Autoreactive T cells target peripheral nerves in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a potentially life-threatening progressive muscle weakness1. Although GBS is considered an autoimmune disease, the mechanisms that underlie its distinct clinical subtypes remain largely unknown. Here, by combining in vitro T cell screening, single-cell RNA sequencing and T cell receptor (TCR) sequencing, we identify autoreactive memory CD4+ cells, that show a cytotoxic T helper 1 (TH1)-like phenotype, and rare CD8+ T cells that target myelin antigens of the peripheral nerves in patients with the demyelinating disease variant. We characterized more than 1,000 autoreactive single T cell clones, which revealed a polyclonal TCR repertoire, short CDR3ß lengths, preferential HLA-DR restrictions and recognition of immunodominant epitopes. We found that autoreactive TCRß clonotypes were expanded in the blood of the same patient at distinct disease stages and, notably, that they were shared in the blood and the cerebrospinal fluid across different patients with GBS, but not in control individuals. Finally, we identified myelin-reactive T cells in the nerve biopsy from one patient, which indicates that these cells contribute directly to disease pathophysiology. Collectively, our data provide clear evidence of autoreactive T cell immunity in a subset of patients with GBS, and open new perspectives in the field of inflammatory peripheral neuropathies, with potential impact for biomedical applications.

[Living-donor robotic-assisted kidney transplantation: French academic center experience]. / Transplantation rénale robot-assistée avec donneur vivant : expérience d'un centre universitaire français.

INTRODUCTION: The main objective was to report the intra-, post-operative and functional outcomes of living-donor robotic-assisted kidney transplantation (RAKT), performed by a surgeon skilled in robotic surgery. The secondary objective was to compare the results of RAKT, based on the surgeon's experience. METHODS: For this retrospective cohort study, we analyzed data from consecutive patients who underwent living-donor RAKT from July 2015 to March 2020 and compared the results of RAKT according to the surgeon's experience (group 1: 1-14th RAKT versus group 2: 15-29th RAKT). RESULTS: Twenty-nine living-donor RAKT were performed. The median age and BMI of the recipients were: 57.0 (44.0-66.0) years and 32.7 (23.5-39.6)kg/m2. The median overall operative time and median console time were: 140.0 (122.5-165.0) and 120.0 (107.5-137.5) minutes. The median rewarming time, arterial, venous and urinary anastomoses durations were: 35.0 (27.5-45.0), 15.0 (11.0-20.0), 12.0 (10.0-16.0), 20.0 (16.0-23.0) minutes. Two (6.9%) minor and 5 (17.2%) major (Clavien-Dindo≥III) postoperative complications occurred. At 2 years of follow-up, patient and transplant survival was 100% (n=29) and 93.1% (n=27). After the 14th RAKT, the rewarming time (P=0.01) and venous anastomosis duration (P=0.004) were statistically shorter. CONCLUSION: Living-donor robotic-assisted kidney transplantation, performed by a surgeon skilled robotic surgery, ensures good functional results in the medium term. LEVEL OF EVIDENCE: 3.

[Renal cell carcinoma in candidates for renal transplantation and recipients of a kidney transplant: The French guidelines from CTAFU]. / Recommandations françaises du Comité de transplantation de l'association française d'urologie (CTAFU) : carcinome rénal sur reins natifs chez le patient transplanté rénal ou en attente de transplantation.

OBJECTIVE: To define guidelines for the management of renal cell carcinoma of the native kidney (NKRCC) in kidney transplant (KTx) recipients and renal cell carcinoma (RCC) in end-stage renal disease (ESRD) patients candidates for renal transplantation. METHOD: A review of the literature following a systematic approach (Medline) was conducted by the CTAFU to report renal cell carcinoma epidemiology, screening, diagnosis and management in KTx candidates and recipients. References were assessed according to a predefined process to propose recommendations with the corresponding levels of evidence. RESULTS: ESRD patients are at higher risk of RCC with a standardized incidence ratio of approximately 4,5 as compared with general population. NKRCC tumors occur in 1 to 3 % of KTx recipients with a 10 to 15-fold increased risk as compared with general population, especially in patients with acquired multicystic kidney disease. Most authors suggest yearly monitoring of the native kidneys using ultrasound imaging. Radical nephrectomy (either open or laparoscopic approach) is the preferred treatment of NKRCC in KTx recipients and RCC in ESRD. Surveillance in a valid option in small or cystic renal masses. In the localized setting, change in immunosuppressive therapy is not recommended besides perioperative avoidance of mTOR inhibitor to limit morbidity. CTAFU does not recommend a mandatory waiting time after nephrectomy for RCC in ESRD patients candidates for renal tranplantation when tumor stage

[Living donor nephrectomy: The French guidelines from CTAFU]. / Recommandations françaises du Comité de transplantation de l'Association française d'urologie (CTAFU) : néphrectomie pour don de rein.

