Multiparameter Immune Profiling of Operational Tolerance in Liver Transplantation

• Published in: American journal of transplantation Vol. 7; no. 2; pp. 309 - 319
• Main Authors: Martínez‐Llordella, M., Puig‐Pey, I, Orlando, G., Ramoni, M., Tisone, G., Rimola, A., Lerut, J., Latinne, D., Margarit, C., Bilbao, I., Brouard, S., Hernández‐Fuentes, M., Soulillou, J. ‐P., Sánchez‐Fueyo, A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-02-2007; Blackwell
• Subjects: Alloimmune responses; Biological and medical sciences; CD4 Antigens - genetics; DNA - genetics; DNA, Viral - genetics; expression profiling; Gene Expression Profiling; Graft Rejection - diagnosis; Graft Rejection - genetics; Graft Rejection - immunology; Hepacivirus - genetics; Hepacivirus - pathogenicity; Humans; Immune Tolerance; Immunophenotyping; Immunosuppressive Agents - administration & dosage; Interleukin-2 Receptor alpha Subunit - genetics; liver transplantation; Liver Transplantation - immunology; Liver Transplantation - pathology; Medical sciences; Middle Aged; Predictive Value of Tests; Receptors, Antigen, T-Cell, gamma-delta - genetics; regulatory T cells; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; T-Lymphocytes, Regulatory - immunology; tolerance; Transplantation Immunology - genetics; Transplantation Tolerance - genetics; Immune response; Digestive system; Liver; Alloimmune responses; expression profiling; Transplantation; Homotransplantation; Allogeneic system; Gene expression profile; Isoimmunization; regulatory T cells; Treatment; Surgery; Immune tolerance; T-Lymphocyte; Graft; Regulatory cell; liver transplantation; tolerance
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2006.01621.x

Immunosuppressive drugs can be completely withdrawn in up to 20% of liver transplant recipients, commonly referred to as ‘operationally’ tolerant. Immune characterization of these patients, however, has not been performed in detail, and we lack tests capable of identifying tolerant patients among recipients receiving maintenance immunosuppression. In the current study we have analyzed a variety of biological traits in peripheral blood of operationally tolerant liver recipients in an attempt to define a multiparameter ‘fingerprint’ of tolerance. Thus, we have performed peripheral blood gene expression profiling and extensive blood cell immunophenotyping on 16 operationally tolerant liver recipients, 16 recipients requiring on‐going immunosuppressive therapy, and 10 healthy individuals. Microarray profiling identified a gene expression signature that could discriminate tolerant recipients from immunosuppression‐dependent patients with high accuracy. This signature included genes encoding for γδ T‐cell and NK receptors, and for proteins involved in cell proliferation arrest. In addition, tolerant recipients exhibited significantly greater numbers of circulating potentially regulatory T‐cell subsets (CD4+CD25+ T‐cells and Vδ1+ T cells) than either non‐tolerant patients or healthy individuals. Our data provide novel mechanistic insight on liver allograft operational tolerance, and constitute a first step in the search for a non‐invasive diagnostic signature capable of predicting tolerance before undergoing drug weaning.
Microarray profiling of peripheral blood on 16 operationally tolerant liver recipients identified some candidate features that could identify patients in which drug weaning is more likely to be successful.