Advanced cutaneous squamous cell carcinoma of the head in two renal transplanted patients treated with cemiplimab.

It is well known that organ transplant recipients are prone to develop non-melanoma skin cancers, particularly cutaneous squamous cell carcinoma (cSCC). This is explained by the long-term use of immunosuppressants and thus the decrease of the immunosurveillance that protects from developing malignant tumours. Solid organ transplant recipients (SOTRs) are 65-250 times more likely to develop cSCC compared to the general population (Am J Transplant 2017; 17: 2509). Moreover, in these patients cSCCs follow a more aggressive course. Close follow-up and regular skin check-ups by a dermatologist are, therefore, crucial in the management of these patients. When detected early, cSCC can be easily and effectively treated by a simple excision. However, when advanced, outcomes are poor. Immune checkpoints inhibitors (ICIs) have been recently added to our arsenal and represent a breakthrough, having proved to be effective in achieving long-term responses. We, hereby, present two cases of difficult-to-treat cSCCs in renal transplanted patients.

Cemiplimab for advanced cutaneous squamous cell carcinoma in kidney transplant recipients.

Background: Kidney transplant recipients (KTR) are at increased risk of cancer due to chronic immunosuppression. Non-melanoma skin cancer has an excess risk of approximately 250 times higher than the general population. Moreover, in solid organ transplant recipients (SOTR) these cancers have a more aggressive behavior, with an increased risk of metastasis and death. Cemiplimab, a human monoclonal IgG4 antibody against programmed cell death (PD-1) has shown considerable clinical activity in metastatic and locally advanced cutaneous squamous cell carcinoma (cSCC) in patients for whom no widely accepted standard of care exists. Cemiplimab has therefore been approved since 2018 for the treatment of advanced cSCC. However, data regarding the use of cemiplimab in SOTR and particularly in KTR are scarce and based on published case reports and small case series. In this study, we report on the real-life outcome of cemiplimab use in a Belgian cohort of seven KTR suffering from advanced cSCC. Objective: To report on the overall response rate (ORR) and safety of cemiplimab in KTR in Belgium. Results: Seven patients suffering from advanced cSCC, treated with cemiplimab, between 2018 and 2022, in Belgium were identified. Three patients were on corticosteroid monotherapy, one patient on tacrolimus monotherapy and three patients were on at least 2 immunosuppressants at start of cemiplimab. The ORR was 42.8%, stable disease was seen in 14.3% and progressive disease was found in 42.8% of the patients, respectively. The median administered number of cycles was 12, interquartile range (IQR) 25-75 [3.5 - 13.5]. All patients were treated with surgery before administration of cemiplimab, 71.4% received additional radiotherapy and only 1 patient was treated with chemotherapy prior to receiving cemiplimab. Biopsy-proven acute renal allograft rejection was observed in one patient, who eventually lost his graft function but showed a complete tumor response to treatment. Low grade skin toxicity was seen in one patient of the cohort. Conclusion: The present case series shows that the use of cemiplimab in KTR with advanced cSCC who failed to respond to previous surgery, chemo - and/or radiotherapy treatment is associated with an ORR of 42.8% with minimal risk of graft rejection (14.3%) and good tolerance.

Caesarean section in the second delivery to prevent anal incontinence after asymptomatic obstetric anal sphincter injury: the EPIC multicentre randomised trial.

OBJECTIVE: To determine whether planned caesarean section (CS) for a second delivery protects against anal incontinence in women with obstetric anal sphincter lesions. DESIGN: Randomised trial. SETTING: Six maternity units in the Paris area. SAMPLE: Women at high risk of sphincter lesions (first delivery with third-degree laceration and/or forceps) but no symptomatic anal incontinence. METHODS: Endoanal ultrasound was performed in the third trimester of the second pregnancy. Women with sphincter lesions were randomised to planned CS or vaginal delivery (VD). MAIN OUTCOME MEASURES: Anal incontinence at 6 months postpartum. Secondary outcomes were urinary incontinence, sexual morbidity, maternal and neonatal morbidities and worsening of external sphincter lesions. RESULTS: Anal sphincter lesions were detected by ultrasound in 264/434 women enrolled (60.8%); 112 were randomised to planned VD and 110 to planned CS. At 6-8 weeks after delivery, there was no significant difference in anal continence between the two groups. At 6 months after delivery, median Vaizey scores of anal incontinence were 1 (interquartile range 0-4) in the CS group and 1 (interquartile range 0-3) in the VD group (P = 0.34). There were no significant differences for urinary continence, sexual functions or for other maternal and neonatal morbidities. CONCLUSIONS: In women with asymptomatic obstetric anal sphincter lesions diagnosed by ultrasound, planning a CS had no significant impact on anal continence 6 months after the second delivery. These results do not support advising systematic CS for this indication. TWEETABLE ABSTRACT: Caesarean section for the second delivery did not protect against anal incontinence in women with asymptomatic obstetric anal sphincter lesions.

