CDX2 as a Prognostic Biomarker in Colon Cancer Dalerba, Piero; Sahoo, Debashis; Clarke, Michael F
The New England journal of medicine,
06/2016, Letnik:
374, Številka:
22
Journal Article
Background. Prevention of alloreactivity by rabbit anti-thymocyte globulins (rATG) may not only result from immunodepletion but also from the induction of T cells that control allogeneic immune ...responses. In the present prospective and controlled study, we investigated the effect of rATG on the frequency, function and phenotype of peripheral immunoregulatory CD4+ T cells in kidney transplant (KTx) patients. Methods. After transplantation, 16 patients received ATG-induction therapy and triple therapy consisting of tacrolimus, MMF and steroids. The control group (n = 18) received triple therapy only. By flow cytometry, T cells were analysed for CD25, FoxP3, CD127, CD45RO and CCR7. To study their suppressive capacities, CD25bright T cells were co-cultured with CD25−/dim effector T cells (Teff) in mixed lymphocyte reactions (MLR), stimulated with donor and third party (3P) antigens. Results. Pre-transplant levels of FoxP3+CD127−/low T cells were 6% of CD4+ T cells. One week post-ATG treatment, no measurable numbers of regulatory T cells were present (P < 0.01). After 4 weeks, the cell numbers of CD4+FoxP3+CD127−/low T cells slowly reappeared and thereafter remained low (P < 0.01). At 14 weeks, a significant shift towards the CD45RO+CCR7+ (central memory) phenotype within CD4+FoxP3+ T cells was observed (P < 0.01). At 26 weeks, the proliferative alloresponses of the PBMC and CD25−/dim Teff profoundly decreased compared to pre-transplant (P = 0.01 and P = 0.02 respectively), while the regulatory capacity of the CD25bright T cells, of which 90% consisted of FoxP3+CD127−/low T cells, remained unaffected. The CD25bright T cells suppressed the anti-donor (94%) and 3P responses (93%). Conclusion. Our findings show that rATG therapy does not spare peripheral immunoregulatory T cells in vivo, but after regeneration preserves their suppressive activity.
Summary
In deceased donor kidney transplantation donor age is known to influence graft survival. The influence of living donor age on graft survival is questioned. We compared the influence of living ...and deceased donor age on the outcome of renal transplantation. All 1821 transplants performed in our center between 1990 and 2009 were included in the analysis. Observation was until April 2012. A total of 941 patients received a deceased donor kidney and 880 a living donor kidney. In multivariate Cox analysis, recipient age, maximum and current panel reactive antibodies, transplant year, HLA‐mismatches, donor age, donor gender, donor type, delayed graft function, and calcineurin inhibitor (CNI) and prednisone as initial immunosuppression were found to have a significant influence on death‐censored graft failure. The influence of both living and deceased donor age followed a J‐shaped curve, above 30 years the risk increased with increasing age. Donor type and donor age had an independent influence. The graft failure risk of deceased donor transplantation is almost twice that of living donor transplantation so that a 60‐year‐old living donor kidney has the same graft failure risk as a 20‐year‐old deceased donor kidney.
