune system (immunosuppression) for life. These drugs have important side effects and we currently don?t have means to know how much treatment each patient needs.
We have recently defined a series of tests that may allow us to identify which kidney transplant recipients do not reject their grafts when taken off immunosuppression. These are very preliminary results. We need to perform several studies to confirm them.
Thus, we are proposing to repeat the study in new groups of patients. If validated our tests could be used to safely minimise or remove immunosuppression in those kidney transplant recipients that don?t need it.
We have recently defined a series of tests that may allow us to identify which kidney transplant recipients do not reject their grafts when taken off immunosuppression. These are very preliminary results. We need to perform several studies to confirm them.
Thus, we are proposing to repeat the study in new groups of patients. If validated our tests could be used to safely minimise or remove immunosuppression in those kidney transplant recipients that don?t need it.
Technical Summary
Studying a cohort of extremely rare but very informative tolerant kidney transplant recipients we have recently defined a set of biomarkers that can identify them with specificity of 0.964 and sensitivity of 0.933. Using molecular profiling, flow cytometry and IFNgamma; ELISpots we identify patients who have been weaned off all immunosuppression for longer than 1 year and whose kidney function has remained stable. A similar set of biomarkers (B cell expansion and molecular expression) was found by the Immune Tolerance Network (USA) on a similar group of patients.
To translate these tolerance biomarker sets into clinically-useful tools, we propose to test if they are predictive of the tolerant state and if their expression is stable with time. We will do this in collaboration with the US based researchers to achieve a common tolerant biomarker set.
? Hypotheses to test:
? More than 80% of the newly recruited tolerant kidney transplant recipients are positive for the common tolerant biomarker set, compared to less than 20% in control groups.
? Stability of the set of biomarkers of tolerance is maintained in more than 90% of the tolerant patients as long as their function remains stable.
? The expanded B cell numbers detected in both studies reflect an expansion of regulatory B cells in peripheral blood from tolerant kidney transplant recipients.
Methods: An observational cross-sectional study in 3 groups of patients:
? Patient groups:
1.- New set of tolerant kidney transplant recipients from the US and Europe. Control groups: healthy controls, stable patients on triple therapy, stable patients on steroid monotherapy, patients with immunologically driven chronic allograft nephropathy and patients with psoriasis in remission.
2.- All tolerant kidney transplant recipients previously studied to test stability of the signature.
3.- Long term kidney transplant recipients with stable function and patients matched for time post-transplantation with deteriorating function in the last 12 months.
Measurements
? Primary outcome: frequency of patients that display the composite set of biomarkers of tolerance.
? Secondary Outcomes: Patient, graft survival, and biopsy proven acute rejection, independently and as a composite variable, graft function (eGFR, CRT), infection rate, cancer rate, major CV events. To compare between patients positive and negative for the biomarkers of tolerance.
Validation of the common tolerant biomarker set will mean that it could be used as a surrogate end point in clinical trials of transplantation tolerance; this will have substantial implications for the management of transplant patients.
To translate these tolerance biomarker sets into clinically-useful tools, we propose to test if they are predictive of the tolerant state and if their expression is stable with time. We will do this in collaboration with the US based researchers to achieve a common tolerant biomarker set.
? Hypotheses to test:
? More than 80% of the newly recruited tolerant kidney transplant recipients are positive for the common tolerant biomarker set, compared to less than 20% in control groups.
? Stability of the set of biomarkers of tolerance is maintained in more than 90% of the tolerant patients as long as their function remains stable.
? The expanded B cell numbers detected in both studies reflect an expansion of regulatory B cells in peripheral blood from tolerant kidney transplant recipients.
Methods: An observational cross-sectional study in 3 groups of patients:
? Patient groups:
1.- New set of tolerant kidney transplant recipients from the US and Europe. Control groups: healthy controls, stable patients on triple therapy, stable patients on steroid monotherapy, patients with immunologically driven chronic allograft nephropathy and patients with psoriasis in remission.
2.- All tolerant kidney transplant recipients previously studied to test stability of the signature.
3.- Long term kidney transplant recipients with stable function and patients matched for time post-transplantation with deteriorating function in the last 12 months.
Measurements
? Primary outcome: frequency of patients that display the composite set of biomarkers of tolerance.
? Secondary Outcomes: Patient, graft survival, and biopsy proven acute rejection, independently and as a composite variable, graft function (eGFR, CRT), infection rate, cancer rate, major CV events. To compare between patients positive and negative for the biomarkers of tolerance.
Validation of the common tolerant biomarker set will mean that it could be used as a surrogate end point in clinical trials of transplantation tolerance; this will have substantial implications for the management of transplant patients.