An unusual case of haemolytic uraemic syndrome following endoscopic retrograde cholangiopancreatography rapidly improved with eculizumab.

Atypical haemolytic uraemic syndrome (aHUS) is a rare but life-threatening complement system-related disorder, characterized by renal failure, non-immune haemolytic anaemia and thrombo-cytopenia. We report on a young woman who developed a pancreatitis-induced aHUS following a routine procedure of endoscopic retrograde cholangiopancreatography. The patient was successively treated by 2 plasma exchanges with fresh frozen plasma and eculizumab, a monoclonal antibody designed to block terminal complement activation. The last treatment resulted in the immediate improvement of haemolytic parameters and to the definitive suspension of plasma exchanges. This is likely the first description of the use of a complement inhibitor to treat post-pancreatitis aHUS. We discussed treatment options and concluded that eculizumab could be a beneficial alternative to plasma exchanges in the management of such complications.

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner.

Cellular necrosis has long been regarded as an incidental and uncontrolled form of cell death. However, a regulated form of cell death termed necroptosis has been identified recently. Necroptosis can be induced by extracellular cytokines, pathogens and several pharmacological compounds, which share the property of triggering the formation of a RIPK3-containing molecular complex supporting cell death. Of interest, most ligands known to induce necroptosis (including notably TNF and FASL) can also promote apoptosis, and the mechanisms regulating the decision of cells to commit to one form of cell death or the other are still poorly defined. We demonstrate herein that intracellular nicotinamide adenine dinucleotide (NAD(+)) has an important role in supporting cell progression to necroptosis. Using a panel of pharmacological and genetic approaches, we show that intracellular NAD(+) promotes necroptosis of the L929 cell line in response to TNF. Use of a pan-sirtuin inhibitor and shRNA-mediated protein knockdown led us to uncover a role for the NAD(+)-dependent family of sirtuins, and in particular for SIRT2 and SIRT5, in the regulation of the necroptotic cell death program. Thus, and in contrast to a generally held view, intracellular NAD(+) does not represent a universal pro-survival factor, but rather acts as a key metabolite regulating the choice of cell demise in response to both intrinsic and extrinsic factors.

[Anti-NEP and anti-PLA2R antibodies in membranous nephropathy: an update]. / Anticorps anti-EPN et anti-PLA2R dans les glomerulopathies extramembraneuses: le point en 2014.

Membranous nephropathy (MN) is the most common cause for nephrotic syndrome in adults and occurs as an idiopathic (primary) or secondary disease. Since the early 2000's, substantial advances have been made in the understanding of the molecular bases of MN. The neutral endopeptidase (NEP) and the receptor for secretory phospholipase A2 (PLA2R) have been identified as target antigens for circulating and deposited antibodies in allo-immune neonatal and adult " idiopathic " MN, respectively. These antibodies recognize specific antigens of podocytes, precipitate as subepithelial immune complexes and activate complement leading to proteinuria. Anti-PLA2R antibodies are of particular clinical importance. Indeed, they are detected in approximately 70% of primary MN in adults, demonstrating that MN actually is an autoimmune condition specific to the kidney. In Europeans, genome-wide studies have shown an association between alleles of PLA2R1 and HLA DQA1 (class II genes of tissue histocompatibility complex) genes and idiopathic MN. Newly developed diagnostic tests detecting circulating anti-PLA2R antibody and PLA2R antigen in glomerular deposits have induced a change in paradigm in the diagnostic approach of idiopathic MN. Measurement of circulating anti-PLA2R antibody is also very useful for the monitoring of MN activity. However, the mechanisms responsible for the formation of anti-PLA2R antibodies as well as those involved in the progression of MN to end-stage renal disease remain to be defined.

