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Tartour E.,University of Paris Descartes | Pere H.,University of Paris Descartes | Maillere B.,French Atomic Energy Commission | Terme M.,University of Paris Descartes | And 11 more authors.
Cancer and Metastasis Reviews | Year: 2011

The immune system regulates angiogenesis in cancer with both pro- and antiangiogenic activities. The induction of angiogenesis is mediated by tumor-associated macrophages and myeloid-derived suppressor cells (MDSC) which produce proinflammatory cytokines, endothelial growth factors (VEGF, bFGF...), and protease (MMP9) implicated in neoangiogenesis. Some cytokines (IL-6, IL-17...) activated Stat3 which also led to the production of VEGF and bFGF. In contrast, other cytokines (IFN, IL-12, IL-21, and IL-27) display an antiangiogenic activity. Recently, it has been shown that some antiangiogenic molecules alleviates immunosuppression associated with cancer by decreasing immunosuppressive cells (MDSC, regulatory T cells), immunosuppressive cytokines (IL-10, TGFβ), and inhibitory molecules on T cells (PD-1). Some of these broad effects may result from the ability of some antiangiogenic molecules, especially cytokines to inhibit the Stat3 transcription factor. The association often observed between angiogenesis and immunosuppression may be related to hypoxia which induces both neoangiogenesis via activation of HIF-1 and VEGF and favors the intratumor recruitment and differentiation of regulatory T cells and MDSC. Preliminary studies suggest that modulation of immune markers (intratumoral MDSC and IL-8, peripheral regulatory T cells...) may predict clinical response to antiangiogenic therapy. In preclinical models, a synergy has been observed between antiangiogenic molecules and immunotherapy which may be explained by an improvement of immune status in tumor-bearing mice after antiangiogenic therapy. In preclinical models, antiangiogenic molecules promoted intratumor trafficking of effector cells, enhance endogenous anti-tumor response, and synergyzed with immunotherapy protocols to cure established murine tumors. All these results warrant the development of clinical trials combining antiangiogenic drugs and immunotherapy. © 2011 Springer Science+Business Media, LLC.


Zuber J.,Service de Transplantation Renale Adulte | Fakhouri F.,Nantes University Hospital Center | Roumenina L.T.,French Institute of Health and Medical Research | Loirat C.,Service de Nephrologie | Fremeaux-Bacchi V.,Service dImmunologie Biologique
Nature Reviews Nephrology | Year: 2012

In the past decade, a large body of evidence has accumulated in support of the critical role of dysregulation of the alternative complement pathway in atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathies. These findings have paved the way for innovative therapeutic strategies based on complement blockade, and eculizumab, a monoclonal antibody targeting the human complement component 5, is now widely used to treat aHUS. In this article, we review 28 case reports and preliminary data from 37 patients enrolled in prospective trials of eculizumab treatment for episodes of aHUS involving either native or transplanted kidneys. Eculizumab may be considered as an optimal first-line therapy when the diagnosis of aHUS is unequivocal and this treatment has the potential to rescue renal function when administered early after onset of the disease. However, a number of important issues require further study, including the appropriate duration of treatment according to an individual's genetic background and medical history, the optimal strategy to prevent post-transplantation recurrence of aHUS and a cost-efficacy analysis. Data regarding the efficacy of eculizumab in the control of C3 glomerulopathies are more limited and less clear, but several observations suggest that eculizumab may act on the most inflammatory forms of this disorder. © 2012 Macmillan Publishers Limited. All rights reserved.