This is an Erratum to BMC Medicine 2015, 13:111 indicating the correct name for one of the authors.Please see related article: http://www.biomedcentral.com/1741-7015/13/111. Authors’ corrected note: ...Jan NM IJzermans last name was incorrectly spelled in the author list and was indicated as Jan NM IJermans in our published article 1. The erratum includes this author’s correct last name. The erratum includes this information. Corrected text: Jan NM IJzermans
Abstract Introduction Living kidney donors comprise a unique group of “patients”, undergoing an operation for the benefit of others. The informed consent process is therefore valued differently. ...Although this is a team effort, the surgeon is responsible for performing the donor nephrectomy, and often the one held accountable, should adverse events occur. Although there is some consensus on how the informed consent procedure should be arranged, practices vary. The aim of this study was to evaluate the surgical informed consent procedure for live donor nephrectomy, with special regards to disclosure of complications. Methods A web-based survey was sent to all kidney transplant surgeons (n=50) in eight transplant centers with questions regarding the local procedure and disclosure of specific details. Results Response rate was 98% (n=49), of which 32 (65%) were involved in living donor education; overall, transplant- (50%), vascular- (31%), and abdominal surgeons (13%), and urologists (6%) performed donor nephrectomies in the eight centers. Informed consent procedures varied, ranging from assumed to signed consent. Bleeding was the only complication every surgeon mentioned. Risk of death was always mentioned by 16 surgeons (50%), sometimes by 13 (41%), three surgeons (9%) never disclosed this disastrous complication. Reported mortality rates ranged from 0.003% to 0.1%. Mentioning frequencies for all other complications varied. Conclusion Important complications are not always disclosed during the surgical informed consent process for live donor nephrectomy. Informed consent procedures vary. To optimally prepare living kidney donors for the procedure, a standardized informed consent procedure for live donor nephrectomy is highly recommended.
In spite of maintenance treatment with immunosuppressive drugs, tubulitis still occurs and can lead to structural kidney graft damage. We hypothesize that human renal tubular epithelial cells (TECs) ...trigger selective proliferation of recipient T-cell subsets with variable sensitivity to immunosuppressive drugs.
Recipient peripheral blood mononuclear cells were cocultured with donor-derived TECs for 7 days. The proliferation of the total CD4 T-cell pool was assessed. Next, we analyzed which CD4 T-cell subset proliferated and how this response was affected by tacrolimus, everolimus, prednisolone, and mycophenolic acid (MPA) in clinically relevant concentrations.
CD4 T-cell proliferation upon TEC encounter was mainly executed by memory T cells. Interestingly, 38%±7% of the proliferating CD4 T-cell pool showed a CD28 phenotype. These proliferating CD4CD28 memory T cells produced high levels of interferon-γ, tumor necrosis factor-α, and the cytolitic protease granzyme B. TEC-reactive CD4 T-cell proliferation was significantly suppressed by tacrolimus, everolimus, prednisolone, and MPA (P<0.05). Surprisingly and in contrast to prednisolone and MPA, neither tacrolimus nor everolimus could inhibit the CD4CD28 T-cell proliferative response.
Our data show substantial proliferation of TEC-reactive CD4CD28 memory T cells, which are resistant to tacrolimus and everolimus. This phenomenon might play an important mechanistic role during cellular rejection under full immunosuppression.
This study aims to validate a previously reported recurrence clinical risk score (CRS).
Salvage transplantation after hepatocellular carcinoma (HCC) resection is limited to patients who recur within ...Milan criteria (MC). Predicting recurrence patterns may guide treatment recommendations.
An international, multicenter cohort of R0 resected HCC patients were categorized by MC status at presentation. CRS was calculated by assigning 1 point each for initial disease beyond MC, multinodularity, and microvascular invasion. Recurrence incidences were estimated using competing risks methodology, and conditional recurrence probabilities were estimated using the Bayes theorem.
From 1992 to 2015, 1023 patients were identified, of whom 613 (60%) recurred at a median follow-up of 50 months. CRS was well validated in that all 3 factors remained independent predictors of recurrence beyond MC (hazard ratio 1.5-2.1, all P < 0.001) and accurately stratified recurrence risk beyond MC, ranging from 19% (CRS 0) to 67% (CRS 3) at 5 years. Among patients with CRS 0, no other factors were significantly associated with recurrence beyond MC. The majority recurred within 2 years. After 2 years of recurrence-free survival, the cumulative risk of recurrence beyond MC within the next 5 years for all patients was 14%. This risk was 12% for patients with initial disease within MC and 17% for patients with initial disease beyond MC.
CRS accurately predicted HCC recurrence beyond MC in this international validation. Although the risk of recurrence beyond MC decreased over time, it never reached zero.
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