Alexis Buggenhout

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 In the absence of acute rejection (AR), rapamycin was withdrawn after month 4.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.

Pediatric En Bloc Dual Kidney‐Pancreas Transplantation Into an Adult Recipient: a Simplified Technique. Benefits of the en bloc kidney‐pancreas transplantation technique in pediatric donors

The lower age limit for pancreas donors is not well defined. Fear of inadequate islet β‐cell mass and of technical complications has hampered the use of pediatric donors. A surgical technique of ‘en bloc’ kidney‐pancreas is described.

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.

Cholecystectomy in cirrhotic patients: pitfalls and reasonable recommendations.

Abstract Cholecystectomy in cirrhotic patients remains a high risk procedure. The recent literature was reviewed in the objective to elaborate (evidence-based) recommendations for therapeutic decision. In patients with Child Pugh A or B cirrhosis, the laparoscopic approach should be preferred as it is associated with reduced morbidity and mortality as compared with open surgery (level B). In patients with decompensated Child Pugh C cirrhosis, the scarcity of literature data renders much more hazardous the definition of robust recommendations. In these patients, two options have to be considered beyond early laparoscopic cholecystectomy: first, a delayed surgery, in order to improve the preoperative patient’s general condition and namely the coagulation, and second, a percutaneous drainage in very severe cases (level C).

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.

Gastric endometriosis associated with transverse colon endometriosis: a case report of a very rare event.

AbstractGastric endometriosis is a very rare event. It enters in the differential diagnosis of cyclical or chronic epigastric pain, especially in the context of endometriotic patients. The diagnosis of a gastric submucosal mass requires further investigations to rule out the presence of malignancy or associated adenocarcinoma. Because of it can be associated with transverse colon endometriosis and/or diaphragmatic endometriosis, careful examination of the upper abdomen at laparoscopy should be emphasized. We report here a very rare case of gastric endometriosis associated with transverse colon endometriosis.

Biased expansion of memory-type CD8(+) T cells as a cause of acute rejection upon immunosuppression withdrawal in a tolerance pilot trial in liver transplantion

Introduction: Renal transplant biopsy allows adequate diagnosis of graft dysfunction.However it has its complications. Renal transplants are occasionally placed intra-peritoneally particularly in simultaneous kidney pancreas transplantation(SPK). Biopsy from such kidneys is expected to be more challenging and fraught with complications compared to extra-peritoneally placed organs due to the absence of external tamponade. Aim: Examine the safety and utility of kidney biopsies of intra-peritoneally placed renal (IPK) transplant in the setting of SPK. Patients and results: All renal transplant biopsies of IPK were performed under ultrasound guidance using an 18 gauge automated biopsy needle. Biopsies were evaluated by light microscopy and further cores were taken if required for adequate pathological evaluation. Patients had bed rest six hours post biopsy with regular observation. If a patient was on warfarin or heparin it was stopped beforehand. However, aspirin was not stopped. All patients had their coagulation profile evaluated before biopsy. From 1/2005 to 10/2008, 43 biopsies of IPK were performed in 20 patients out of 41 with SPK. All biopsies had adequate material for pathological diagnosis.24 biopsies revealed rejection, while 19 biopsies revealed other pathological diagnoses (ATN, CNI toxicity). One patient suffered from bleeding that required exploration and 4 patients received blood transfusion (2 of them though because they had a low Hb prior to the IPK biopsy). There were minor episodes of post biopsy haematuria early following the procedure but none was associated with clots in the urine or required catheterisation for retention. Conclusion: Renal transplant biopsy of intra-peritoneally placed adult kidneys in the context of SPK provides valuable information to aid diagnosis and management of patients, and it is safe, therefore it should not be avoided. However it should be dealt with more cautiously than biopsies from extra-peritoneally placed kidneys