Zuber J.,University of Paris Descartes | Le Quintrec M.,Service de Nephrologie | Sberro-Soussan R.,University of Paris Descartes | Loirat C.,University Paris Diderot | And 2 more authors.
Nature Reviews Nephrology | Year: 2011

After renal transplantation, hemolytic uremic syndrome (HUS) may occur either as a recurrent or de novo form. Over the past decade, much effort has been devoted to elucidating the pathogenesis of atypical HUS (aHUS). Approximately 60g-70% patients with aHUS have mutations in regulatory factors of the complement system or antibodies against complement factor H. The risk of post-transplant recurrence of aHUS depends on the genetic abnormality involved, and ranges from 15% to 20% in patients with mutations in the gene that encodes membrane cofactor protein and from 50% to 100% in patients with mutations in the genes that encode circulating regulators of complement. Given the poor outcomes associated with recurrence, isolated renal transplantation had been contraindicated in patients at high risk of aHUS recurrence. However, emerging therapies, including pre-emptive plasma therapy and anti-C5 component monoclonal antibody (eculizumab) treatment have provided promising results and should further limit indications for the risky procedure of combined liverg-kidney transplantation. Studies from the past 2 years have demonstrated genetic abnormalities in complement regulators in 30% of renal transplant recipients who experienced de novo HUS after renal transplantation. This finding suggests that the burden of endothelial injury in a post-transplantation setting may trigger de novo HUS in the presence of mild genetic susceptibility to HUS. © 2010 Macmillan Publishers Limited. All rights reserved.


Fridman W.H.,French Institute of Health and Medical Research | Fridman W.H.,University of Paris Descartes | Galon J.,French Institute of Health and Medical Research | Galon J.,University of Paris Descartes | And 10 more authors.
Cancer Research | Year: 2011

Leukocyte infiltrates into or around tumor cell nests are found in the context of protumorigenic inflammation and anticancer immunosurveillance. Hence, the detailed composition, density, architecture, and function of leukocyte infiltrates must be analyzed to understand their prognostic impact. The ectopic presence within tumors of high endothelial venule cells, which are normally characteristic for secondary lymphoid organs, correlates with a more pronounced infiltration by T lymphocytes and has a positive predictive impact on local advanced breast cancer treated with neoadjuvant chemotherapy. Recent progress in the field indicates that immune infiltrates of the primary tumors, as well as of metastases, are not only independent prognostic biomarkers but can also constitute predictive factors, suggesting that the pretherapeutic immune response can determine the efficacy of conventional chemotherapies. Moreover, accumulating evidence indicates that chemotherapy can stimulate anticancer immune responses coupled with an increased intratumoral lymphoid infiltration, which correlates with tumor mass reduction and patient survival. Improved methods for the automation of immunohistochemistry and digitalized image analyses will pave the way to an improved understanding of the complex interplay between cancer parenchyma, stroma, and immune effectors, as well as to the routine evaluation of immune-related parameters to the clinical management of cancer patients. ©2011 AACR.


Canaud G.,University of Paris Descartes | Bienaime F.,University of Paris Descartes | Tabarin F.,University of Paris Descartes | Bataillon G.,University Pierre and Marie Curie | And 8 more authors.
New England Journal of Medicine | Year: 2014

Background: Although thrombosis is considered the cardinal feature of the antiphospholipid syndrome, chronic vascular lesions are common, particularly in patients with lifethreatening complications. In patients who require transplantation, vascular lesions often recur. The molecular pathways involved in the vasculopathy of the antiphospholipid syndrome are unknown, and adequate therapies are lacking. Methods: We used double immunostaining to evaluate pathway activation in the mammalian target of rapamycin complex (mTORC) and the nature of cell proliferation in the vessels of patients with primary or secondary antiphospholipid syndrome nephropathy. We also evaluated autopsy specimens from persons who had catastrophic antiphospholipid syndrome. The molecular pathways through which antiphospholipid antibodies modulate the mTORC pathway were evaluated in vitro, and potential pharmacologic inhibitors were also tested in vitro. Finally, we studied the effect of sirolimus in kidney-transplant recipients with the antiphospholipid syndrome. Results: The vascular endothelium of proliferating intrarenal vessels from patients with antiphospholipid syndrome nephropathy showed indications of activation of the mTORC pathway. In cultured vascular endothelial cells, IgG antibodies from patients with the antiphospholipid syndrome stimulated mTORC through the phosphatidyl-inositol 3-kinase (PI3K)-AKT pathway. Patients with antiphospholipid syndrome nephropathy who required transplantation and were receiving sirolimus had no recurrence of vascular lesions and had decreased vascular proliferation on biopsy as compared with patients with antiphospholipid antibodies who were not receiving sirolimus. Among 10 patients treated with sirolimus, 7 (70%) had a functioning renal allograft 144 months after transplantation versus 3 of 27 untreated patients (11%). Activation of mTORC was also found in the vessels of autopsy specimens from patients with catastrophic antiphospholipid syndrome. Conclusions: Our results suggest that the mTORC pathway is involved in the vascular lesions associated with the antiphospholipid syndrome. Copyright © 2014 Massachusetts Medical Society. All rights reserved.


