DIAPORAMA: PROPAGACIÓN DE HEVEA BRASILIENSIS MUELL. ARG. UA: PRODUCCIÓN DE CULTIVOS TROPICALES L31235 (6O SEMESTRE LICENCIATURA: INGENIERO AGRÓNOMO FITOTECNISTA (OPTATIVA))

SÓLO VISIÓN PROYECTABLE

Assessing immunocompetence in minipigs in translational safety sciences – a perspective

The porcine immune system has been studied especially with regard to infectious diseases of the domestic pig, highlighting the economic importance of the pig in agriculture. Recently, in particular minipigs have received attention as alternative species to dogs or non-human primates in drug safety evaluations. The increasing number of new drug targets investigated to modulate immunological pathways has triggered renewed interest to further explore the porcine immune system. Comparative immunological studies of minipigs with other species broaden the translational models investigated in drug safety evaluations. The porcine immune system overall seems functionally similar to other mammalian species, but there are some anatomical and immunophenotypical differences. Here, we briefly review current knowledge of the innate and adaptive immune system in (mini)pigs. In conclusion, more systematic and cross-species comparisons are needed to assess the significance of immunological findings in minipigs in the context of translational safety sciences

Deficiency in the Metabolite-Sensing Receptor SUCNR1 (GPR91) Leads to Outer Retinal Lesions akin to dry-Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a prominent cause of blindness in the Western world. To date, its molecular pathogenesis as well as the sequence of events leading to retinal degeneration remain largely ill-defined. While the invasion of choroidal neovessels in the retina is the primary mechanism that precipitates loss of sight, an earlier dry form precedes it. Here we provide the first evidence for the protective role of the RPE-resident metabolite receptor, succinate receptor 1 (SUCNR1; G-Protein coupled Receptor-91 (GPR91), in preventing dry AMD-like lesions of the subretinal space. Genetic analysis of 925 patients with geographic atrophy and 1199 AMD-free peers revealed an increased risk of developing geographic atrophy associated with intronic variants in the SUCNR1 gene. In mice, outer retinal expression of SUCNR1 is largely confined to the Retinal Pigment Epithelium (RPE) as well as microglial cells and decreases progressively with age. Accordingly, Sucnr1-/- mice show signs of premature sub-retinal dystrophy with accumulation of oxidized-LDL, abnormal thickening of Bruch’s membrane and a pronounced buildup of lipid-bloated subretinal microglia. The accumulation of microglia in Sucnr1-/- mice is likely triggered by the inefficient clearance of oxidized lipids by the RPE as bone marrow transfer of wild-type microglia into Sucnr1-/- mice did not salvage the patho-phenotype and systemic lipolysis was equivalent between wild-type and control mice. Our findings suggest that deficiency in SUCNR1 is a possible contributing factor to the pathogenesis of dry AMD.and thus broaden our understanding of this clinically unmet nee

Immunosuppression Profile of CFZ533 (Iscalimab), a Non-Depleting Anti-CD40 Antibody, and the Presence of Opportunistic Infections in a Rhesus Monkey Toxicology Study

Immunosuppression Profile of CFZ533 (Iscalimab), a Non-Depleting Anti-CD40 Antibody, and the Presence of Opportunistic Infections in a Rhesus Monkey Toxicology Study

Supplementary Data Ulrich et al 2018 Non-clinical Safety Assessment of CFZ533

Supplemental Data to Ulrich et al., 2018: Non-clinical Safety Assessment of CFZ53

T-cell assays confirm immunogenicity of tungsten-induced erythropoietin aggregates associated with pure red cell aplasia

