Virus‐specific T cells can recognize allogeneic HLA (allo‐HLA) through TCR cross‐reactivity. The allospecificity often differs by individual (private cross‐reactivity) but also can be shared by ...multiple individuals (public cross‐reactivity); however, only a few examples of the latter have been described. Because these could facilitate alloreactivity prediction in transplantation, we aimed to identify novel public cross‐reactivities of human virus‐specific CD8+ T cells directed against allo‐HLA by assessing their reactivity in mixed‐lymphocyte reactions. Further characterization was done by studying TCR usage with primer‐based DNA sequencing, cytokine production with ELISAs, and cytotoxicity with 51chromium‐release assays. We identified three novel public allo‐HLA cross‐reactivities of human virus‐specific CD8+ T cells. CMV B35/IPS CD8+ T cells cross‐reacted with HLA‐B51 and/or HLA‐B58/B57 (23% of tetramer‐positive individuals), FLU A2/GIL (influenza IMP58‐66 HLA‐A*02:01/GILGFVFTL) CD8+ T cells with HLA‐B38 (90% of tetramer‐positive individuals), and VZV A2/ALW (varicella zoster virus IE62593‐601 HLA‐A*02:01/ALWALPHAA) CD8+ T cells with HLA‐B55 (two unrelated individuals). Cross‐reactivity was tested against different cell types including endothelial and epithelial cells. All cross‐reactive T cells expressed a memory phenotype, emphasizing the importance for transplantation. We conclude that public allo‐HLA cross‐reactivity of virus‐specific memory T cells is not uncommon and may create novel opportunities for alloreactivity prediction and risk estimation in transplantation.
Screening for alloreactivity of virus‐specific memory T cells unmasks several public virus‐specific T cell receptors that cross‐react with the same allogeneic HLA in multiple unrelated individuals.
Background.
Pneumocystis jiroveci pneumonia (PCP) is an important cause of morbidity and mortality in renal transplant recipients (RTRs). Chemoprophylaxis with trimethoprim/sulphamethoxazole is ...recommended during the early post-transplantation period, but the optimal duration has not been determined and a main drawback of chemoprophylaxis is the development of resistance of the commensal faecal flora. A cluster outbreak of PCP occurred in our outpatient Renal Transplant Unit. We aimed to investigate risk factors for PCP in RTRs to determine who should receive long-term chemoprophylaxis.
Methods. In a case-control study, we investigated common demographic variables and immunological parameters. Nine PCP cases diagnosed between August 2006 and April 2007 were matched with 18 control patients, who did not develop PCP, received their transplant in the same time-period and had a similar follow-up period with a comparable immunosuppressive drug regimen.
Results. The median time from transplantation to PCP was 19 months. We observed no significant differences in gender, age, donor type or number of rejections. In PCP cases, the median lymphocyte count just before PCP diagnosis was 0.49 (0.26-0.68), which was significantly reduced compared to the control patients after a similar follow-up period (median 1.36, 0.59-3.04, P = 0.002). This lymphocytopaenia was chronic and existed in most patients already for many months. CD4+ T-cell counts were also significantly reduced in the PCP cases. We found no difference in the Th1, Th2 and Th17 subsets between PCP cases and control patients.
Conclusion. Long-term prophylactic therapy for PCP may be indicated for RTR with persistent severe lymphocytopaenia.
