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Tumor-associated macrophages (TAMs) contribute to the maintenance of a strong immunosuppressive environment, supporting tumor progression and resistance to treatment. To date, the mechanisms that drive acquisition of these immunosuppressive features are still poorly defined. Heme oxygenase-1 (HO-1) is the rate-limiting enzyme that catabolizes free heme. It displays important cytoprotective, antiinflammatory, and antioxidant properties. A growing body of evidence suggests that HO-1 may also promote tumor development. Herein, we show that HO-1 is highly expressed in monocytic cells in the tumor microenvironment (TME) once they differentiate into TAMs. Deletion of HO-1 in the myeloid compartment enhances the beneficial effects of a therapeutic antitumor vaccine by restoring CD8+ T cell proliferation and cytotoxicity. We further show that induction of HO-1 plays a major role in monocyte education by tumor cells by modulating their transcriptional and epigenetic programs. These results identify HO-1 as a valuable therapeutic target to reprogram the TME and synergize with current cancer therapies to facilitate antitumor response., info:eu-repo/semantics/published

We report the case of a 74-year-old woman admitted to the emergency unit for resting dyspnea. Clinical presentation, cardiac MRI and echocardiography were consistent with cardiac tamponade requiring emergency pericardiocentesis. Cytologic examination of the pericardial fluid revealed the presence of CD68pos CD1aneg S100neg foamy histiocytes (Fig. 1). Additional investigations complied with the diagnosis of Erdheim-Chester histiocytosis. Treatment with αIFN was initiated but the patient developed severe neutropenia that contraindicated further administration. The detection of BRAFV600E mutation on histiocytes isolated from the pericardial liquid and CNS involvement (cerebral masses) prompted the administration of vemurafenib, a selective BRAFV600E kinase inhibitor. Four months after the initiation of low-dose vemurafenib, pericarditis almost resolved and cerebral masses decreased by 50% (Fig. 2). To our knowledge, analysis of pericardial fluid allowing the diagnosis of Erdheim-Chester disease and the detection of the BRAFV600E mutation has in fact been rarely described in the literature. This case report and the successful evolution under vemurafenib also support the use of BRAFV600E inhibitors in αIFN-intolerant patients with BRAFV600E mutation, particularly in case of heart and central nervous system involvement.

Introduction Au cours de l’infection aigue par le Parvovirus B19, des lesions de vascularite ont ete parfois signalees se limitant generalement a une poussee de purpura vasculaire predominant aux membres inferieurs, mais des signes systemiques plus graves peuvent parfois simuler en tout point une vascularite necrosante (manifestations neurologiques, digestives ou rhumatologiques). Des associations entre purpura rhumatoide et infection a Parvovirus B19 ont ete decrites. Le Parvovirus B19 est suspecte sans que cela soit demontre dans la genese du purpura rhumatoide. Observation Nous decrivons le cas d’un patient âge de 27 ans sans antecedents particuliers, qui a ete hospitalise pour purpura des membres inferieurs, associe a des douleurs abdominales diffuses crampoides et des douleurs neuropathiques en decharges electriques fulgurantes. Le patient se plaignait egalement d’arthralgies invalidantes touchant petites et moyennes articulations. Ce tableau rappelait fortement un purpura rhumatoide. Une biopsie des lesions purpuriques au niveau des membres inferieurs a atteste de la presence d’une vascularite leucocytoclasique touchant les petits vaisseaux, mais l’immunofluorescence est revenue negative. Le taux d’IgA dans le sang etait normal. Une etiologie virale pouvant expliquer le tableau a ete recherchee. Le bilan a confirme la presence d’une infection recente a Parvovirus B19 (serologie positive en IgM). La PCR revient positive dans le sang. Une PCR n’a pas pu etre faite sur la biopsie cutanee vue la fixation prealable des lames. Le patient a ete mis sous corticoides pendant 3 jours en attendant les resultats de la biopsie. Quand le diagnostic fut etabli, l’abstention therapeutique a ete choisie pour la suite de la prise en charge. L’evolution a ete vite favorable avec la disparition des douleurs abdominales suivie de l’effacement progressif du purpura, l’amelioration des douleurs neuropathiques et la disparition du syndrome inflammatoire. Conclusion Le diagnostic d’une infection a Parvovirus B19 responsable d’une vascularite avec atteinte systemique a ete retenu sans que l’association a un purpura rhumatoide ne soit etablie. Mais une surveillance reguliere du patient est necessaire afin de guetter une nouvelle poussee voir l’apparition d’une veritable vasculite a IgA. L’association entre infection a Parvovirus B19 et l’induction d’une veritable vascularite a ete decrite et pose des questions sur le caractere viro-induit des vascularites et sur la physiopathologie de ces maladies qui reste encore mal comprise.