OBJECTIVE: To propose surgical recommendations for living donor nephrectomy. METHOD: Following a systematic approach, a review of the literature (Medline) was conducted by the CTAFU regarding functional and anatomical assessment of kidney donors, including which side the kidney should be harvested from. Distinct surgical techniques and approaches were evaluated. References were considered with a predefined process to propose recommendations with the corresponding levels of evidence. RESULTS: The recommendations clarify the legal and regulatory framework for kidney donation in France. A rigorous assessment of the donor is one of the essential prerequisites for donor safety. The impact of nephrectomy on kidney function needs to be anticipated. In case of modal vascularization of both kidneys without a relative difference in function or urologic abnormality, removal of the left kidney is the preferred choice to favor a longer vein. Mini-invasive approaches for nephrectomy provide faster donor recovery, less donor pain and shorter hospital stay than open surgery. CONCLUSION: These French recommendations must contribute to improving surgical management of candidates for kidney donation.

[Urinary stones in renal transplant recipients and donors: The French guidelines from CTAFU]. / Recommandations françaises du Comité de transplantation de l'association française d'urologie (CTAFU) : lithiase urinaire chez le receveur ou le donneur en transplantation rénale.

OBJECTIVE: To define guidelines for the management of kidney stones in kidney transplant (KTx) donor or recipients. METHOD: Following a systematic approach, a review of the literature (Medline) was conducted by the CTAFU to report kidney stone epidemiology, diagnosis and management in KTx donors and recipients with the corresponding level of evidence. RESULTS: Prevalence of kidney stones in deceased donor is unknown but reaches 9.3% in living donors in industrialized countries. Except in Maastrich 2 donors, diagnosis is done on systematic pre-donation CT scan according to standard french procedure. No prospective study has compared therapeutic strategies available for the management of kidney stones in KTx donor: ureteroscopy or an extra corporeal lithotripsy in case of living donor prior to donation, ex vivo approach (pyelotomy or ureteroscopy), ureterocopy in the KTx recipient or surveillance. De novo kidney stones result from a lithogenesis process to be identified and treated in order to avoid recurrences. The context of solitary functional kidney renders the prevention of recurrence of great importance. Diagnosis is suspected when identification of a renal graft dysfunction, hematuria or urinary tract infection with renal pelvis dilatation. Stone size and location are determined by computed tomography. There are no prospective, controlled studies on kidney stone management in the KTx. The therapeutic strategies are similar to standard management in general population. CONCLUSION: These French recommendations should contribute to improve kidney stones management in KTx donor and recipients.

Management of renal transplant urolithiasis: a multicentre study by the French Urology Association Transplantation Committee.

PURPOSE: Urolithiasis is rare among renal transplant recipients and its management has not been clearly defined. METHODS: This multicentre retrospective study was organised by the Comité de Transplantation de l'Association Française d'Urologie (French Urology Association transplantation committee). Statistical analysis was performed with SPSS 19 software. RESULTS: Ninety-five patients were included in this study. Renal transplant urolithiasis was an incidental finding in 55% of cases, mostly on a routine follow-up ultrasound examination. One half of symptomatic stones were due to urinary tract infection and the other half were due to an episode of acute renal failure. The initial management following diagnosis of urolithiasis was double J stenting (27%), nephrostomy tube placement (21%), or watchful waiting (52%). Definitive management consisted of: watchful waiting (48%), extracorporeal lithotripsy (13%), rigid or flexible ureteroscopy (26%), percutaneous nephrolithotomy (11%) and surgical pyelotomy (2%). All transplants remained functional following treatment of the stone. The main limitation is the retrospective design. CONCLUSIONS: The incidence of lithiasis could be higher in kidney transplanted patients due to a possible anatomical or metabolical abnormalities. The therapeutic management of renal transplant urolithiasis appears to be comparable to that of native kidney urolithiasis.

