Anti-Il19 Monoclonal antibody, clone SO20

Probiotics constitute an attractive alternative in the battle against microbial infections. Oral administration of certain strains of lactobacilli isolated from human milk has resulted in an effective reduction of the bacterial load as well as an improvement of the mastitis-associated symptoms. Nevertheless, little is yet known about the potential molecular mechanisms and specific targets implicated in these effects. Transcriptomic profiling has been used to search for disease-associated and therapy-responsive molecules in different disorders and experimental models. We have applied for the first time a gene expression-based molecular approach to explore for potential targets responsive to intervention with a probiotic in: (i) breast milk somatic cells (n = 17) and (ii) blood leukocytes (n = 19). Women with mastitis ingested a new strain of lactobacilli, Lactobacillus salivarius PS2 (3x capsules per day, each capsule contained similar to 9.5 log10 CFU) for 21 days. We applied Affymetrix microarrays and Taqman one-step quantitative reverse transcription PCR (RT-qPCR) to analyze and compare gene expression changes between samples pre- and post-treatment. Our results substantiate the involvement of inflammatory and cell-growth related pathways and genes in the breast milk somatic cells following the intake of L. salivarius PS2. Individual analyses of selected genes: (1) supported the upregulation of STC1 and IL19 and the downregulation of PLAUR and IFNGR1 in the somatic cells of the patients as potential targets responsive to the probiotic, (2) detected a lack of a relationship between the gene expression responses in the two types of cells, and (3) evidenced a substantial interindividual variability in the gene expression changes in both types of cells. Our study provides an insight into the essentiality of incorporating the study of tissue-specific interindividual molecular responsivity into future clinical intervention trials to further understand the complexity of human gene expression responses to therapy and the potentiality of selecting appropriate responsive targets.

Author summary The immune response toSarcoptes scabieiinfestation is poorly defined. There have been few studies of crusted scabies, a debilitating clinical variant of the disease characterised by extremely high mite numbers. In this study, we used a pig model to explore differences in gene expression between clinical variants of scabies, including a focus on immune events occurring prior to the development of clinical signs. In early infestation, genes relating to inflammation, immune recognition and cell migration were potently suppressed in pigs with crusted scabies. This suggests that these pigs lacked the ability to mount a timely, effective immune response, allowing mites to proliferate unchecked. In later infestation, the large numbers of mites then triggered a strong inflammatory response leading to severe skin pathology. Gene expression profiles in crusted scabies shared similarities with other inflammatory skin diseases such as psoriasis. This is the first study to compare immune responses in crusted and ordinary scabies in early infestation and reveals new insights into the progression of disease. Findings may lead to the development of new approaches to diagnose and treat this important, but neglected disease. Scabies is a neglected tropical disease of global significance. Our understanding of host-parasite interactions has been limited, particularly in crusted scabies (CS), a severe clinical manifestation involving hyper-infestation ofSarcoptes scabieimites. Susceptibility to CS may be associated with immunosuppressive conditions but CS has also been seen in cases with no identifiable risk factor or immune deficit. Due to ethical and logistical difficulties with undertaking research on clinical patients with CS, we adopted a porcine model which parallels human clinical manifestations. Transcriptomic analysis using microarrays was used to explore scabies pathogenesis, and to identify early events differentiating pigs with ordinary (OS) and crusted scabies. Pigs with OS (n = 4), CS (n = 4) and non-infested controls (n = 4) were compared at pre-infestation, weeks 1, 2, 4 and 8 post-infestation. In CS relative to OS, there were numerous differentially expressed genes including pro-inflammatory cytokines (IL17A, IL8, IL19, IL20 and OSM) and chemokines involved in immune cell activation and recruitment (CCL20, CCL27 and CXCL6). The influence of genes associated with immune regulation (CD274/PD-L1 and IL27), immune signalling (TLR2, TLR8) and antigen presentation (RFX5, HLA-5 and HLA-DOB) were highlighted in the early host response to CS. We observed similarities with gene expression profiles associated with psoriasis and atopic dermatitis and confirmed previous observations of Th2/17 pronounced responses in CS. This is the first comprehensive study describing transcriptional changes associated with the development of CS and significantly, the distinction between OS and CS. This provides a basis for clinical follow-up studies, potentially identifying new control strategies for this severely debilitating disease.