Introduction L’enteropathie associee a l’Olmesartan est une entite recemment decrite. Cela a ete decrit pour la premiere fois en 2012 par la Mayo Clinic qui ont rapporte une serie de 22 cas. Puis il s’en suivit quelques cas rapportes dans la litterature. Le but de ce travail est de rapporter un nouveau cas severe d’une sprue associee a l’Olmesartan, pour rappeler l’importance de rechercher une cause medicamenteuse lors de diarrhee chronique et severe. Observation Nous rapportons le cas d’un patient de 80 ans, suivi pour une hypertension arterielle traitee par l’olmesartan. Il s’est presente avec une diarrhee chronique et un amaigrissement depuis 4 mois. L’evolution a ete marquee par l’apparition d’une confusion et une deshydratation importante ayant entraine une insuffisance renale aigue associee a une acidose metabolique. Notre patient a ete admis aux soins intensifs ou il a ete stabilise et a eu une hemofiltration. Il fut transfere en medecine interne pour le bilan etiologique de cette diarrhee chronique. Multiples hemocultures et coprocultures se sont averees negatives, une endoscopie digestive totale etait normale. Le patient presentait un syndrome de malabsorption tres important et une atropie villositaire diffuse. Les serologies pour la maladie cœliaques etaient negatives et les autres causes de sprue ont ete exclues. Devant la suspicion d’une cause medicamenteuse, l’olmesartan a ete stoppe, une semaine apres le patient commencait a s’ameliorer jusqu’a amendement total des symptomes apres 4 semaines de l’arret. Conclusion Les praticiens ne doivent pas omettre de reviser la liste des medicaments de leurs patients devant des symptomes digestifs associes ou non a une atrophie villositaire, surtout chez les sujets âges polymediques ou une atteinte digestive severe peut engager le pronostic vital. Les sartans doivent etre stoppes devant l’apparition de tout symptome digestif notamment une diarrhee inexpliquee.

Activation of innate immunity through Toll-like receptors (TLR) can abrogate transplantation tolerance by revealing hidden T cell alloreactivity. Separately, the cholinergic anti-inflammatory pathway has the capacity to dampen macrophage activation and cytokine release during endotoxemia and ischemia reperfusion injury. However, the relevance of the α7 nicotinic acetylcholine receptor (α7nAChR)-dependent anti-inflammatory pathway in the process of allograft rejection or maintenance of tolerance remains unknown. The aim of our study is to investigate whether the cholinergic pathway could impact T cell alloreactivity and transplant outcome in mice. For this purpose, we performed minor-mismatched skin allografts using donor/recipient combinations genetically deficient for the α7nAChR. Minor-mismatched skin grafts were not rejected unless the mice were housed in an environment with endogenous pathogen exposure or the graft was treated with direct application of imiquimod (a TLR7 ligand). The α7nAChR-deficient recipient mice showed accelerated rejection compared to wild type recipient mice under these conditions of TLR activation. The accelerated rejection was associated with enhanced IL-17 and IFN-γ production by alloreactive T cells. An α7nAChR-deficiency in the donor tissue facilitated allograft rejection but not in recipient mice. In addition, adoptive T cell transfer experiments in skin-grafted lymphopenic animals revealed a direct regulatory role for the α7nAChR on T cells. Taken together, our data demonstrate that the cholinergic pathway regulates alloreactivity and transplantation tolerance at multiple levels. One implication suggested by our work is that, in an organ transplant setting, deliberate α7nAChR stimulation of brain dead donors might be a valuable approach for preventing donor tissue inflammation prior to transplant., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

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.

