αvß8 integrin-expression by BATF3-dependent dendritic cells facilitates early IgA responses to Rotavirus.

Secretory intestinal IgA can protect from re-infection with rotavirus (RV), but very little is known about the mechanisms that induce IgA production during intestinal virus infections. Classical dendritic cells (cDCs) in the intestine can facilitate both T cell-dependent and -independent secretory IgA. Here, we show that BATF3-dependent cDC1, but not cDC2, are critical for the optimal induction of RV-specific IgA responses in the mesenteric lymph nodes. This depends on the selective expression of the TGFß-activating integrin αvß8 by cDC1. In contrast, αvß8 on cDC1 is dispensible for steady state immune homeostasis. Given that cDC2 are crucial in driving IgA during steady state but are dispensable for RV-specific IgA responses, we propose that the capacity of DC subsets to induce intestinal IgA responses reflects the context, as opposed to an intrinsic property of individual DC subsets.

Face Transplantation: Partial Graft Loss of the First Case 10 Years Later.

Ten years after the first face transplantation, we report the partial loss of this graft. After two episodes of acute rejection (AR) occurred and completely reversed in the first posttransplantation year, at 90 months posttransplantation the patient developed de novo class II donor-specific antibodies, without clinical signs of AR. Some months later, she developed several skin rejection episodes treated with steroid pulses. Despite rapid clinical improvement, some months later the sentinel skin graft underwent necrosis. Microscopic examination showed intimal thickening, thrombosis of the pedicle vessel, and C4d deposits on the endothelium of some dermal vessels of the facial graft. Flow magnetic resonance imaging of the facial graft showed a decrease of the distal right facial artery flow. Three steroid pulses of 500 mg each, followed by intravenous immunoglobulins (2 g/kg), five sessions of plasmapheresis, and three cycles of bortezomib 1.3 mg/m2 , were administered. Despite rescue therapy with eculizumab, necrosis of the lips and the perioral area occurred, which led to surgical removal of the lower lip, labial commissures, and part of the right cheek in May 2015. In January 2016, the patient underwent conventional facial reconstruction because during the retransplantation evaluation a small-cell lung carcinoma was discovered, causing the patient's death in April 2016.

Anti-Donor HLA Antibody Response After Pancreatic Islet Grafting: Characteristics, Risk Factors, and Impact on Graft Function.

Pancreatic islet grafting restores endogenous insulin production in type 1 diabetic patients, but long-term outcomes remain disappointing as a result of immunological destruction of allogeneic islets. In solid organ transplantation, donor-specific anti-HLA antibodies (DSA) are the first cause of organ failure. This retrospective multicentric study aimed at providing in-depth characterization of DSA response after pancreatic islet grafting, identifying the risk factor for DSA generation and determining the impact of DSA on graft function. Forty-two pancreatic islet graft recipients from the Groupe Rhin-Rhône-Alpes-Genève pour la Greffe d'Ilots de Langerhans consortium were enrolled. Pre- and postgrafting sera were screened for the presence of DSA and their ability to activate complement. Prevalence of DSA was 25% at 3 years postgrafting. The risk of sensitization increased steeply after immunosuppressive drug withdrawal. DSA repertoire diversity correlated with the number of HLA and eplet mismatches. DSA titer was significantly lower from that observed in solid organ transplantation. No detected DSA bound the complement fraction C3d. Finally, in contrast with solid organ transplantation, DSA did not seem to negatively affect pancreatic islet graft survival. This might be due to the low DSA titers, specific features of IgG limiting their ability to activate the complement and/or the lack of allogenic endothelial targets in pancreatic islet grafts.

Epstein-Barr virus-associated smooth muscle tumors in a composite tissue allograft and a pediatric liver transplant recipient.

Epstein-Barr virus (EBV) is known to establish latent infections in B-lymphocytes that can cause lymphoproliferative disorders particularly in immunocompromised patients. More recently, the development of rare EBV-associated smooth muscle tumors has been reported in transplant recipients. We herein describe 2 new cases of EBV-associated post-transplant smooth muscle tumors (EBV-PTSMT), including the first in a facial composite tissue graft recipient. Among the striking features shared by these 2 patients were their young ages, the fact that they were naïve for EBV before the transplantation, that they developed a post-transplant lymphoproliferative disorder before the diagnosis of EBV-PTSMT, and that they responded favorably to reduction of immunosuppression. Radiological and histologic features of EBV-PTSMT are shown. Finally, pathophysiology and therapeutic management of EBV-PTSMT are discussed based on a comprehensive review of the literature.

Human mesenchymal stem cells and immunosuppressive drug interactions in allogeneic responses: an in vitro study using human cells.

