Immune Portrayal of a New Therapy Targeting Microbiota in an Animal Model of Psoriasis.

BACKGROUND: Despite all the available treatments, psoriasis remains incurable; therefore, finding personalized therapies is a continuous challenge. Psoriasis is linked to a gut microbiota imbalance, highlighting the importance of the gut-skin axis and its inflammatory mediators. Restoring this imbalance can open new perspectives in psoriasis therapy. We investigated the effect of purified IgY raised against pathological human bacteria antibiotic-resistant in induced murine psoriatic dermatitis (PSO). METHODS: To evaluate the immune portrayal in an imiquimod experimental model, before and after IgY treatment, xMAP array and flow cytometry were used. RESULTS: There were significant changes in IL-1α,ß, IL-5, IL-6, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17a, IFN-γ, TNF-α, IP-10/CXCL10, MCP-1/CCL2, MIP-1α/CCL3, MIP-1ß/CCL4, MIG/CXCL9, and KC/CXCL1 serum levels. T (CD3ε+), B (CD19+) and NK (NK1.1+) cells were also quantified. In our model, TNF-α, IL-6, and IL-1ß cytokines and CXCL1 chemokine have extremely high circulatory levels in the PSO group. Upon experimental therapy, the cytokine serum values were not different between IgY-treated groups and spontaneously remitted PSO. CONCLUSIONS: Using the murine model of psoriatic dermatitis, we show that the orally purified IgY treatment can lead to an improvement in skin lesion healing along with the normalization of cellular and humoral immune parameters.

Healthy Ageing Reflected in Innate and Adaptive Immune Parameters.

Purpose: The aim of the paper is to establish and quantify the relation between healthy ageing and the innate and adaptive immune parameters as indicators of age-related diseases. Patients: In order to observe the immunological changes that occur according to age, several humoral and cellular immune parameters were investigated for 288 healthy donors (30-80 years). Subjects' selection was done using clinical, biochemical and immunological parameters of inclusion/exclusion criteria from SENIEUR protocol. Results: Age-related changes were observed for both humoral and cellular immune parameters. Lymphocyte immunophenotyping revealed several significant differences in the distribution of cells, both intra- and inter-age groups, namely decreased values of T-CD3+, T-CD8+ and NK cells, and elevated values for T-CD4+, T-CD4+/T-CD8+ ratio and B cells. The percentages of unstimulated neutrophils that show basal oxidative activity and the intensity of this activity had an increasing tendency age-related. The percentage of N-Formyl-Methionyl-Leucyl-Phenylalanine stimulated neutrophils clearly decreases with age, and is associated with an increasing intensity of oxidative activity. Our data also have shown an increased percentage of oxidative neutrophils after phorbol 12-myristate 13-acetate stimulation and an elevated oxidative activity with age. Conclusion: Overall healthy ageing is governed by some immune-related deregulations that account for immune exhaustion due to numerous developed immune processes during a life-time and the age-related diseases.

Therapeutic potential of interleukin-15 in cancer (Review).

The immune system is dysfunctional in cancer, and therapeutic approaches designated to restore immunity and increase long-term overall survival are desirable. The role of immunotherapy is to trigger the immune system to recognize and destroy tumor cells. Interleukin-15 (IL-15) is a member of the common gamma-chain (γc) cytokines that promote the differentiation and expansion of T cells, B cells and natural killer (NK) cells, leading to enhanced antitumor responses. This suggests that IL-15 is a promising candidate for anticancer therapy. Renewed interest in cancer immunotherapy has led to an increased number of preclinical studies and clinical trials that have investigated the reliability and potency of IL-15-based agents, not only as single therapy, but also in combination with others. This review provides a description of these studies which show the advantages and disadvantages of IL-15 as an immunotherapeutic agent. We present here the role of IL-15 and pharmacologically improved IL-15 superagonists as a single treatment or in combination with other therapeutic agents.

Oxidative Stress: A Possible Trigger for Pelvic Organ Prolapse.