A new HLA allocation procedure of kidneys from deceased donors in the current era of immunosuppression.

INTRODUCTION: It has recently been proposed to replace the current Eurotransplant kidney allocation based primarily on mismatches (MM) at the 3 HLA loci by a simpler system based on full HLA-DR compatibility. The present study analyzes this system in the current era of immunosuppression. METHODS: From 1999 to 2012, 723 renal grafts were performed on 586 patients who were treated with a calcineurin inhibitor, mycophenolate mofetil, and in most cases antilymphocyte globulins. Four groups of HLA MM were compared: (A) A+B 2-4/DR 1-2 MM (n = 397), (B) A+B 2-4 MM/DR 0 MM (n = 106), (C) A+B 0-1 MM/DR 1-2 MM (n = 138), and (D) A+B 0-1/DR 0 MM (n = 82). RESULTS: Acute rejection episodes were less frequent during the first post-transplantation year in group D than in the other groups (P = .018). Patient survival was lower in group A than in the other groups (P = .008). Immunologic graft survival was higher in group D than in the other groups in univariate (P = .015) and multivariate analyses (P = .033; 96.4% vs 90.1% at 10 years). CONCLUSIONS: In the current era of immunosuppression, allocation of kidneys from deceased donors could be performed primarily according to full DR compatibility then to the best A+B matching, affording excellent graft outcome to most recipients.

Patient and graft outcome in current era of immunosuppression: a single centre pilot study.

OBJECTIVES: The present single centre study aims at analyzing the impact on renal allograft outcome of the important changes which occurred in the transplant population and immunosuppressive therapy during the last two decades. METHODS: From 2000 to 2013, 779 single kidney transplantations were performed on 635 patients who all received on an intent-to-treat basis steroids, a calcineurin inhibitor, mycophenolate mofetil and an induction therapy with either antithymocyte globulin or an antagonist directed to the interleukin (IL)-2 receptor. Uni- and multivariate analyses of patient and immunologic graft survival were conducted. RESULTS: The sole factor predicting patient survival is recipient's age: 10-year survival rates are 94·7, 81·6 and 57·9% for the <45, 45-60 and >60 years age groups, respectively (P<0·001). Peak (>50% panel reactive antibodies) anti-human leucocyte antigens (HLA) sensitization, cold ischaemia time and HLA-B and -DR mismatches (MM) influence graft outcome: at 10 years, the difference in 10-year survival rates is 5·9% between grafts from sensitized and not sensitized patients (90·9 vs 96·8%, P = 0·002), 3·8% between grafts with <18 and ≧18 hours cold ischaemia (96·6 vs 92·8%, P = 0·003), 7·3% between grafts with no MM and either B or DR MM versus those with B and DR MM (96·8 vs 89·5%, P = 0·002). CONCLUSION: In our single centre experience, graft survival was most strongly determined by HLA matching, offering excellent long term graft outcome to most patients.

[Estimation of the glomerular filtration rate in 2014 by tests and equations: strengths and weaknesses]. / L'estimation de la filtration glomérulaire en 2014: intérêts et limites des tests et formules.

The accurate estimation of the glomerular filtration rate (GFR) is a goal of multiple interests regarding clinical, research and public health aspects. The strong relationship between progressive loss of renal function and mortality underlines the need for early diagnosis and close follow-up of renal diseases. Creatinine is the commonest biomarker of GFR in use. By reason of non-renal determinants of GFR, it is required to integrate creatinine values within equations that take in account its most important determinants (i.e., age, sex). The CKD-EPI 2009 equation is now recommended as the first line equation to estimate GFR within the general population. In this indication, it should replace MDRD that tends to overestimate the prevalence of stage 3 chronic kidney disease with GFR around 60 ml/min. However, many questions remain about the accuracy of GFR equations in specific situations such as extremes of age or body weight. The identification of new biomarkers, less determined by non-renal determinants, is of importance. Among these biomarkers, cystatin-C is more accurate to estimate GFR when it is combined to creatinine (i.e., equation CKD-EPI 2012). However the indica. tions for using cystatin-C instead of creatinine alone are still unclear and its use remains limited in routine practice. In conclusion, neither biomarker nor equation gives an accurate estimation for the whole range of GFR and for all patient populations. Limits of prediction are relying on both biomarker's properties and the range of GFR that is concerned, but also rely on the measurement methods. Therefore, it is crucial to interpret the estimated GFR according to the strengths and weaknesses of the equation in use.