Allelic and Epitopic Characterization of Intra-Kidney Allograft Anti-HLA Antibodies at Allograft Nephrectomy.

The reasons for the increased incidence of de novo anti-human leukocyte antibody (HLA) donor-specific antibodies (DSAs) observed after kidney allograft nephrectomy are not fully understood. One advocated mechanism suggests that at graft loss, DSAs are not detected in the serum because they are fixed on the nonfunctional transplant; removal of the kidney allows DSAs to then appear in the blood circulation. The aim of our study was to compare anti-HLA antibodies present in the serum and in the graft at the time of an allograft nephrectomy. Using solid-phase assays, anti-HLA antibodies were searched for in the sera of 17 kidney transplant patients undergoing allograft nephrectomy. No anti-HLA antibodies were detected in the graft if they were not also detected in the serum. Eleven of the 12 patients who had DSAs detected in their sera also had DSAs detected in the grafts. Epitopic analysis revealed that most anti-HLA antibodies detected in removed grafts were directed against the donor. In summary, our data show that all anti-HLA antibodies that were detected in grafts were also detected in the sera. These intragraft anti-HLA antibodies are mostly directed against the donor at an epitopic level but not always at an antigenic level.

Prostate cancer before renal transplantation: A multicentre study.

INTRODUCTION: The surgical issues of renal transplantation (RT) after localized prostate cancer (PC) treatment and oncological outcomes after transplantation in patients on the waiting list with a history of PC were unknown. We conducted a retrospective multicentre study including all patients with PC diagnosed before the kidney transplantation. METHODS: Fifty-two patients were included from December 1993 to December 2015. The median age at diagnosis of PC was 59.8years old. RESULTS: The median PSA rate at diagnosis was 7ng/mL. Twenty-seven, Twenty-four, and one PC were respectively low, intermediate and high risk according to d'Amico classification. Forty-three patients were treated by radical prostatectomy (RP): 28 retropubic, 15 laparoscopic and 3 by a perineal approach. Eighteen patients had a lymph node dissection. Four patients were treated with external radiotherapy and 2 by brachytherapy. Eight patients underwent radiotherapy after surgery. The median time between PC treatment and RT was 35.7 months. The median operating time for the renal transplantation was 180min (IQR 150-190; min 90-max 310) with a median intraoperative bleeding of 200mL (IQR 100-290; min 50-max 2000). A history of lymphadenectomy did not significantly lengthen operative time (P=0.34). No recurrence of PC was observed after a median follow of 36months. CONCLUSION: PC discovered before RT should be treated with RP to assess the risk of recurrence and decrease waiting for a RT. If the PC is at low risk of recurrence, it seems possible to shorten the waiting time before the RT after a multidisciplinary discussion meeting. LEVEL OF EVIDENCE: 4.

[Polycystic kidney disease and kidney transplantation]. / Prise en charge de la polykystose rénale autosomique dominante avant transplantation rénale.

OBJECTIVES: To perform a state of the art about autosomal dominant polykystic kidney disease (ADPKD), management of its urological complications and end stage renal disease treatment modalities. MATERIAL AND METHODS: An exhaustive systematic review of the scientific literature was performed in the Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of the following keywords (MESH): "autosomal dominant polykystic kidney disease", "complications", "native nephrectomy", "kidney transplantation". Publications obtained were selected based on methodology, language, date of publication (last 10 years) and relevance. Prospective and retrospective studies, in English or French, review articles; meta-analysis and guidelines were selected and analyzed. This search found 3779 articles. After reading titles and abstracts, 52 were included in the text, based on their relevance. RESULTS: ADPKD is the most inherited renal disease, leading to end stage renal disease requiring dialysis or renal transplantation in about 50% of the patients. Many urological complications (gross hematuria, cysts infection, renal pain, lithiasis) of ADPKD required urological management. The pretransplant evaluation will ask the challenging question of native nephrectomy only in case of recurrent kidney complications or large kidney not allowing graft implantation. The optimum timing for native nephrectomy will depend on many factors (dialysis or preemptive transplantation, complication severity, anuria, easy access to transplantation, potential living donor). CONCLUSION: Pretransplant management of ADPKD is challenging. A conservative strategy should be promoted to avoid anuria (and its metabolic complications) and to preserve a functioning low urinary tract and quality of life. When native nephrectomy should be performed, surgery remains the gold standard but renal arterial embolization may be a safe option due to its low morbidity.

