Resveratrol Prevents Endothelial Cells Injury in High-Dose Interleukin-2 Therapy against Melanoma

Immunotherapy with high-dose interleukin-2 (HDIL-2) is an effective treatment for patients with metastatic melanoma and renal cell carcinoma. However, it is accompanied by severe toxicity involving endothelial cell injury and induction of vascular leak syndrome (VLS). In this study, we found that resveratrol, a plant polyphenol with anti-inflammatory and anti-cancer properties, was able to prevent the endothelial cell injury and inhibit the development of VLS while improving the efficacy of HDIL-2 therapy in the killing of metastasized melanoma. Specifically, C57BL/6 mice were injected with B16F10 cells followed by resveratrol by gavage the next day and continued treatment with resveratrol once a day. On day 9, mice received HDIL-2. On day 12, mice were evaluated for VLS and tumor metastasis. We found that resveratrol significantly inhibited the development of VLS in lung and liver by protecting endothelial cell integrity and preventing endothelial cells from undergoing apoptosis. The metastasis and growth of the tumor in lung were significantly inhibited by HDIL-2 and HDIL-2 + resveratrol treatment. Notably, HDIL-2 + resveratrol co-treatment was more effective in inhibiting tumor metastasis and growth than HDIL-2 treatment alone. We also analyzed the immune status of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSC) and FoxP3+CD4+ regulatory T cells (Treg). We found that resveratrol induced expansion and suppressive function of MDSC which inhibited the development of VLS after adoptive transfer. However, resveratrol suppressed the HDIL-2-induced expansion of Treg cells. We also found that resveratrol enhanced the susceptibility of melanoma to the cytotoxicity of IL-2-activated killer cells, and induced the expression of the tumor suppressor gene FoxO1. Our results suggested the potential use of resveratrol in HDIL-2 treatment against melanoma. We also demonstrated, for the first time, that MDSC is the dominant suppressor cell than regulatory T cell in the development of VLS

Targeting Toll-like receptor 7/8 enhances uptake of apoptotic leukemic cells by monocyte-derived dendritic cells but interferes with subsequent cytokine-induced maturation

Therapeutic vaccination with dendritic cells (DC) is an emerging investigational therapy for eradication of minimal residual disease in acute myeloid leukemia. Various strategies are being explored in manufacturing DC vaccines ex vivo, e.g., monocyte-derived DC (MoDC) loaded with leukemia-associated antigens (LAA). However, the optimal source of LAA and the choice of DC-activating stimuli are still not well defined. Here, loading with leukemic cell preparations (harboring both unknown and known LAA) was explored in combination with a DC maturation-inducing cytokine cocktail (CC; IL-1β, IL-6, TNF-α, and PGE2) and Toll-like receptor ligands (TLR-L) to optimize uptake. Since heat shock induced apoptotic blasts were more efficiently taken up than lysates, we focused on uptake of apoptotic leukemic cells. Uptake of apoptotic blast was further enhanced by the TLR7/8-L R848 (20–30%); in contrast, CC-induced maturation inhibited uptake. CC, and to a lesser extent R848, enhanced the ability of MoDC to migrate and stimulate T cells. Furthermore, class II-associated invariant chain peptide expression was down-modulated after R848- or CC-induced maturation, indicating enhanced processing and presentation of antigenic peptides. To improve both uptake and maturation, leukemic cells and MoDC were co-incubated with R848 for 24 h followed by addition of CC. However, this approach interfered with CC-mediated MoDC maturation as indicated by diminished migratory and T cell stimulatory capacity, and the absence of IL-12 production. Taken together, our data demonstrate that even though R848 improved uptake of apoptotic leukemic cells, the sequential use of R848 and CC is counter-indicated due to its adverse effects on MoDC maturation

Cross-talk between cd1d-restricted nkt cells and γδ cells in t regulatory cell response