Cyclosporine A drives a Th17- and Th2-mediated posttransplant obliterative airway disease.

Calcineurin-inhibitor refractory bronchiolitis obliterans (BO) represents the leading cause of late graft failure after lung transplantation. T helper (Th)2 and Th17 lymphocytes have been associated with BO development. Taking advantage of a fully allogeneic trachea transplantation model in mice, we addressed the pathogenicity of Th cells in obliterative airway disease (OAD) occurring in cyclosporine A (CsA)-treated recipients. We found that CsA prevented CD8(+) T cell infiltration into the graft and downregulated the Th1 response but affected neither Th2 nor Th17 responses in vivo. In secondary mixed lymphocyte cultures, CsA dramatically decreased donor-specific IFN-γ production, enhanced IL-17 production and did not affect IL-13. As CD4(+) depletion efficiently prevented OAD in CsA-treated recipients, we further explored the role of Th2 and Th17 immunity in vivo. Although IL-4 and IL-17 deficient untreated mice developed an OAD comparable to wild-type recipients, a single cytokine deficiency afforded significant protection in CsA-treated recipients. In conclusion, CsA treatment unbalances T helper alloreactivity and favors Th2 and Th17 as coexisting pathways mediating chronic rejection of heterotopic tracheal allografts.

CT scan does not improve the reproducibility of trochanteric fracture classification: a prospective observational study of 53 cases.

INTRODUCTION: The reproducibility of various classification systems for trochanteric fractures is poor. This problem could be related to a lack of readability when using conventional X-rays. HYPOTHESIS: Computed tomography scanning (CT scan) will improve the interobserver reproducibility of the AO classification for trochanteric fractures. PATIENTS AND METHODS: This was a prospective, observational, descriptive study following a group of 53 patients with trochanteric fractures. The fractures were evaluated with conventional X-rays, CT scan slices and 3D reconstruction (3DR). The resulting images were blinded and analysed by two observers using two classification systems: AO and Evans modified by Jensen (EVJE). A sample size of 53 was needed to show an improvement in the interobserver reproducibility when deciding the AO classification type with CT scan images. Kappa coefficients were used to measure interobserver reproducibility and agreement; agreement is the degree of consistency in the analysis by one observer who views the same fracture on two different imaging modalities. RESULTS: The interobserver reproducibility for the AO classification was 0.28 for X-rays, 0.33 for CT scan and 0.28 for 3DR. For the EVJE classification, these coefficients were 0.50 for X-rays, 0.35 for CT scan and 0.47 for 3DR. The agreement rate between the two imaging modalities was between 0.38 and 0.58 for X-rays/CT scan and between 0.79 and 0.86 for CT scan/3DR. DISCUSSION: The primary objective of this study was not achieved. CT imaging does not improve the interobserver reproducibility of various classification systems for trochanteric fractures. However, by providing images as slices, the complex nature of fractures in this area was revealed. The challenges related to classifying various fractures are not exclusively related to a "readability" problem, but also an understanding and analysis problem. LEVEL OF EVIDENCE: Prospective diagnostic study, level III.

Impact of interleukin-2-expanded regulatory T cells in various allogeneic combinations on mouse skin graft survival.

The impact of in vivo regulatory T cells (Treg) expansion using short-term injections of interleukin-2 (IL-2) coupled to a specific anti-IL-2 antibody was examined in various allogeneic combinations of murine skin transplantations. In a model of a single major histocompatibility complex (MHC) class II disparity, the IL-2-expanded Tregs infiltrated the transplanted skin, inhibited Th1 alloreactivity, and prevented acute graft rejection. However, in the presence of increased load of CD4-recognized alloantigens, exogenous IL-2 only moderately prolonged graft survival as attested by CD8 T cell-depletion in full minor plus major mismatched recipients treated with IL-2. If direct CD8 alloreactivity remained intact, the IL-2/anti-IL-2-mediated Tregs expansion failed to delay allograft rejection. This observation was confirmed by the inability of expanded Tregs to delay rejection of multiple minor disparate (MHC matched) skin allografts. Altogether, these results warn that cross-reactive CD8(+) T cells represent an important hurdle to Treg-based tolerance induction.