Pelvic organ prolapse is a frequent health problem in women, encountered worldwide, its physiopathology being still incompletely understood. The integrity of the pelvic-supportive structures is a key element that prevents the prolapse of the pelvic organs. Numerous researchers have underlined the role of connective tissue molecular changes in the pathogenesis of pelvic organ prolapse and have raised the attention upon oxidative stress as an important element involved in its appearance. The advancements made over the years in terms of molecular biology have allowed researchers to investigate how the constituent elements of the pelvic-supportive structures react in conditions of oxidative stress. The purpose of this paper is to underline the importance of oxidative stress in the pathogenesis of pelvic organ prolapse, as well as to highlight the main oxidative stress molecular changes that appear at the level of the pelvic-supportive structures. Sustained mechanical stress is proven to be a key factor in the appearance of pelvic organ prolapse, correlating with increased levels of free radicals production and mitochondrial-induced fibroblasts apoptosis, the rate of cellular apoptosis depending on the intensity of the mechanical stress, and the period of time the mechanical stress is applied. Oxidative stress hinders normal cellular signaling pathways, as well as different important cellular components like proteins, lipids, and cellular DNA, therefore significantly interfering with the process of collagen and elastin synthesis.

Reinforcing involvement of NK cells in psoriasiform dermatitis animal model.

Psoriasis (Ps) is a chronic inflammatory immune-mediated disease with skin and joint manifestations, characterized by abnormal and rapid proliferation of keratinocytes and infiltration of psoriatic lesions with immune cells. Extensive literature suggests that Ps is a T-cell mediated disease its pathogenesis being highly related to innate and adaptative immune cells. Although natural killer (NK) cells are involved in the inflammatory process of Ps through pro-inflammatory cytokine secretion (tumor necrosis factor α, interferon γ), their role in this pathology is not yet fully elucidated. In order to study the involvement of NK subpopulations in the pathogenesis of Ps we used the imiquimod-based mouse model of psoriasiform dermatitis and NK cells complex phenotype patterns from peripheral blood (PB) and spleen were investigated. Skin inflammation and the disease severity were assessed using in vivo measurements (erythema, desquamation and induration parameters, PASI modified score), splenomegaly assessment and histopathological evaluation. Phenotypic characterization of NK cells in imiquimod (IMQ)-treated mice was performed by flow cytometry, for both PB and spleen cell suspension. A large panel of surface markers was used: maturation and activation markers [cluster of differentiation (CD)49b, CD11b, CD43, CD27, KLRG1, CD335, CD69, CD28, gp49R, CD45R, CD11c] and markers for cytokine receptors (CD25, CD122, CD132). Our experimental data showed important differences in IMQ-treated mouse NK cell phenotype as compared to control group. The maturation markers (CD11b, CD43, CD27, KLRG1) were found increased on NK cells, in periphery and spleen, while CD49b+NK1.1+ was significantly lower, and the alterations correlated with the severity of the disease. Our findings reflect the immune engagement toward activatory profile of NK cells and draw attention to evaluating Ps intensity correlated with the mature profile of circulating NK cells.

Peripheral immune cell markers in children with recurrent respiratory infections in the absence of primary immunodeficiency.

The immune system of a child has a degree of immaturity that is maintained until 6-7 years of age. Immaturity may be due to age-related functional disorders in the immune response. A healthy child can contract a series of infections which contribute to the maturation of the immune system during the pre-pubertal period. If repeated infections with prolonged or severe complications occur during childhood, the presence of an immunodeficiency should then be considered. Much more frequent than primary immunodeficiency are recurrent infections (frequently involving the upper respiratory tract), which are less severe and occur under the conditions of an immune system with no apparent major defects. A child can present with 4 to 8 episodes of respiratory infections within a year, during the first 5 years of its life. The average duration of infection is 8 days and up to 2 weeks; if the child presents with 3 episodes of acute infections over a period of 6 months, the respiratory infections are then considered recurrent. The aim of this study was to identify the immunological changes or deviations that cause this clinical syndrome in children. For this purpose, 30 children with recurrent respiratory infections and 10 healthy children were included. Immunoglobulin levels were examined and immunophenotyping was performed. We found that the serum immunoglobulin levels were in the normal range in 70% of the children. On the contrary, our data revealed changes in peripheral cell populations, the most important being the decrease in the T-cluster of differentiation (CD)8+ and total B cell percentages and the increase in the number of memory B cells. The data obtained herein indicated that the decrease in the number of total B cells was mainly due to the decrease in the number of naive IgD+ B cells. On the whole, the findings of this study indicate that recurrent respiratory infections may be associated with an altered cellular immune response. In such situations, the investigation of immunological parameters, such as T and B cell subtypes could complete the clinical diagnosis and guide the treatment strategy, thus increasing the quality of life of patients.

