Nathalie Boon

Expansion of memory-type CD8⁺ T cells correlates with the failure of early immunosuppression withdrawal after cadaver liver transplantation using high-dose ATG induction and rapamycin

Background We report on a pilot study investigating the feasibility of early immunosuppression withdrawal after liver transplantation (LT) using antithymocyte globulin (ATG) induction and rapamycin. Methods LT recipients received 3.75 mg/kg per day ATG from days 0 to 5 followed by rapamycin-based immunosuppression. In the absence of acute rejection (AR), rapamycin was withdrawn after month 4. Immunomonitoring included analysis of peripheral T-cell phenotypes and clonality, cytokine production in mixed lymphocyte reaction, and characterization of intragraft infiltrating cells. Results Ten patients were enrolled between October 2009 and July 2010. In the first three patients, complete withdrawal of immunosuppression after month 4 led to AR. No further withdrawals of immunosuppressive were attempted. Two AR occurred in the remaining seven patients. ATG induced profound T-cell depletion followed by CD8+ T-cell reexpansion exhibiting memory/effector-like phenotype associated with progressive oligoclonal T-cell expansion (V&bgr;/HPRT ratio) and gradually enhanced anti-cytomegalovirus and anti–Epstein-Barr virus T-cell frequencies. Patients developing AR were characterized by decreased TCAIM expression. AR were associated with increased donor-specific production of interferon (IFN)-&ggr; and interleukin (IL)-17, increased intragraft expression of IFN-&ggr; mRNA, and significant CD8+ T-cell infiltrates colocalizing with IL-17+ cells. Conclusion High-dose ATG followed by short-term rapamycin treatment failed to promote early operational tolerance to LT. AR correlates with expansion of memory-type CD8+ T cells and increased levels of IFN-&ggr; and IL-17 in mixed lymphocyte reaction and in the graft. This suggests that resistance and preferential expansion of effector memory T-cell in lymphopenic environment could represent the major barrier for establishment of tolerance to LT in approaches using T-cell–depleting induction.

Acute Liver Transplant Rejection Upon Immunosuppression Withdrawal in a Tolerance Induction Trial: Potential Role of IFN-gamma-secreting CD8(+) T Cells

We designed a pilot trial in cadaveric liver transplantation to determine whether induction with antithymocyte globulins (ATG) and sirolimus would allow immunosuppression withdrawal. Patients received ATG 3.75 mg/kg per day from day 1 to 5 after transplantation followed by sirolimus for 4 to 6 months. We monitored interleukin (IL)-7 serum levels, interferon (IFN)-γ, and IL-2 mRNA accumulation in mixed leukocyte reaction and intragraft IFN-γ mRNA expression. In the first three patients, immunosuppression discontinuation was followed by reversible acute rejection occurring on days 280, 246, and 163 posttransplantation, corresponding to days 140, 40, and 39 after drug withdrawal, respectively. At the time of rejection, blood CD8+ T-cells counts had returned to or above pretransplant levels in two of three patients, whereas CD4+ T-cell count remained low. IL-7 serum levels rose in all three patients in the first months after transplantation and IFN-γ mRNA accumulated in mixed leukocyte reaction between recipient T cells and donor spleen cells at the time of rejection. High levels of IFN-γ mRNA were consistently detected in liver biopsy performed at the time of rejection. In conclusion, lymphopenia-induced IL-7 production after induction with ATG and sirolimus might lead to emergence of IFN-γ-secreting CD8+ T-cells responsible for acute rejection after immunosuppression withdrawal.

Induction of tolerance in solid organ transplantation: the rationale to develop clinical protocols in liver transplantation.

Minimization or withdrawal of immunosuppressive treatments after organ transplantation represents a major objective for improving quality of life and long-term survival of grafted patients. Such a goal may be reached under some clinical conditions, particularly in liver transplantation, making these patients good candidates for tolerance trials. In this context in liver transplantation, the central questions are (1) how to promote the natural propensity of the liver graft to be accepted, (2) which type of immunosuppressive drug should be used for induction and maintenance, and (3) which biomarkers could be used to discriminate tolerant patients from those requiring long-term immunosuppression. Induction therapies using aggressive T-cell-depleting agents may favor graft acceptance. However, persistent and/or rapidly reemerging cell lines, such as memory-type cells or CD8(+) T cells, could represent a significant barrier for induction of tolerance. The type of maintenance drugs also remains questionable. Calcineurin inhibitors may be eventually deleterious in the context of tolerance protocols, through inhibitory effects on regulatory T cells, that are not observed with rapamycin. In conclusion, significant efforts must be made to achieve reliable strategies for immunosuppression minimization or withdrawal after organ transplantation into the clinics.

Liver Transplantation in Cases of Portal Vein Thrombosis in the Recipient: A Case Report and Review of the Various Options

Several surgical techniques have been developed to allow liver transplantation in cases of complete portal vein thrombosis in the recipient. Despite this, these transplantations remain associated with a significant complication rate. We report herein a case of liver transplantation in a patient with complete portal vein thrombosis, underlying the potential pitfalls and the risk of intestinal sutures in case of hepaticojejunostomy. We discuss the technical options and their relative indications in such cases.

Insulin resistance is associated with esophageal varices in alcoholic liver disease patients.

Background and aim Insulin resistance plays an important role in chronic liver disease, where it has been associated with the progression of fibrosis and correlated with portal hypertension in cirrhotic patients with mixed etiology. However, the impact of insulin resistance in alcoholic liver disease remains mostly unknown. The aim of this study was to evaluate the association between insulin resistance, portal hypertension, severity of liver disease, and mortality in patients with alcoholic cirrhosis. Patients and methods A total of 106 consecutive alcoholic cirrhotic patients undergoing hepatic venous pressure gradient measurement at Erasme Hospital were included. Insulin resistance was estimated using the homeostatic model assessment-2 index. Results The median model for end-stage liver disease (MELD) score was 15 (9–21) and the mean hepatic venous pressure gradient was16.3±6 mmHg. Twenty-six percent of the patients had compensated cirrhosis. Insulin resistance was significantly associated with portal hypertension in compensated cirrhotic patients and with the presence of esophageal varices, but was not associated with the MELD score and mortality. MELD score was the only independent covariate associated with mortality at 6 (P<0.001) and 12 months (P<0.001). Conclusion Insulin resistance is associated with the presence of esophageal varices, suggesting that the presence of insulin resistance could be harmful to alcoholic liver disease patients.