Immunogenicity of biotherapeutics and the elicitation of anti-drug antibodies (ADA) are a key concern for their efficacy, pharmacokinetics and safety. Prediction of clinical immunogenicity on the basis of quality attributes of biopharmaceuticals or by utilizing preclinical in vitro and in vivo screening remains challenging. Even fully human biotherapeutics have the potential for immunogenicity, and one important factor that might enhance potential immunogenicity is protein aggregation. A particularly severe consequence of immunogenicity of a biotherapeutic is the rare development of antibody-mediated pure red cell aplasia (PRCA) in anemic patients treated with aggregated forms of recombinant human erythropoietin (rhEPO). Here, we investigated in vitro T cell responses to (i) heat-induced rhEPO aggregates, (ii) tungsten-induced rhEPO aggregates in clinical lots associated with rhEPO-neutralizing antibodies and PRCA, and (iii) ex vivo T cell recall responses of patients treated with rhEPO without PRCA, and of a patient who developed PRCA after treatment with a clinical batch with elevated levels of tungsten and aggregates. To our knowledge, this is the first time that T cell assays confirm the root cause of increased rhEPO immunogenicity associated with PRCA

GPR91 deletion enhances mast cell activation while preventing arthritic disease

While searching for a role of succinate on skin inflammation we discovered that its specific receptor, GPR91/SUCNR1 is also expressed by mast cells. Sucnr1-/- mast cells displayed enhanced reactivity to allergen-IgE crosslinking. However, such responses were acute in nature and did not contribute to the enhancement of asthma or arthritis and, we therefore suggest, they are due to alterations during mast cell differentiation. The fact that sucnr1-/- mice were protected from arthritis development, using two different in vivo models, indicates that GPR91 antagonists may have great therapeutic potential in autoimmune disease

Correction: Immunosuppressive FK506 treatment leads to more frequent EBV-associated lymphoproliferative disease in humanized mice

[This corrects the article DOI: 10.1371/journal.ppat.1008477.]

Immunosuppressive FK506 treatment leads to more frequent EBV-associated lymphoproliferative disease in humanized mice

Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication after organ transplantation frequently associated with the Epstein-Barr virus (EBV). Immunosuppressive treatment is thought to allow the expansion of EBV-infected B cells, which often express all eight oncogenic EBV latent proteins. Here, we assessed whether HLA-A2 transgenic humanized NSG mice treated with the immunosuppressant FK506 could be used to model EBV-PTLD. We found that FK506 treatment of EBV-infected mice led to an elevated viral burden, more frequent tumor formation and diminished EBV-induced T cell responses, indicative of reduced EBV-specific immune control. EBV latency III and lymphoproliferation-associated cellular transcripts were up-regulated in B cells from immunosuppressed animals, akin to the viral and host gene expression pattern found in EBV-PTLD. Utilizing an unbiased gene expression profiling approach, we identified genes differentially expressed in B cells of EBV-infected animals with and without FK506 treatment. Upon investigating the most promising candidates, we validated sCD30 as a marker of uncontrolled EBV proliferation in both humanized mice and in pediatric patients with EBV-PTLD. High levels of sCD30 have been previously associated with EBV-PTLD in patients. As such, we believe that humanized mice can indeed model aspects of EBV-PTLD development and may prove useful for the safety assessment of immunomodulatory therapies

GPR91 exacerbates rheumatoid arthritis via extracellular succinate released by intact inflammatory macrophages

When SUCNR1/GPR91 expressing macrophages are activated by inflammatory signals they change their metabolism and accumulate succinate. Here we show that during this activation macrophages release succinate into the extracellular milieu. They simultaneously upregulate GPR91 which functions as an autocrine and paracrine sensor for extracellular succinate to enhance IL-1 production. GPR91 deficient mice lack this metabolic sensor and show reduced macrophage activation and production of IL-1 during antigen-induced arthritis (AIA). Succinate is abundant in synovial fluids from rheumatoid arthritis (RA) patients, and these fluids elicit IL-1 release from macrophages in a GPR91-dependent manner. Together, we reveal a GPR91/succinate-dependent feed-forward loop of macrophage activation and propose GPR91 antagonists as novel therapeutic principles to treat RA