OBJECTIVES: The use of mesenchymal stem cells (MSC), which display immunosuppressive activity, seems to be a promising therapeutic approach in solid organ transplantation. However, little is known about their interactions with immunosuppressive drugs. The objective of this study was to assess these interactions in allogeneic responses. METHODS: We studied the effects on alloimmune responses in mixed lymphocyte reactions of MSC plus five agents-cyclosporine, tacrolimus, rapamycin, mycophenolate acid (MPA), and dexamethasone (DEX). RESULTS: Human MSC isolated from bone marrow were characterized by their phenotype and their ability to differentiate into adipocytes or osteoblastes. MSC plus the agents inhibited allogeneic lymphocyte proliferation in a dose-dependent manner. Calcineurin inhibitors and rapamycin antagonized the inhibitory effect of MSC, whereas MPA promoted it and DXM did not modify it. CONCLUSION: MPA seems to be the best immunosuppressant to associated with MSC for transplanted patients.

Composite tissue allograft extends a helping hand to transplant immunologists.

The first successful human hand transplantation, performed on September 1998, has translated the scope of 'composite tissue allotransplantation' from research concepts into clinical practice. Beyond microsurgical problems that have been overcome several years ago, the main obstacle that still prevents the generalization of composite tissue allotransplantation is immunologic. This review, which summarizes the evidence obtained both from experimental animal models and from the first recipients of a hand transplant, is focused on the two immunological characteristics of composite allografts that set them apart from other solid organ allografts: (i) they contain skin tissue that elicits a strong immune response; and (ii) they contain lymphoid tissues (such as bone marrow and lymph nodes) that have the potential both to attack the recipient, and also to down-modulate the host immune response and induce tolerance. While on one hand, the composite tissue allografts raise new challenges to transplant immunologists, on the other they provide answers to questions that have remained unresolved for a long time. In this sense, composite tissue allografts extend a helping hand to transplant immunologists.

Nephrotic syndrome associated with hemophagocytic syndrome.

Hemophagocytic syndrome (HPS) is defined by bone marrow and organ infiltration by activated, nonmalignant macrophages, which phagocytose blood cells. The clinical spectrum of HPS is broad, but renal involvement has rarely been investigated. We report a previously unknown renal manifestation of HPS: nephrotic syndrome. This multicentric retrospective study included patients fulfilling the following criteria: (i) no history of nephropathy; (ii) HPS diagnosis with histologic evidence of hemophagocytosis; (iii) occurrence of nephrotic syndrome during HPS; and (iv) available renal histology. Using the same criteria, we also searched the literature for additional cases. We identified nine patients retrospectively and found two additional cases in the literature (five males and six females, whose mean age was 34 +/- 27 years). Black African patients predominated (63.6%). HPS was due to lymphoma (six cases), infectious disease (three cases), and autoimmune disease (one case), and was primary in one patient. Acute renal failure was associated with nephrotic syndrome in 10/11 cases. Renal histology showed acute tubular necrosis associated with collapsing glomerulopathy in five patients (all Africans with negative human immunodeficiency virus serology), minimal change glomerulopathy in four, and thrombotic-microangiopathy with abnormal podocytes in two. Death occurred in seven cases. Nephrotic syndrome should be included among the renal complications of HPS with acute renal failure. We postulate that abnormal T-cell activation and/or high pro-inflammatory cytokine levels during HPS might cause podocyte injuries, especially among African patients with a susceptible genetic background.

Mycobacterium xenopi pulmonary infection in two renal transplant recipients under sirolimus therapy.

Opportunistic infection is a major threat to immunocompromised patients. However, infection due to Mycobacterium xenopi is rare in renal transplant recipients. We report two new cases of M. xenopi pulmonary infection (one case of interstitial pneumopathy and one of a pulmonary nodule) in renal transplant recipients, detected in the same center at an interval of a few months. Both patients were on an immunosuppressive regimen including a recent switch to sirolimus. Sirolimus is a new immunosuppressive drug already known to be responsible for interstitial pneumonitis. It also inhibits interleukin-12-induced proliferation of activated T lymphocytes, which is critical for the development of the cell-mediated immunity that protects against mycobacteria. These two case reports suggest that sirolimus therapy may lead to an impairment of the immune response against intracellular pathogens such as M. xenopi.

[Endocrine hypertension in pregnancy]. / Hypertensions artérielles endocriniennes au cours de la grossesse.

Hypertension is a frequent complication of pregnancy and may compromise fetal and maternal outcome. Hypertension may be pregnancy-induced, essential or secondary to endocrine disorders. Most cases of endocrine hypertension are the consequence of adrenal diseases. Pheochromocytoma, hypercorticism, primary aldosteronism or glucocorticoid-remediable aldosteronism can be present or diagnosed at any term and may cause severe hypertension. The most hazardous form of endocrine hypertension during pregnancy is pheochromocytoma because it may involve paroxysmal arrhythmia and/or hypertension during labor. Clinical clues and biological tests are similar to those used in non-pregnant subjects. Tests for tumor location are limited to ultrasound and magnetic resonance scans in order to avoid maternal and fetal irradiation. Medication to prepare for pheochromocytoma surgery uses alpha- and beta-blockers. The timing of surgery depends on the term of pregnancy at the diagnosis of the tumor.