The recent interest for Th17 cells immediately raised questions about their possible involvement in allogeneic processes. Indeed, IL-17-producing innate immune cells and Th17 cells have now been related to allograft rejection and ischemia-reperfusion injury in clinical settings and in experimental models. Some of them clearly established a link between the presence of these cells and the development of long-term graft dysfunction. A pivotal role of a Th17-mediated pathway in transplant damage has been demonstrated independently of MHC disparities with T cells recognizing either autoantigen or minor transplantation antigen. The ambiguous relationship between regulatory T cells (Treg) and Th17 cells also complicates Treg-based therapy. Herein, we briefly discuss recent studies reporting Th17 and IL-17 involvements in allograft rejection processes.

Th17-mediated immune responses have been recently identified as novel pathogenic mechanisms in a variety of conditions; however, their importance in allograft rejection processes is still debated. In this paper, we searched for MHC or minor Ag disparate models of skin graft rejection in which Th17 immune responses might be involved. We found that T cell-derived IL-17 is critical for spontaneous rejection of minor but not major Ag-mismatched skin grafts. IL-17 neutralization was associated with a lack of neutrophil infiltration and neutrophil depletion delayed rejection, suggesting neutrophils as an effector mechanism downstream of Th17 cells. Regulatory T cells (Tregs) appeared to be involved in Th17 reactivity. We found that in vivo Treg depletion prevented IL-17 production by recipient T cells. An adoptive cotransfer of Tregs with naive monospecific antidonor T cells in lymphopenic hosts biased the immune response toward Th17. Finally, we observed that IL-6 was central for balancing Tregs and Th17 cells as demonstrated by the prevention of Th17 differentiation, the enhanced Treg/Th17 ratio, and a net impact of rejection blockade in the absence of IL-6. In conclusion, the ability of Tregs to promote the Th17/neutrophil-mediated pathway of rejection that we have described should be considered as a potential drawback of Treg-based cell therapy.

In bone marrow-transplanted patients, chronic graft-versus-host disease is a complication that results from the persistent stimulation of recipient minor histocompatibility Ag (mHA)-specific T cells contained within the graft. In this study, we developed a mouse model where persistent stimulation of donor T cells by recipient's mHA led to multiorgan T cell infiltration. Exposure to systemic mHA, however, deeply modified T cell function and chronically stimulated T cells developed a long-lasting state of unresponsiveness, or immune adaptation, characterized by their inability to mediate organ immune damages in vivo. However, analysis of the gene expression profile of adapted CD4+ T cells revealed the specific coexpression of genes known to promote differentiation and function of Th1 effector cells as well as genes coding for proteins that control T cell activity, such as cell surface-negative costimulatory molecules and regulatory cytokines. Strikingly, blockade of negative costimulation abolished T cell adaptation and stimulated strong IFN-gamma production and severe multiorgan wasting disease. Negative costimulation was also shown to control lethal LPS-induced toxic shock in mice with adapted T cells, as well as the capacity of adapted T cells to reject skin graft. Our results demonstrate that negative costimulation is the molecular mechanism used by CD4+ T cells to adapt their activity in response to persistent antigenic stimulation. The effector function of CD4+ T cells that have adapted to chronic Ag presentation can be activated by stimuli strong enough to overcome regulatory signals delivered to the T cells by negative costimulation., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Spontaneous rupture of a liver haemangioma is a rare but life-threatening acute clinical situation following haemorrhage within the liver, the subcapsular space and the peritoneal cavity in cases of capsular rupture. Rupture of a liver haemangioma has been reported to occur spontaneously in the majority of cases. In the past, prompt surgical treatment was recommended but was associated with high morbidity and mortality. Currently, conservative management and, in cases of recurrent haemorrhage, delayed surgery may be proposed. We report a case of spontaneous rupture of hepatic haemangioma treated by arterial embolisation and conservative means. The literature is also reviewed.