Post-traumatic bone and/or joint limb infections due to Clostridium spp.

BACKGROUND: Clostridium spp. are saprophytic Gram-positive bacteria found in soil and capable of generating endospores. Spore germination occurs when environmental conditions are favorable. Clostridium spp. can cause infections of compound fractures and deep wounds contaminated from soil micro-organisms. HYPOTHESIS: Clostridium spp. infections of traffic-related injuries are particularly severe events whose outcome is uncertain even with aggressive medical and surgical treatment. MATERIALS AND METHODS: We retrospectively reviewed 12 patients (median age, 45 years) with Clostridium spp. bone and/or joint infections complicating compound limb fractures with soil contamination and extensive soft-tissue damage. Prophylactic amoxicillin-clavulanic acid therapy was administred, followed by emergency surgical wound debridment and lavage. Fracture fixation was performed immediately in nine patients (external in four and internal in five) or at a later time on three patients. The immediate outcome was unfavourable in all 12 cases, requiring early reoperation after a median of 10 days (range, 5-25 days). RESULTS: Median time to Clostridium strain identification was 14.5 days (range, 5-160). All infections were polymicrobial. Surgical wound excision, hardware removal (in four cases), and antibiotic therapy produced a favourable outcome in one patient, with no recurrence after 2 years of follow-up; the outcome was unfavourable in 11 cases, with delayed fracture union, septic non-union, impaired healing, and/or chronic sinus tract drainage. Several second-line treatments were used in these 11 patients: intramedullary nailing without bone grafting in four patients, with three failures; decortication and grafting in two patients, with failure in both; nailing with decortication in one patient, who had a good outcome; and the induced membrane procedure described by Masquelet in four patients, all of whom had good outcomes. After a median follow-up of 24 months (range, 18-53 months), the bone infection had subsided in eight patients. The remaining four patients had septic non-union. DISCUSSION: Clostridium spp. infections are particularly severe. The diagnosis is delayed and identification of the organism is challenging. The treatment is difficult and results in unfavorable outcomes in one-third of cases. The identification of Clostridium in specimens from an osteoarticular infection indicates a need for extremely extensive and aggressive surgical resection, as spore resistance may impair the in vivo efficacy of antimicrobial agents. LEVEL OF EVIDENCE: IV (retrospective cohort study).

CTLA4-Ig restores rejection of MHC class-II mismatched allografts by disabling IL-2-expanded regulatory T cells.

Allograft acceptance and tolerance can be achieved by different approaches including inhibition of effector T cell responses through CD28-dependent costimulatory blockade and induction of peripheral regulatory T cells (Tregs). The observation that Tregs rely upon CD28-dependent signals for development and peripheral expansion, raises the intriguing possibility of a counterproductive consequence of CTLA4-Ig administration on tolerance induction. We have investigated the possible negative effect of CTLA4-Ig on Treg-mediated tolerance induction using a mouse model of single MHC class II-mismatched skin grafts in which long-term acceptance was achieved by short-term administration of IL-2/anti-IL-2 complex. CTLA4-Ig treatment was found to abolish Treg-dependent acceptance in this model, restoring skin allograft rejection and Th1 alloreactivity. CTLA4-Ig inhibited IL-2-driven Treg expansion, and prevented in particular the occurrence of ICOS(+) Tregs endowed with potent suppressive capacities. Restoring CD28 signaling was sufficient to counteract the deleterious effect of CTLA4-Ig on Treg expansion and functionality, in keeping with the hypothesis that costimulatory blockade inhibits Treg expansion and function by limiting the delivery of essential CD28-dependent signals. Inhibition of regulatory T cell function should therefore be taken into account when designing tolerance protocols based on costimulatory blockade.

[Acute kidney injury and drug-induced nephropathies]. / Insuffisance (atteinte) rénale aiguë et néphrotoxicité médicamenteuse.