Pell G.,Service de Nephrologie transplantation Renale | Shweke N.,Service de Nephrologie transplantation Renale | Van Huyen J.-P.D.,Service dAnatomo pathologie | Tricot L.,Service de Nephrologie transplantation Renale | And 4 more authors.
American Journal of Kidney Diseases | Year: 2011

Intravenous injection of angiogenesis-inhibitor drugs is used widely to treat cancers. Associated renal complications primarily involve proteinuria and hypertension, and thrombotic microangiopathies also have been described. Intravitreal antivascular endothelial growth factor (VEGF) therapy currently is used by ophthalmologists to treat neovascularization in age-related macular degeneration. However, there is some evidence that intravitreal anti-VEGF injections may result in systemic absorption, with the potential for injury in organs that are reliant on VEGF, such as the kidney. We report the first case to our knowledge of a patient who developed an acute decrease in kidney function, nonimmune microangiopathic hemolytic anemia with schistocytes, and thrombocytopenia after 4 intravitreal injections of ranibizumab. Light microscopy of a kidney biopsy specimen showed segmental duplications of glomerular basement membranes with endothelial swelling and several recanalized arteriolar thrombi. Because of the increasing use of intravitreal anti-VEGF agents, ophthalmologists and nephrologists should be aware of the associated risk of kidney disease. Early detection is crucial so that intravitreal injections can be stopped before severe kidney disease occurs. © 2011 National Kidney Foundation, Inc.


Pages F.,French Institute of Health and Medical Research | Pages F.,University of Paris Descartes | Pages F.,University Pierre and Marie Curie | Galon J.,French Institute of Health and Medical Research | And 13 more authors.
Oncogene | Year: 2010

The natural history of a tumor includes phases of in situ growth, invasion, extravasation and metastasis. During these phases, tumor cells interact with their microenvironment and are influenced by signals coming from stromal, endothelial, inflammatory and immune cells. Indeed, tumors are often infiltrated by various numbers of lymphocytes, macrophages or mast cells. It is generally believed that the latter produce factors that maintain chronic inflammation and promote tumor growth, whereas lymphocytes may control cancer outcome, as evidenced in mouse models. In this study, we analyze data from large cohorts of human tumors, clearly establishing that infiltration of the primary tumor by memory T cells, particularly of the Th1 and cytotoxic types, is the strongest prognostic factor in terms of freedom from disease and overall survival at all stages of clinical disease. We review data suggesting that tertiary lymphoid structures adjacent to tumors and composed of mature dendritic cells (T and B cells organized as germinal centers) may be the site of an antitumor reaction. We propose an immune scoring based on the type, density and location of lymphocyte infiltrates as a novel prognostic factor for use in addition to tumor node metastasis staging to predict disease-free survival and to aid in decisions regarding adjuvant therapies in early stage human cancers. © 2010 Macmillan Publishers Limited All rights reserved.