CD1d is a non-classical major histocompatibility class 1-like molecule which primarily presents either microbial or endogenous glycolipid antigens to T cells involved in innate immunity. Natural killer T (NKT) cells and a subpopulation of γδ T cells expressing the Vγ4 T cell receptor (TCR) recognize CD1d. NKT and Vγ4 T cells function in the innate immune response via rapid activation subsequent to infection and secrete large quantities of cytokines that both help control infection and modulate the developing adaptive immune response. T regulatory cells represent one cell population impacted by both NKT and Vγ4 T cells. This review discusses the evidence that NKT cells promote T regulatory cell activation both through direct interaction of NKT cell and dendritic cells and through NKT cell secretion of large amounts of TGFβ, IL-10 and IL-2. Recent studies have shown that CD1d-restricted Vγ4 T cells, in contrast to NKT cells, selectively kill T regulatory cells through a caspase-dependent mechanism. Vγ4 T cell elimination of the T regulatory cell population allows activation of autoimmune CD8+ effector cells leading to severe cardiac injury in a coxsackievirus B3 (CVB3) myocarditis model in mice. CD1d-restricted immunity can therefore lead to either immunosuppression or autoimmunity depending upon the type of innate effector dominating during the infection

Mise en évidence de mouvements sur la moraine et le glacier rocheux de Sainte-Anne (Queyras, Alpes du Sud - France) : le rôle du pergélisol alpin

Abstract. — Movments difficult to interpretate have been proved on the moraine of the Ste Anne glacier by means of photogrammetry. The average annual velocity was of 0,36 m a year from 1948 to 71. A new statistical method of counting orientated blocks on the surface of rock-glaciers determines two directions of flow on accumulation. One of them, being of secondary importance, corresponds to the actual mov- ment (rightwards regarding the main direction of flow). In order to explain the older and main direction of the flow, it is necessary to refer to the internal permafrost, which can be indirectly pointed out in the Ste Anne cirque. The transition from moraine to rock-glacier has been put forwards (as a hypothesis) in the last Holocene cold fluctuations. According to this schedule, the Little Ice Age is only responsible for a reactivation of the rightwards moving accumulation.Résumé. — Des mouvements, d'interprétation délicate, ont été mis en évidence sur la moraine du glacier de Sainte-Anne, par photogrammétrie. La vitesse moyenne annuelle de déplacements a été de 0,36 m /an entre 1948 et 1971. Une méthode nouvelle de comptage des blocs orientés à la surface des glaciers rocheux détermine deux directions d'écoulement sur l'accumulation, dont l'une, secondaire correspond au mouvement actuel (oblique par rapport à la direction d'écoulement principal). Pour expliquer la direction d'écoulement principale, la plus ancienne il faut faire appel à des variations de la géométrie du pergélisol, par ailleurs assez facile à mettre en évidence de façon indirecte dans le cirque de Sainte- Anne. Un essai de reconstitution du passage de la moraine au glacier rocheux est proposé dans le cadre des dernières périodes froides holocènes. Dans ce schéma, Le Petit Age glaciaire n'est responsable que d'une réactivation de la forme.Evin Michèle, Assier A. Mise en évidence de mouvements sur la moraine et le glacier rocheux de Sainte-Anne (Queyras, Alpes du Sud - France) : le rôle du pergélisol alpin. In: Revue de géographie alpine, tome 71, n°2, 1983. pp. 165-178

A CONTRIBUTION TO THE MATHEMATICAL THEORY OF DIFFRACTION:PART II: RECOVERING THE FAR-FIELD ASYMPTOTICS OF THE QUARTER-PLANE PROBLEM

We apply the stationary phase method developed in (Assier, Shanin & Korolkov, QJMAM, 76(1), 2022) to the problem of wave diffraction by a quarter-plane. The wave field is written as a double Fourier transform of an unknown spectral function. We make use of the analytical continuation results of (Assier & Shanin, QJMAM, 72(1), 2018) to uncover the singularity structure of this spectral function. This allows us to provide a closed-form far-field asymptotic expansion of the field by estimating the double Fourier integral near some special points of the spectral function. All the known results on the far-field asymptotics of the quarter-plane problem are recovered, and new mathematical expressions are derived for the secondary diffracted waves in the plane of the scatterer