CD8(+) T-cell responses against latent viruses can cover considerable portions of the CD8(+) T-cell compartment for many decades, yet their initiation and maintenance remains poorly characterized in ...humans. A key question is whether the clonal repertoire that is raised during the initial antiviral response can be maintained over these long periods. To investigate this we combined next-generation sequencing of the T-cell receptor repertoire with tetramer-sorting to identify, quantify and longitudinally follow virus-specific clones within the CD8(+) T-cell compartment. Using this approach we studied primary infections of human cytomegalovirus (hCMV) and Epstein Barr virus (EBV) in renal transplant recipients. For both viruses we found that nearly all virus-specific CD8(+) T-cell clones that appeared during the early phase of infection were maintained at high frequencies during the 5-year follow-up and hardly any new anti-viral clones appeared. Both in transplant recipients and in healthy carriers the clones specific for these latent viruses were highly dominant within the CD8(+) T-cell receptor Vβ repertoire. These findings suggest that the initial antiviral response in humans is maintained in a stable fashion without signs of contraction or changes of the clonal repertoire.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Radiofrequency ablation (RFA) is safe and effective for eradicating Barrett's esophagus (BE) and BE-associated early neoplasia. Most RFA studies have limited the baseline length of BE (<10 ...cm), and therefore little is known about RFA for longer BE. Objective To assess the safety and efficacy of RFA with or without prior endoscopic resection (ER) for BE ≥10 cm containing neoplasia. Design Prospective trial. Setting Two tertiary-care centers. Patients This study involved consecutive patients with BE ≥10 cm with early neoplasia. Intervention Focal ER for visible abnormalities, followed by a maximum of 2 circumferential and 3 focal RFA procedures every 2 to 3 months until complete remission. Main Outcome Measurements Complete remission, defined as endoscopic resolution of BE and no intestinal metaplasia (CR-IM) or neoplasia (CR-neoplasia) in biopsy specimens. Results Of the 26 patients included, 18 underwent ER for visible abnormalities before RFA. The ER specimens showed early cancer in 11, high-grade intraepithelial neoplasia (HGIN) in 6, and low-grade intraepithelial neoplasia (LGIN) in 1. The worst residual histology, before RFA and after any ER, was HGIN in 16 patients and LGIN in 10 patients. CR-neoplasia and CR-IM were achieved in 83% (95% confidence interval CI, 63%-95%) and 79% (95% CI, 58%-93%), respectively. None of the patients had fatal or severe complications and 15% (95% CI, 4%-35%) had moderate complications. During a mean (± standard deviation) follow-up of 29 (± 9.1) months, no neoplasia recurred. Limitations Tertiary-care center, short follow-up. Conclusion ER for visible abnormalities, followed by RFA of residual BE is a safe and effective treatment for BE ≥10 cm containing neoplasia, with a low chance of recurrence of neoplasia or BE during follow-up.
•LCNEC has radiological characteristics of both SCLC and NSCLC.•LCNEC can be classified in molecular SCLC-like and NSCLC-like subtypes.•Molecular LCNEC subtypes could not be identified based on ...radiological imaging.•Most LCNEC are molecular SCLC-like, but have a radiological NSCLC-like appearance.•These results highlight LCNEC as a unique tumor entity.
Radiological characteristics and radiomics signatures can aid in differentiation between small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). We investigated whether molecular subtypes of large cell neuroendocrine carcinoma (LCNEC), i.e. SCLC-like (with pRb loss) vs. NSCLC-like (with pRb expression), can be distinguished by imaging based on (1) imaging interpretation, (2) semantic features, and/or (3) a radiomics signature, designed to differentiate between SCLC and NSCLC.
Pulmonary oncologists and chest radiologists assessed chest CT-scans of 44 LCNEC patients for ‘small cell-like’ or ‘non-small cell-like’ appearance. The radiologists also scored semantic features of 50 LCNEC scans. Finally, a radiomics signature was trained on a dataset containing 48 SCLC and 76 NSCLC scans and validated on an external set of 58 SCLC and 40 NSCLC scans. This signature was applied on scans of 28 SCLC-like and 8 NSCLC-like LCNEC patients.
Pulmonary oncologists and radiologists were unable to differentiate between molecular subtypes of LCNEC and no significant differences in semantic features were found. The area under the receiver operating characteristics curve of the radiomics signature in the validation set (SCLC vs. NSCLC) was 0.84 (95% confidence interval (CI) 0.77-0.92) and 0.58 (95% CI 0.29-0.86) in the LCNEC dataset (SCLC-like vs. NSCLC-like).
LCNEC appears to have radiological characteristics of both SCLC and NSCLC, irrespective of pRb loss, compatible with the SCLC-like subtype. Imaging interpretation, semantic features and our radiomics signature designed to differentiate between SCLC and NSCLC were unable to separate molecular LCNEC subtypes, which underscores that LCNEC is a unique disease.
Weekly chemotherapy and concurrent radiotherapy for 5 weeks before curative resection in patients with esophageal or esophagogastric-junction cancer resulted in a pathologically complete response in ...29% of patients and doubled the median overall survival to 4 years.
With new diagnoses in more than 480,000 patients annually, esophageal cancer is the eighth most common cancer worldwide.
1
It is a highly lethal disease, causing more than 400,000 deaths per year.
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The incidence of esophageal adenocarcinoma is rapidly rising, whereas that of squamous-cell carcinoma remains unchanged.
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Despite adequate preoperative staging, 25% of patients treated with primary surgery have microscopically positive resection margins (R1), and the 5-year survival rate rarely exceeds 40%.
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The role of neoadjuvant chemoradiotherapy has been debated for several decades. In most randomized trials, no survival benefit could be shown, and the trials were criticized for inadequate trial . . .
Cytomegalovirus (CMV) is the most frequent infectious complication following solid organ transplantation (SOT). The virus, is responsible for both direct (viral syndrome, hepatitis, pneumonitis, ...colitis, etc.) and indirect effects (rejection, infections by other microorganisms and graft dysfunction). In this evidence-based guideline we deal with the most important aspects of CMV infection in SOT recipients, including pre- and post-transplant diagnosis assessment and risk factors, with special emphasis on the prevention and treatment of this viral infection. Overall, adequate management of CMV infection is a critical aspect of transplant patient care.