Nilsson S.C.,Skåne University Hospital | Kalchishkova N.,Skåne University Hospital | Trouw L.A.,Leiden University | Fremeaux-Bacchi V.,Service dImmunologie Biologique | And 2 more authors.
European Journal of Immunology | Year: 2010

The complement system is regulated by inhibitors such as factor I (FI), a serine protease that degrades activated complement factors C4b and C3b in the presence of specific cofactors. Mutations and polymorphisms in FI and its cofactors are associated with atypical hemolytic uremic syndrome (aHUS). All 14 complement factor I mutations associated with aHUS analyzed in this study were heterozygous and generated premature stop codons (six) or amino acid substitutions (eight). Almost all of the mutants were expressed by human embryonic kidney 293 cells but only six mutants were secreted into the medium, three of which were at lower levels than WT. The remaining eight mutants were not secreted but sensitive to deglycosylation with endoglycosidase H, indicating that they were retained early in the secretory pathway. Six secreted mutants were purified and five of them were functionally altered in degradation of C4b/C3b in the fluid-phase in the presence of various cofactors and on endothelial cells. Three mutants cleaved surfacebound C3b less efficiently than WT. The D501N mutant was severely impaired both in solution and on surface irrespective of the cofactor used. In conclusion, mutations in complement factor I affect both secretion and function of FI, which leads to impaired regulation of the complement system in aHUS. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.


Lapeyraque A.-L.,CHU Sainte Justine | Fremeaux-Bacchi V.,Service dImmunologie Biologique | Robitaille P.,CHU Sainte Justine
Pediatric Nephrology | Year: 2011

Atypical hemolytic uremic syndrome (aHUS) is a rare, chronic, life-threatening disease due to complement dysregulation. The use of early-onset plasma therapy is recommended, but optimal long-term treatment regimen is not well defined. Eculizumab, a monoclonal humanized anti-C5 antibody, has shown success in patients with aHUS. We report a 7-year-old girl with aHUS associated with factor H mutations successfully treated with eculizumab. Weekly plasma infusion (PI) of 25-30 ml/kg with short-term intensified PI during aHUS exacerbations was effective for 4.3 years. Progressive mild renal failure (stage 2) was attributed to chronic glomerular lesions. Subsequently, she exhibited aHUS exacerbation unresponsive to intensified PI. Eculizumab was initiated at 600 mg, resulting in immediate and complete inhibition of terminal complement activation. During the week following treatment, we observed a complete reversal of aHUS activity. She has been receiving 600 mg eculizumab every 2 weeks for the last 12 months. She had no aHUS exacerbation, and serum creatinine level returned to normal. In this patient, eculizumab led to control of PI-resistant aHUS exacerbation and chronic microangiopathic hemolytic activity. Clinical trials are ongoing to assess the safety and efficacy of this drug in the management of aHUS. © 2010 IPNA.


Fakhouri F.,Nantes University Hospital Center | Fremeaux-Bacchi V.,Service dImmunologie Biologique | Noel L.-H.,French Institute of Health and Medical Research | Cook H.T.,Imperial College London | Pickering M.C.,Imperial College London
Nature Reviews Nephrology | Year: 2010

Several distinct pathological patterns of glomerular inflammation are associated with abnormal regulation of the complement system, specifically, with dysregulation of the alternative pathway of the complement system. However, these conditions share the pathological finding of complement C3 (C3) deposited within the glomerulus in the absence of substantial immunoglobulin. This finding has alerted us and others to the possible presence of genetic and acquired complement dysregulation in individual patients. This article summarizes our current understanding of the relationship between dysregulation of the complement system and glomerular inflammation. Here, we suggest that glomerular pathologies that are characterized by the isolated deposition of C3 could usefully be classified by the term C3 glomerulopathy. In our view, this classification would alert the pathologist and nephrologist to the importance of screening for acquired and genetic abnormalities in complement regulation. In the future, it could help to identify individuals who might benefit from therapeutic inhibition of the complement system. © 2010 Macmillan Publishers Limited. All rights reserved.

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