Natural killer cell monitoring in cutaneous melanoma - new dynamic biomarker.

Melanoma is responsible for most skin cancer deaths in humans. The immune system plays a major role in regulating tumor cell proliferation by initiating defence responses against tumor aggression. Research on murine cancer models allow for a better understanding of immune response in malignancies, revealing specific changes of the immune status in the presence of tumors. Melanoma resistance to conventional therapies and its high immunogenicity justify the development of new therapies. These features reinforce melanoma as a suitable model for studying antitumor immunity. Recent findings on NK cell activation in cancer patients indicate that several important parameters, such as tumor capacity to modulate the function and phenotype of NK cells, require consideration for the choice of an NK-based therapy. In this study, we investigated T-CD4+ and T-CD8+ lymphocytes, B lymphocytes and NK cells in peripheral blood and spleen cells suspension from melanoma-bearing mice compared to healthy controls in order to assess the potential for tumor growth-promoting immunosuppression. Our results indicate that in a melanoma-bearing mouse model the percentage of NK cells in spleen is reduced and that their phenotype is different compared to control mouse NK cells.

Phenotypic changes of lymphocyte populations in psoriasiform dermatitis animal model.

Psoriasis is a T cell mediated, chronic inflammatory autoimmune skin disease that affects up to 2-3% of the global population and leads to a decrease in quality of life. Experimental data accumulated in recent years highlighted the important role played by the immune system in the pathogenesis of this disease. Non-human psoriasis models are an important research tool that attempts to reproduce the clinical features of the disease in order to explain the pathogenesis of psoriasis and to identify possible therapeutic targets. Imiquimod-based murine model of psoriatic dermatitis is an alternative to traditional models of experimental psoriasis in mice and the induced dermatitis closely mimics the pathologic changes in human psoriasis. In order to emphasize changes in immune cell populations involved in lesion pathogenesis, we performed a murine model of psoriasiform dermatitis model by topical IMQ application. The progress and the severity of IMQ-induced skin inflammation were clinically (PASI score) and histopathologically evaluated. The immunological changes induced by IMQ treatment in lymphocyte populations from peripheral blood and spleen were evaluated by flow cytometry. The main changes observed in peripheral blood were the significantly increased T-CD8a+ lymphocyte and NK1.1+ cell percentages and the decreased T-CD4+ and B lymphocyte percentages in IMQ-treated mice. In spleen samples, lymphocytes showed the same tendency of variation as in peripheral blood, but without statistical significance. A significant decrease of B cells percentages was observed in spleen suspensions. Data obtained in skin samples may suggest the involvement of CD3ε+, CD4+ and CD8a+ cells in the lesional process. This murine model was analyzed by performing a basic cellular profile at three levels: peripheral blood, spleen and skin. The evaluation aimed to establish the immune framework of this experimental model that could further be used for etipathogenic mechanism identification and/or for studies regarding targeted therapies.

Regulatory T cells and TH1/TH2 cytokines as immunodiagnosis keys in systemic autoimmune diseases.

We assessed Helper T-cell involvement and possibilities to quantify the cell-based immune response in systemic autoimmune diseases (SAID) in 14 systemic lupus erythematosus (SLE) and 7 rheumatoid arthritis (RA) patients. The goals of investigation were T-CD4+/T-CD8+ ratio, regulatory T cells (Treg) status and TH1/TH2 serum cytokine profiles (IFN-gamma and IL-2, respectively IL-4 and IL-6). SLE group proved significant decreased average Treg value as compared to RA group and controls and showed significant low Treg incidence (86% patients). The distribution of high T-CD4+/T-CD8+ ratio registered no significant distinction among LES and RA groups. SAID patients presented low serum IFN-gamma (86% RA, 60% SLE), high IL-2 (57% RA) and high IL-6 (53% LES), but no significant IL-4 modification. We conclude that Treg percentage remains the only cellular criterion for SAID immune evaluation. In the same time, different secretion mechanisms seem to be involved in SAID, i.e. TH2 in SLE and TH1 in RA.