Splenic B1 B Cells Acquire a Proliferative and Anti-Inflamatory Profile During Pregnancy in Mice

B cells are a heterogeneous cell population with differential ontogeny, anatomical location, and functions. B1 B cells are a distinct subpopulation characterized by their unique capacity of self-renewal, the production of large quantities of IL-10, and the ability to secrete protective, anti-inflammatory natural antibodies (NAbs), presumably upon down-regulation of CD1d expression. Although natural antibodies are thought to be protective, due to their polyreactivity, their participation in certain autoimmune diseases has been suggested. In the context of pregnancy, the role of B1 B cells has been discussed controversially. While in human pregnancies B1 B cells and natural/polyreactive antibodies they produce are involved in the development of preeclampsia, in mice they promote healthy gestation and fetal protection. In this work, we aimed to functionally characterize the splenic B1 B cell population during pregnancy in mice. Functional enrichment analysis using only up-regulated transcripts from a transcriptomic profile performed on total splenic B cells from pregnant compared to non-pregnant mice showed augmented cell cycle and DNA replication pathways. Proliferation studies by flow cytometry showed augmented Ki-67 proliferation marker expression and percentages of B1 B cells. Furthermore, B1 B cells produced higher levels of IL-10 and lower levels of TNF-α leading to an increased IL-10/TNF-α ratio and showing an immunoregulatory phenotype. Finally, we observed lower expression of CD1d on B1 B cells, suggesting a higher capacity to produce NAbs in the context of pregnancy. In summary, our results showed not only an expanded and proliferative splenic B1 B cell population during pregnancy but also the acquisition of immunomodulatory capacities suggesting its critical role in the intricate process of pregnancy tolerance

Clinical veterinary boron neutron capture therapy (BNCT) studies in dogs with head and neck cancer: Bridging the gap between translational and clinical studies

Translational Boron Neutron Capture Therapy (BNCT) studies performed by our group and clinical BNCT studies worldwide have shown the therapeutic efficacy of BNCT for head and neck cancer. The present BNCT studies in veterinary patients with head and neck cancer were performed to optimize the therapeutic efficacy of BNCT, contribute towards exploring the role of BNCT in veterinary medicine, put in place technical aspects for an upcoming clinical trial of BNCT for head and neck cancer at the RA-6 Nuclear Reactor, and assess the feasibility of employing the existing B2 beam to treat large, deep-seated tumors. Five dogs with head and neck cancer with no other therapeutic option were treated with two applications of BNCT mediated by boronophenyl-alanine (BPA) separated by 3–5 weeks. Two to three portals per BNCT application were used to achieve a potentially therapeutic dose over the tumor without exceeding normal tissue tolerance. Clinical and Computed Tomography results evidenced partial tumor control in all cases, with slight-moderate mucositis, excellent life quality, and prolongation in the survival time estimated at recruitment. These exploratory studies show the potential value of BNCT in veterinary medicine and contribute towards initiating a clinical BNCT trial for head and neck cancer at the RA-6 clinical facility.Fil: Schwint, Amanda Elena. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Monti Hughes, Andrea. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica; ArgentinaFil: Santa Cruz, Gustavo Alberto. Comisión Nacional de Energía Atómica; ArgentinaFil: González, Sara Josefina. Comisión Nacional de Energía Atómica. Gerencia del Área de Investigación y Aplicaciones No Nucleares. Gerencia Física (Centro Atómico Constituyentes). Proyecto Tandar; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Longhino, Juan Manuel. Comisión Nacional de Energía Atómica; ArgentinaFil: Provenzano, Lucas. Comisión Nacional de Energía Atómica. Gerencia del Área de Investigación y Aplicaciones No Nucleares. Gerencia Física (Centro Atómico Constituyentes). Proyecto Tandar; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Oña, Paulina. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Instituto de Tecnologías Nucleares para la Salud; ArgentinaFil: Rao, Monica. Hospital Veterinario; ArgentinaFil: Cantarelli, María de los Ángeles. Hospital Veterinario; ArgentinaFil: Leiras, Andrea. No especifíca;Fil: Olivera, María Silvina. Comisión Nacional de Energía Atómica; ArgentinaFil: Trivillin, Verónica Andrea. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alessandrini, Paula. No especifíca;Fil: Brollo, Fabricio Raul. Comisión Nacional de Energía Atómica; ArgentinaFil: Boggio, Esteban Fabián. Comisión Nacional de Energía Atómica; ArgentinaFil: Costa, Hernan. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Instituto de Tecnologías Nucleares para la Salud; ArgentinaFil: Ventimiglia, Romina. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Instituto de Tecnologías Nucleares para la Salud; ArgentinaFil: Binia, Sergio. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Instituto de Tecnologías Nucleares para la Salud; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; ArgentinaFil: Nievas, Susana Isabel. Comisión Nacional de Energía Atómica; ArgentinaFil: Santa Cruz, Iara S.. Comisión Nacional de Energía Atómica; Argentin

Neonatal Astrocyte Damage Is Sufficient to Trigger Progressive Striatal Degeneration in a Rat Model of Glutaric Acidemia-I

BACKGROUND: We have investigated whether an acute metabolic damage to astrocytes during the neonatal period may critically disrupt subsequent brain development, leading to neurodevelopmental disorders. Astrocytes are vulnerable to glutaric acid (GA), a dicarboxylic acid that accumulates in millimolar concentrations in Glutaric Acidemia I (GA-I), an inherited neurometabolic childhood disease characterized by degeneration of striatal neurons. While GA induces astrocyte mitochondrial dysfunction, oxidative stress and subsequent increased proliferation, it is presently unknown whether such astrocytic dysfunction is sufficient to trigger striatal neuronal loss. METHODOLOGY/PRINCIPAL FINDINGS: A single intracerebroventricular dose of GA was administered to rat pups at postnatal day 0 (P0) to induce an acute, transient rise of GA levels in the central nervous system (CNS). GA administration potently elicited proliferation of astrocytes expressing S100β followed by GFAP astrocytosis and nitrotyrosine staining lasting until P45. Remarkably, GA did not induce acute neuronal loss assessed by FluoroJade C and NeuN cell count. Instead, neuronal death appeared several days after GA treatment and progressively increased until P45, suggesting a delayed onset of striatal degeneration. The axonal bundles perforating the striatum were disorganized following GA administration. In cell cultures, GA did not affect survival of either striatal astrocytes or neurons, even at high concentrations. However, astrocytes activated by a short exposure to GA caused neuronal death through the production of soluble factors. Iron porphyrin antioxidants prevented GA-induced astrocyte proliferation and striatal degeneration in vivo, as well as astrocyte-mediated neuronal loss in vitro. CONCLUSIONS/SIGNIFICANCE: Taken together, these results indicate that a transient metabolic insult with GA induces long lasting phenotypic changes in astrocytes that cause them to promote striatal neuronal death. Pharmacological protection of astrocytes with antioxidants during encephalopatic crisis may prevent astrocyte dysfunction and the ineluctable progression of disease in children with GA-I