The efficacy of autologous (αβ) T-cell–based treatment strategies in chronic lymphocytic leukemia (CLL) has been modest. The Vγ9Vδ2-T cell subset consists of cytotoxic T lymphocytes with potent ...antilymphoma activity via a major histocompatibility complex–independent mechanism. We studied whether Vγ9Vδ2-T cells can be exploited as autologous effector lymphocytes in CLL. Healthy control Vγ9Vδ2-T cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived Vγ9Vδ2-T cells proved dysfunctional with respect to effector cytokine production and degranulation, despite an increased frequency of the effector-type subset. Consequently, cytotoxicity against malignant B cells was hampered. A comparable dysfunctional phenotype was observed in healthy Vγ9Vδ2-T cells after coculture with CLL cells, indicating a leukemia-induced mechanism. Gene-expression profiling implicated alterations in synapse formation as a conceivable contributor to compromised Vγ9Vδ2-T–cell function in CLL patients. Dysfunction of Vγ9Vδ2-T cells was fully reversible upon activation with autologous monocyte-derived dendritic cells (moDCs). moDC activation resulted in efficient expansion and predominantly yielded Vγ9Vδ2-T cells with a memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (TH1) phenotype in Vγ9Vδ2-T cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in Vγ9Vδ2-T cells. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of Vγ9Vδ2-T cells as effector T cells in CLL immunotherapy and favor further exploration of combining Vγ9Vδ2-T-cell–based therapy with ibrutinib.
•Healthy Vγ9Vδ2-T cells recognize and lyse CLL cells, but CLL-derived Vγ9Vδ2-T cells have impaired cytotoxicity and cytokine production.•Vγ9Vδ2-T–cell dysfunction is reversible upon ex vivo activation with autologous moDCs, and ibrutinib promotes an antitumor TH1 phenotype.
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An increasing number of elderly patients (≥65 years) receive a donor kidney from elderly donors after brain death (DBD) or after circulatory death (DCD). These organs are allocated within the ...Eurotransplant Senior Program, but outcomes must be evaluated. From the Dutch Organ Transplantation Registry, we selected 3597 recipients (≥18 years) who received a first DBD or DCD kidney during 2002-2012, and categorized them as young or elderly recipients receiving a graft from either a young or elderly donor, stratified by donor type. In multiple logistic regression analysis, elderly recipients of elderly DCD kidneys experienced more delayed graft function and acute rejection than did elderly recipients of young DBD kidneys (odds ratios 10.43 95% confidence interval (95% CI), 5.75 to 18.91 and 2.78 95% CI, 1.35 to 5.73, respectively). In Cox regression analysis, elderly recipients of elderly DCD kidneys had a 5-year mortality risk higher than that of elderly recipients of young DBD kidneys (hazard ratio, 1.86; 95% CI, 1.15 to 3.02). Elderly recipients of elderly kidneys had a 5-year mortality rate comparable to that of waitlisted elderly patients remaining on dialysis. Among elderly recipients, 63.8% of those who received elderly DCD kidneys, 45.5% of those who received elderly DBD kidneys, and approximately 26% of those who received young DBD or DCD kidneys had an eGFR<30 ml/min per 1.73 m
(including primary nonfunction) after 1 year. In conclusion, improving donor selection and preservation is warranted if the allocation of elderly DCD grafts to elderly recipients is to be expanded.
While the guidelines for vaccination in renal transplant recipients recommend the use of pneumococcal polysaccharide (PPS) and tetanus toxoid (TT), their efficacy in immunocompromised renal ...transplant recipients is not known. Here we tested the effect of everolimus on immune responses after vaccination by measuring the capacity of 36 stable renal transplant recipients to mount cellular and humoral responses after vaccination. Twelve patients in each treatment arm received immunosuppressive therapy consisting of prednisolone (P) plus cyclosporine (CsA), mycophenolate sodium (MPA), or everolimus. Patients were vaccinated with the T-cell-dependent antigens immunocyanin and TT, and the T-cell-independent PPS. Treatment with CsA partially inhibited and MPA completely abolished the capacity to mount a primary humoral response, whereas everolimus left this largely intact. Recall responses were inhibited by MPA only. All drug combinations inhibited cellular responses against TT. In patients treated with MPA, B-cell numbers were severely reduced. Thus, combined with P, treatment with MPA completely disturbed primary and secondary humoral responses. Everolimus or CsA allowed the boosting of T-cell-dependent and -independent secondary humoral responses. Treatment with everolimus allowed a primary response.
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