Role of Sphingosine-1-Phosphate in Transplant Vasculopathy Evoked by Anti-HLA Antibody.

Transplant vasculopathy (TV) represents the main cause of late graft failure and limits the long-term success of organ transplantation. Cellular and humoral immune responses contribute to the pathogenesis of the concentric and diffuse intimal hyperplasia of arteries of the grafted organ. We recently reported that the mitogenic signaling, evoked in human vascular smooth muscle cells (hmSMC) by the anti-HLA class I monoclonal antibody W6/32, implicates neutral sphingomyelinase-2, suggesting a role for sphingolipids in intimal hyperplasia of TV. Here, we investigated whether the mitogenic sphingolipid, sphingosine-1-phosphate (S1P), is involved in intimal hyperplasia elicited by W6/32. Studies were done on cultured hmSMC and on an in vivo model of TV, consisting of human mesenteric arteries grafted into SCID/beige mice, injected weekly with W6/32. hmSMC migration and DNA synthesis elicited by W6/32 were inhibited by the sphingosine kinase-1 (SK1) inhibitor dimethylsphingosine, the anti-S1P antibody Sphingomab and the S1PR1/R3 inhibitor VPC23019. W6/32 stimulated SK1 activity, while siRNA silencing SK1, S1PR1 and S1PR3 inhibited hmSMC migration. In vivo, Sphingomab significantly reduced the intimal thickening induced by W6/32. These data emphasize the role of S1P in intimal hyperplasia elicited by the humoral immune response, and open perspectives for preventing TV with S1P inhibitors.

De novo kidney graft tumors: results from a multicentric retrospective national study.

De novo tumors in renal allografts are rare and their prevalence is underestimated. We therefore analyzed renal cell carcinomas arising in renal allografts through a retrospective French renal transplant cohort. We performed a retrospective, multicentric survey by sending questionnaires to all French kidney transplantation centers. All graft tumors diagnosed after transplantation were considered as de novo tumors. Thirty-two centers participated in this study. Seventy-nine tumors were identified among 41 806 recipients (Incidence 0.19%). Patients were 54 men and 25 women with a mean age of 47 years old at the time of diagnosis. Mean tumor size was 27.8 mm. Seventy-four (93.6%), 53 (67%) and 44 tumors (55.6%) were organ confined (T1-2), low grade (G1-2) and papillary carcinomas, respectively. Four patients died of renal cell carcinomas (5%). The mean time lapse between transplantation and RCC diagnosis was 131.7 months. Thirty-five patients underwent conservative surgery by partial nephrectomy (n = 35, 44.3%) or radiofrequency (n = 5; 6.3%). The estimated 5 years cancer specific survival rate was 94%. Most of these tumors were small and incidental. Most tumors were papillary carcinoma, low stage and low grade carcinomas. Conservative treatment has been preferred each time it was feasible in order to avoid a return to dialysis.

[Kidney transplantation in obese recipients: review of the Transplantation Committee of the French Association of Urology]. / Transplantation rénale et receveurs obèses : revue du comité de transplantation de l'Association française d'urologie.

INTRODUCTION: Transplantation Committee of the French Association of Urology (CTAFU) conducted a review of the complication of kidney transplantation in obese recipients. MATERIAL AND METHODS: A bibliographic research in French and English using Medline with the keywords "obesity", "body mass index", "kidney transplantation", "graft function", "survival", "wound complications", "graft rejection" and "graft survival" was performed. We limited the review for the last fifteen years because of the change in immunosuppressive treatment area. Only studies with more than 20 obese patients were selected. RESULTS: Wound or infectious postoperative complications and delayed graft function are more frequent in obese patients than in non-obese recipients. Similarly, transplant survival at 5 years is lower in obese patients. On the other hand, patient survival and acute rejection are the same between the two groups if recipient selection is carefully made, particularly with regard to heart complication. CONCLUSION: Kidney transplantation in obese patients is not an easy surgery with known complication. Obese patients will take time before transplantation to explain all the risk and a regular heart follow-up is crucial if we don't want to reduce patient survival. But obese survival is better if we proceed to kidney transplantation than if they stay on dialysis, arguing for a non-exclusion of the waiting list. So there is the need for a national study concerning obese patients on waiting list to enact future guidelines.

