Validation Study of an Operational Tolerance Signature in Korean Kidney Transplant Recipients

Operational tolerance (OT), defined as maintaining stable graft function without immunosuppression after transplant surgery, is an ideal goal for kidney transplant recipients (KTRs). Recent investigations have demonstrated the distinctive features of B cells, T cells, and dendritic cell-related gene signatures and the distributions of circulating lymphocytes in these patients; nonetheless, substantial heterogeneities exist across studies. This study was conducted to determine whether previously reported candidate gene biomarkers and the profiles of lymphocyte subsets of OT could be applied in Korean KTRs. Peripheral blood samples were collected from 153 patients, including 7 operationally tolerant patients. Quantitative real-time PCR and flow cytometry were performed to evaluate gene expression and lymphocyte subsets, respectively. Patients with OT showed significantly higher levels of B cell-related gene signatures (IGKV1D-13 and IGKV4-1), while T cell-related genes (TOAG-1) and dendritic cell-related genes (BNC2, KLF6, and CYP1B1) were not differentially expressed across groups. Lymphocyte subset analyses also revealed a higher proportion of immature B cells in this group. In contrast, the distributions of CD4⁺ T cells, CD8⁺ T cells, mature B cells, and memory B cells showed no differences across diagnostic groups. An OT signature, generated by the integration of IGKV1D-13, IGKV4-1, and immature B cells, effectively discriminated patients with OT from those in other diagnostic groups. Finally, the OT signature was observed among 5.6% of patients who had stable graft function for more than 10 years while on immunosuppression. In conclusion, we validated an association of B cells and their related signature with OT in Korean KTRs.

In vitro immune cell monitoring as a guide for long-term immunosuppression in adult liver transplant recipients

BACKGROUNDS/AIMS: We evaluated the clinical usability of immune cell monitoring in adult liver transplantation (LT) recipients. METHODS: This study was composed of two parts as using calcineurin phosphatase (CNP) activity assay and ImmuKnow assay independently as in vitro monitoring tools of immune cell function in adult LT recipients. RESULTS: There was a rough correlation between CNP activity and tacrolimus concentration in 33 patients. This association was evident in patients who were only administered tacrolimus, but disappeared after the co-administration of mycophenolate. In 118 healthy individuals, the mean proportion of helper T-cells was 37.4+/-8.1%. According to ImmuKnow assay, their immune responses were strong in 12 patients (10.2%), moderate in 92 patients (78.0%), and low in 14 patients (11.9%). In 85 patients waiting for LT, there was a rough correlation between the ImmuKnow ATP level and age. Their immune responses were strong in 0 patients (0%), moderate in 8 patients (9.4%), and low in 77 patients (90.6%). There was a difference in the ImmuKnow ATP levels between healthy individuals and patients with liver disease. In 137 LT recipients, there was no correlation between the ImmuKnow ATP levels and tacrolimus concentration. This trend did not change after grouping the patients according to co-administration with mycophenolate. Eight recipients experienced acute rejection, but none showed strong immune response. CONCLUSIONS: We think that both CNP activity assay and ImmuKnow assay are too limited to objectively determine the level of immunosuppression. Further studies should be performed to identify other methods for immune function monitoring.

Tolerancia inmune y trasplante hepático: introducción para clínicos / Immune tolerance and liver transplant: introduction for clinicians

Immunologic tolerance is the absence of immune response to an allograft, which is specific to graft and, therefore, implies an appropriate immune response to a third party. In clinical practice, a related concept is more frequently used: operational tolerance. Although its frequency is unknown in most of solid organ transplants it is present in the 20 percent of hepatic receptors. This means that tolerant receptors are able to maintain a normal graft function in complete absence of immunosuppressive drugs, avoiding the frequent –and sometimes severe– adverse effects related to its use. In this paper we aim to present physicians who are familiar to liver transplantation to basic concepts related to immune tolerance and operational tolerance in humans.

La tolerancia inmune es la ausencia de una respuesta efectora dirigida al injerto, la cual es específica y, por lo tanto, implica una apropiada respuesta inmune a una tercera parte. En la práctica clínica, un concepto relacionado, es frecuentemente utilizado: la tolerancia operacional. Su frecuencia es desconocida en el trasplante de la mayor parte de órganos sólidos, pero se estima que se desarrolla en el 20 por ciento de los receptores hepáticos. Estos receptores son capaces de mantener una función normal del injerto en ausencia completa e indefinida de inmunosupresores, lo cual les permite evitar los frecuentes y algunas veces graves efectos adversos relacionados con el uso de inmunosupresores. Este artículo pretende introducir a los médicos dedicados al trasplante hepático, a los conceptos básicos relacionados con la tolerancia inmune y la tolerancia operacional en humanos.