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Concise Review: Apoptotic Cell-Based Therapies-Rationale, Preclinical Results and Future Clinical Developments
Concise Review: Apoptotic Cell-Based Therapies-Rationale, Preclinical Results and Future Clinical Developments
Stem Cells
2016 Jun

Saas, P.
Daguindau, E.
Perruche, S.

The objectives of this review are to summarize the experimental data obtained using apoptotic cell-based therapies, and then to discuss future clinical developments. Indeed, apoptotic cells exhibit immunomodulatory properties that are reviewed here by focusing on more recent mechanisms. These immunomodulatory mechanisms are in particular linked to the clearance of apoptotic cells (called also efferocytosis) by phagocytes, such as macrophages, and the induction of regulatory T cells. Thus, apoptotic cell-based therapies have been used to prevent or treat experimental inflammatory diseases. Based on these studies, we have identified critical steps to design future clinical trials. This includes: the administration route, the number and schedule of administration, the appropriate apoptotic cell type to be used, as well as the apoptotic signal. We also have analyzed the clinical relevancy of apoptotic-cell-based therapies in experimental models. Additional experimental data are required concerning the treatment of inflammatory diseases (excepted for sepsis) before considering future clinical trials. In contrast, apoptotic cells have been shown to favor engraftment and to reduce acute graft-versus-host disease (GvHD) in different relevant models of transplantation. This has led to the conduct of a phase 1/2a clinical trial to alleviate GvHD. The absence of toxic effects obtained in this trial may support the development of other clinical studies based on this new cell therapy. Stem Cells 2016;34:1464-1473.

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Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation
Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation
J Biol Chem
2016 Jan

Sun, X.
Haas, M. E.
Miao, J.
Mehta, A.
Graham, M. J.
Crooke, R. M.
Pais de Barros, J. P.
Wang, J. G.
Aikawa, M.
Masson, D.
Biddinger, S. B.

Diabetes is characterized by increased lipogenesis as well as increased endoplasmic reticulum (ER) stress and inflammation. The nuclear hormone receptor liver X receptor (LXR) is induced by insulin and is a key regulator of lipid metabolism. It promotes lipogenesis and cholesterol efflux, but suppresses endoplasmic reticulum stress and inflammation. The goal of these studies was to dissect the effects of insulin on LXR action. We used antisense oligonucleotides to knock down Lxralpha in mice with hepatocyte-specific deletion of the insulin receptor and their controls. We found, surprisingly, that knock-out of the insulin receptor and knockdown of Lxralpha produced equivalent, non-additive effects on the lipogenic genes. Thus, insulin was unable to induce the lipogenic genes in the absence of Lxralpha, and LXRalpha was unable to induce the lipogenic genes in the absence of insulin. However, insulin was not required for LXRalpha to modulate the phospholipid profile, or to suppress genes in the ER stress or inflammation pathways. These data show that insulin is required specifically for the lipogenic effects of LXRalpha and that manipulation of the insulin signaling pathway could dissociate the beneficial effects of LXR on cholesterol efflux, inflammation, and ER stress from the negative effects on lipogenesis.

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Human ectonucleotidase-expressing CD25high Th17 cells accumulate in breast cancer tumors and exert immunosuppressive functions
Human ectonucleotidase-expressing CD25high Th17 cells accumulate in breast cancer tumors and exert immunosuppressive functions
Oncoimmunology
2016 Jan

Thibaudin, M.
Chaix, M.
Boidot, R.
Vegran, F.
Derangere, V.
Limagne, E.
Berger, H.
Ladoire, S.
Apetoh, L.
Ghiringhelli, F.

Th17 cells contribute to the development of some autoimmune and allergic diseases by driving tissue inflammation. However, the function of Th17 cells during cancer progression remains controversial. Here, we show that human memory CD25high Th17 cells suppress T cell immunity in breast cancer. Ectonucleotidase-expressing Th17 cells accumulated in breast cancer tumors and suppressed CD4+ and CD8+ T cell activation. These cells expressed both Rorgammat and Foxp3 genes and secreted Th17 related cytokines. We further found that CD39 ectonucleotisase expression on tumor-infiltrating Th17 cells was driven by TGF-betaand IL-6. Finally, immunohistochemical analysis of localized breast cancer revealed that high-tumor infiltration by IL-17+ cells was associated with a poor clinical outcome and impeded the favorable effect of high CD8+ infiltration. Altogether, these findings suggest that intratumoral Th17 cells compromise anticancer immune responses in breast cancer patients.

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In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent
In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent
Haematologica
fevrier 2015

Angelot-Delettre, F.
Roggy, A.
Frankel, A. E.
Lamarthee, B.
Seilles, E.
Biichle, S.
Royer, B.
Deconinck, E.
Rowinsky, E. K.
Brooks, C.
Bardet, V.
Benet, B.
Bennani, H.
Benseddik, Z.
Debliquis, A.
Lusina, D.
Roussel, M.
Solly, F.
Ticchioni, M.
Saas, P.
Garnache-Ottou, F.

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Effects of TNFalpha inhibitors on adiposity and other cardiovascular risk factors: implications for the cardiovascular prognosis in patients with rheumatoid arthritis
Effects of TNFalpha inhibitors on adiposity and other cardiovascular risk factors: implications for the cardiovascular prognosis in patients with rheumatoid arthritis
Expert Opin Drug Saf
avril 2015

Toussirot, E.

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ATG-induced accelerated immune senescence: clinical implications in renal transplant recipients
ATG-induced accelerated immune senescence: clinical implications in renal transplant recipients
American Journal of Transplantation
April 2015

Crepin, T.
Carron, C.
Roubiou, C.
Gaugler, B.
Gaiffe, E.
Simula-Faivre, D.
Ferrand, C.
Tiberghien, P.
Chalopin, J. M.
Moulin, B.
Frimat, L.
Rieu, P.
Saas, P.
Ducloux, D.
Bamoulid, J.

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Multi-state relative survival modelling of colorectal cancer progression and mortality
Multi-state relative survival modelling of colorectal cancer progression and mortality
Cancer Epidemiol
25 mars 2015

Gilard-Pioc, S.
Abrahamowicz, M.
Mahboubi, A.
Bouvier, A. M.
Dejardin, O.
Huszti, E.
Binquet, C.
Quantin, C.

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Impact of donor hematopoietic cells mobilized with G-CSF and plerixafor on murine acute graft-versus-host-disease
Impact of donor hematopoietic cells mobilized with G-CSF and plerixafor on murine acute graft-versus-host-disease
Cytotherapy
23 mars 2015

Arbez, J.
Saas, P.
Lamarthee, B.
Malard, F.
Couturier, M.
Mohty, M.
Gaugler, B.

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Transforming growth factor-beta released by apoptotic white blood cells during red blood cell storage promotes transfusion-induced alloimmunomodulation
Transforming growth factor-beta released by apoptotic white blood cells during red blood cell storage promotes transfusion-induced alloimmunomodulation
Transfusion
21 mars 2015

Vallion, R.
Bonnefoy, F.
Daoui, A.
Vieille, L.
Tiberghien, P.
Saas, P.
Perruche, S.

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Fatty acid composition of adipose tissue and colorectal cancer: a case-control study
Fatty acid composition of adipose tissue and colorectal cancer: a case-control study
Am J Clin Nutr
Janvier 2015

Cottet, V.
Vaysse, C.
Scherrer, M. L.
Ortega-Deballon, P.
Lakkis, Z.
Delhorme, J. B.
Deguelte-Lardiere, S.
Combe, N.
Bonithon-Kopp, C.

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