[Should we consider a complementary treatment after a renal colic drained by an ureteral stent?]. / Faut-il envisager un traitement complémentaire après une colique néphrétique drainée par une sonde JJ ?

PURPOSE: The aim of the study was to evaluate if only ureteral stent removing after complicated renal colic (RC) could prevent from complementary treatment (shock-wawe lithortripsy or ureteroscopy). PATIENTS AND METHODS: Data from 95 patients, 39 women and 56 men, who had an ureteral stent for complicated RC from 2005 to 2010 were retrospectively collected. Mean age was 46.4 ± 17.2 years. After the initial management, another hospitalization was organized where patients had ureteral stent removing under local anesthesia, then an abdominal CT-scan without injection and complementary treatment of ureteral stones (none or ESWL or ureteroscopy). Parameters studied were age, sex, stone size, location of calcul. Quantitative values were compared with Student's t test. Qualitative values were compared with the Chi(2). P<0.05 was considered statistically significant. RESULTS: Mean duration between the two hospitalizations were 1.58 ± 1.84 months. Sixty-one patients (64.2%) had no more urolithiasis. In these patients, mean size of urolithiasis was 5.85 ± 2.33 mm. Location of urolithiasis in distal, mild and proximal ureter was 77%, 3% and 20% respectively. Thirty-four patients (35.8%) had persistant lithiasis after CT-scan. Location of stone in distal, mild and proximal ureter was 17.5%, 5.8% and 76.7% respectively. CONCLUSION: After management of complicated renal colic by ureteral stent, 64% of patients had spontaneous elimination of stones after removing of ureteral stent, especially in women and pelvic ureter.

Duodenal villous atrophy: a cause of chronic diarrhea after solid-organ transplantation.

Persistent diarrhea is commonly observed after solid organ transplantation (SOT). A few cases of mycophenolate mofetil (MMF)-induced duodenal villous atrophy (DVA) have been previously reported in kidney-transplant patients with chronic diarrhea. Herein, we report on the incidence and characteristics of DVA in SOT patients with chronic diarrhea. One hundred thirty-two SOT patients with chronic diarrhea underwent an oesophago-gastroduodenoscopy (OGD) and a duodenal biopsy after classical causes of diarrhea have been ruled out. DVA was diagnosed in 21 patients (15.9%). It was attributed to mycophenolic acid (MPA) therapy in 18 patients (85.7%) (MMF [n = 14] and enteric-coated mycophenolate sodium [n = 4]). MPA withdrawal or dose reduction resulted in diarrhea cessation. The incidence of DVA was significantly higher in patients with chronic diarrhea receiving MPA compared to those who did not (24.6% vs. 5.1%, p = 0.003). DVA was attributed to a Giardia lamblia parasitic infection in two patients (9.5%) and the remaining case was attributed to azathioprine. In these three patients, diarrhea ceased after metronidazole therapy or azathioprine dose reduction. In conclusion, DVA is a frequent cause of chronic diarrhea in SOT recipients. MPA therapy is the most frequent cause of DVA. An OGD should be proposed to all transplant recipients who present with persistent diarrhea.

Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha.

Using granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin 4 we have established dendritic cell (DC) lines from blood mononuclear cells that maintain the antigen capturing and processing capacity characteristic of immature dendritic cells in vivo. These cells have typical dendritic morphology, express high levels of major histocompatibility complex (MHC) class I and class II molecules, CD1, Fc gamma RII, CD40, B7, CD44, and ICAM-1, and lack CD14. Cultured DCs are highly stimulatory in mixed leukocyte reaction (MLR) and are also capable of triggering cord blood naive T cells. Most strikingly, these DCs are as efficient as antigen-specific B cells in presenting tetanus toxoid (TT) to specific T cell clones. Their efficiency of antigen presentation can be further enhanced by specific antibodies via FcR-mediated antigen uptake. Incubation of these cultured DCs with tumor necrosis factor alpha (TNF-alpha) or soluble CD40 ligand (CD40L) for 24 h results in an increased surface expression of MHC class I and class II molecules, B7, and ICAM-1 and in the appearance of the CD44 exon 9 splice variant (CD44-v9); by contrast, Fc gamma RII is markedly and sometimes completely downregulated. The functional consequences of the short contact with TNF-alpha are in increased T cell stimulatory capacity in MLR, but a 10-fold decrease in presentation of soluble TT and a 100-fold decrease in presentation of TT-immunoglobulin G complexes.

Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4(+) T cells.

Memory T lymphocytes proliferate in vivo in the absence of antigen maintaining a pool of central memory T cells (T(CM)) and effector memory T cells (T(EM)) with distinct effector function and homing capacity. We compared human CD4(+) naive T, T(CM), and T(EM) cells for their capacity to proliferate in response to cytokines, that have been implicated in T cell homeostasis. Interleukin (IL)-7 and IL-15 expanded with very high efficiency T(EM), while T(CM) were less responsive and naive T cells failed to respond. Dendritic cells (DCs) and DC-derived cytokines allowed naive T cells to proliferate selectively in response to IL-4, and potently boosted the response of T(CM) to IL-7 and IL-15 by increasing the expression of the IL-2/IL-15Rbeta and the common gamma chain (gamma(c)). The extracellular signal regulated kinase and the p38 mitogen-activated protein (MAP) kinases were selectively required for TCR and cytokine-driven proliferation, respectively. Importantly, in cytokine-driven cultures, some of the proliferating T(CM) differentiated to T(EM)-like cells acquiring effector function and switching chemokine receptor expression from CCR7 to CCR5. The sustained antigen-independent generation of T(EM) from a pool of T(CM) cells provides a plausible mechanism for the maintenance of a polyclonal and functionally diverse repertoire of human CD4(+) memory T cells.

Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products.

We have previously demonstrated that human peripheral blood low density mononuclear cells cultured in granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 develop into dendritic cells (DCs) that are extremely efficient in presenting soluble antigens to T cells. To identify the mechanisms responsible for efficient antigen capture, we studied the endocytic capacity of DCs using fluorescein isothiocyanate-dextran, horseradish peroxidase, and lucifer yellow. We found that DCs use two distinct mechanisms for antigen capture. The first is a high level of fluid phase uptake via macropinocytosis. In contrast to what has been found with other cell types, macropinocytosis in DCs is constitutive and allows continuous internalization of large volumes of fluid. The second mechanism of capture is mediated via the mannose receptor (MR), which is expressed at high levels on DCs. At low ligand concentrations, the MR can deliver a large number of ligands to the cell in successive rounds. Thus, while macropinocytosis endows DCs with a high capacity, nonsaturable mechanism for capture of any soluble antigen, the MR gives an extra capacity for antigen capture with some degree of selectivity for non-self molecules. In addition to their high endocytic capacity, DCs from GM-CSF + IL-4-dependent cultures are characterized by the presence of a large intracellular compartment that contains high levels of class II molecules, cathepsin D, and lysosomal-associated membrane protein-1, and is rapidly accessible to endocytic markers. We investigated whether the capacity of DCs to capture and process antigen could be modulated by exogenous stimuli. We found that DCs respond to tumor necrosis factor alpha, CD40 ligand, IL-1, and lipopolysaccharide with a coordinate series of changes that include downregulation of macropinocytosis and Fc receptors, disappearance of the class II compartment, and upregulation of adhesion and costimulatory molecules. These changes occur within 1-2 d and are irreversible, since neither pinocytosis nor the class II compartment are recovered when the maturation-inducing stimulus is removed. The specificity of the MR and the capacity to respond to inflammatory stimuli maximize the capacity of DCs to present infectious non-self antigens to T cells.

Ceramide inhibits antigen uptake and presentation by dendritic cells.

Ceramides are intramembrane diffusible mediators involved in transducing signals originated from a variety of cell surface receptors. Different adaptive and differentiative cellular responses, including apoptotic cell death, use ceramide-mediated pathways as an essential part of the program. Here, we show that human dendritic cells respond to CD40 ligand, as well as to tumor necrosis factor-alpha and IL-1 beta, with intracellular ceramide accumulation, as they are induced to differentiate. Dendritic cells down-modulate their capacity to take up soluble antigens in response to exogenously added or endogenously produced ceramides. This is followed by an impairment in presenting soluble antigens to specific T cell clones, while cell viability and the capacity to stimulate allogeneic responses or to present immunogenic peptides is fully preserved. Thus, ceramide-mediated pathways initiated by different cytokines can actively modulate professional antigen-presenting cell function and antigen-specific immune responses.