All types of acute kidney injury (AKI) (functional /pre-renal, parenchymal/intra-renal, obstructive/post-renal) result in a sharp drop of the glomerular filtration rate, with variable reversibility according to the initial cause. In one case out of five, drug intake can be related to the onset of AKI. Antibiotics, analgesics and nonsteroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists are the agents mostly involved, as well as iodinated radio-contrast agents. Mechanisms are often complex: toxic cellular effect directed on a nephron segment (tubular necrosis) associated or not with intraglomerular hemodynamic changes, or immune process leading to acute tubule-interstitial nephritis. Each underlying risk factor (age > 60 year, cardiac or hepatic failure, hypertension, diabetes, intra-vascular volume depletion, preexisting or unknown chronic kidney disease) must be taken into consideration by the prescribing physician because it reduces the chance of functional recovery and worsens the renal and the overall prognosis. A pre-renal additional component is often present and avoidable thanks to a strict hemodynamic monitoring. The present article summarizes some recent physiopathological aspects of AKI and makes the link between clinical situations and currently prescribed drugs. Lessons from the radio-contrast induced nephropathy are examined by taking into account prevention aspects and risk factors screening. An effective collaboration between the general practitioner and the nephrologist would benefit in optimizing the treatment of difficult cases.

A brief focus on memory cells in transplantation.

T and B memory cells are critical for host defences against pathogens. However, converging lines of evidence indicate that alloreactive memory T cells can play a detrimental role in the transplantation setting. This emergence of memory cells seems to be facilitated by several induction therapies and immunosuppressive agents, which lead to T cell loss. Herein, we briefly review some clinical and experimental observations from the literature, highlighting the immunological risk associated with enhanced T-cell memory responses.

Endotoxin-induced myeloid-derived suppressor cells inhibit alloimmune responses via heme oxygenase-1.

Inflammation and cancer are associated with impairment of T-cell responses by a heterogeneous population of myeloid-derived suppressor cells (MDSCs) coexpressing CD11b and GR-1 antigens. MDSCs have been recently implicated in costimulation blockade-induced transplantation tolerance in rats, which was under the control of inducible NO synthase (iNOS). Herein, we describe CD11b+GR-1+MDSC-compatible cells appearing after repetitive injections of lipopolysaccharide (LPS) using a unique mechanism of suppression. These cells suppressed T-cell proliferation and Th1 and Th2 cytokine production in both mixed lymphocyte reaction and polyclonal stimulation assays. Transfer of CD11b+ cells from LPS-treated mice in untreated recipients significantly prolonged skin allograft survival. They produced large amounts of IL-10 and expressed heme oxygenase-1 (HO-1), a stress-responsive enzyme endowed with immunoregulatory and cytoprotective properties not previously associated with MDSC activity. HO-1 inhibition by the specific inhibitor, SnPP, completely abolished T-cell suppression and IL-10 production. In contrast, neither iNOS nor arginase 1 inhibition did affect suppression. Importantly, HO-1 inhibition before CD11b+ cell transfer prevented the delay of allograft rejection revealing a new MDSC-associated suppressor mechanism relevant for transplantation.

[Decision making on breech delivery: information as a way to reconcile maternal autonomy and medical responsibility]. / Peut-on concilier autonomie maternelle et responsabilité médicale dans les décisions de voies d'accouchement des foetus en siège? Rôle de l'information.

As far as breech vaginal delivery remains an acceptable option, each case has to be evaluated in order to determine whether in that particular situation it is medically relevant. When vaginal delivery is to be envisaged, maternal consent is needed. This implies seeking medical information that allows women to express their autonomy and to be part of the decision regarding their delivery. This article concerns a physicians reflection on medical information and on connections between the obstetrician's responsibility, that of the future mother, and autonomy. Understanding information as necessarily arising from an exchange between the care giver and the future mother is the condition that allows the coexistence of maternal autonomy and medical responsibility.

[Involvement of natural regulatory lymphocytes in allograft tolerance]. / Implication des lymphocytes régulateurs naturels dans la tolérance d'allogreffe.

Naturally occurring regulatory T-cells (Tregs) play a critical role in the homeostasis of healthy immune system. A Treg deficiency is responsible for immune system dysregulation, immune hyperreactivity and autoimmunity. Herein, we investigated the role of Tregs, either in the context of antibody-induced transplantation tolerance, mixed donor/recipient chimerism or in models of spontaneous graft acceptance without immunosuppression. We also investigated their capacities to control endotoxin-mediated immune response in the context of lymphopaenia-driven homeostatic T-cell proliferation. Finally, although Tregs adequately control Th1 and Th2 immunity, they are inefficient in regulating IL-17 producing T cells in vitro and in vivo and rather promote them.