Local cytokine production in patients with external genital endometriosis

The article presents the results of the investigation of cytokine production by endometrioid heterotopias in organotypic cultivation in comparison with the cell secretory activity of peritoneal fluid and endometrial tissue in women with external genital endometriosis. The obtained results show systemic changes of regulation of cytokine production in the process of external genital endometriosis development.

Altered mRNA Expression of Interleukin-1 Receptors in Myocardial Tissue of Patients with Left Ventricular Assist Device Support

Serum levels of cytokines interleukin 1 beta (IL-1β) and interleukin 33 (IL-33) are highly abnormal in heart failure and remain elevated after mechanical circulatory support (MCS). However, local cytokine signaling induction remains elusive. Left (LV) and right ventricular (RV) myocardial tissue specimens of end-stage heart failure (HF) patients without (n = 24) and with MCS (n = 39; 594 ± 57 days) were analyzed for cytokine mRNA expression level of IL-1B, interleukin 1 receptor 1/2 (IL-1R1/2), interleukin 1 receptor-like 1 (IL-1RL1), IL-33 and interleukin-1 receptor accessory protein (IL-1RaP). MCS patients showed significantly elevated IL-1B expression levels (LV: 2.0 fold, p = 0.0058; RV: 3.3 fold, p < 0.0001). Moreover, IL-1R1, IL-1RaP and IL-33 expression levels strongly correlated with each other. IL-1RL1 and IL-1R2 expression levels were significantly higher in RV myocardial tissue (RV/LV ratio IL-1R2 HF: 4.400 ± 1.359; MCS: 4.657 ± 0.655; IL-1RL1 HF: 3.697 ± 0.876; MCS: 4.529 ± 0.5839). In addition, IL1-RaP and IL-33 RV expression levels were significantly elevated in MCS. Furthermore, IL-33 expression correlates with C-reactive protein (CRP) plasma levels in HF, but not in MCS patients. Increased expression of IL-1B and altered correlation patterns of IL-1 receptors indicate enhanced IL-1β signaling in MCS patients. Correlation of IL-1 receptor expression with IL-33 may hint towards a link between both pathways. Moreover, diverging expression in LV and RV suggests specific regulation of local cytokine signaling.

Case Report: Local Cytokine Release Syndrome in an Acute Lymphoblastic Leukemia Patient After Treatment With Chimeric Antigen Receptor T-Cell Therapy: A Possible Model, Literature Review and Perspective

Chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable clinical efficacy in treatment of many malignancies especially for B-cell hematologic malignancies. However, the application of CAR-T cells is hampered by potentially adverse events, of which cytokine release syndrome (CRS) is one of the severest and the most studied. Local cytokine-release syndrome (L-CRS) at particular parts of the body has been reported once in a while in B-cell lymphoma or other compartmental tumors. The underlying mechanism of L-CRS is not well understood and the existing reports attempting to illustrate it only involve compartmental tumors, some of which even indicated L-CRS only happens in compartmental tumors. Acute lymphoblastic leukemia (ALL) is systemic and our center treated a B-cell ALL patient who exhibited life threatening dyspnea, L-CRS was under suspicion and the patient was successfully rescued with treatment algorithm of CRS. The case is the firstly reported L-CRS related to systemic malignancies and we tentatively propose a model to illustrate the occurrence and development of L-CRS of systemic malignancies inspired by the case and literature, with emphasis on the new recognition of L-CRS.

Features of the local cytokine profile in patients with secondary corneal dystrophy of various etiologies

Goal. To study the features of the local cytokine profile of patients with secondary corneal dystrophy of various etiologies. Material and methods. The study was conducted among 4 patients: 1 – with bullous kerathopathy, 1 – with secondary postherpetic corneal dystrophy, 1 – with secondary keratectasia and 1 – with secondary corneal dystrophy of neurogenic origin. The quantitative content of cytokines in the lacrimal fluid was studied: interleukin (IL) 1β, 6, 4, 10, transforming growth factor β2 (TGF-β2). Results. All patients had in 3.0-4.3-fold increase in IL-1β and a 2.0-4.1-fold increase in IL-6. In bullous kerathopathy and secondary corneal dystrophy of neurogenic origin, there was in 1.1-and 1.2-fold increase in IL-4 in both cases, and a slight increase in IL-10 and TGF-β2. At the same time, in secondary keratectasia and secondary postherpetic corneal dystrophy, there was a decrease in the level of these cytokines: IL-4 by 1.7 and 1.3 times, respectively, IL-10 by 1.2 times in both cases, and TGF-β2 by 1.5 and 1.3 times, respectively. Conclusion. The study of the local cytokine profile in patients with secondary corneal dystrophy of different etiologies indicates the presence of similar aspects of pathogenesis, which is of some interest and deserves further study. The obtained results open up prospects for the development of personalized cytokine therapy for secondary corneal dystrophy of various etiologies. Key words: secondary corneal dystrophy, immunology, cytokines.

Treatment optimization of patients with genital endometriosis

The aim of the research: to optimize the treatment of patients with combined genital pathology, including internal endometriosis (adenomyosis) and inflammatory diseases. Materials and methods: prospective study has been conducted on 160 women with adenomyosis. There were 24 (15 %) patients with the I degree of adenomyosis spreading, 72 (45.0 %) women with the II degree, 33 (20.6 %) patients with the III degree, and 31 (19.4 %) woman with the IV degree of adenomyosis spreading. Microbial flora analysis included bacterioscopic, bacteriological research methods with determination of sensitivity to antibiotics, and PCR method. The concentration of cytokines in the culture medium (supernatant) was determined by the enzyme immunoassay. Results: the obtained data from the study indicate a high percentage of the combination of adenomyosis with chronic inflammatory diseases of the pelvic organs. An immuno-inflammatory reaction preceding adenomyosis is accompanied by the violation of the local cytokine balance. In turn, the increased activity of cytokines and the presence of infectious agents can participate in the relapse of endometriosis. Conclusion: considering the immuno-inflammatory reaction, accompanied by the violation of the local cytokine balance in the development of adenomyosis. The study substantiates the necessity of using antimicrobial therapy in patients with combined genital pathology, including adenomyosis and inflammatory diseases

The Adjuvants Polyphosphazene (PCEP) and a Combination of Curdlan Plus Leptin Promote a Th17-Type Immune Response to an Intramuscular Vaccine in Mice

Our aim was to determine whether polyphosphazene (PCEP), Curdlan (β-glucan, a dectin-1 agonist), and Leptin could act as adjuvants to promote a Th17-type adaptive immune response in mice. Mice were vaccinated via the intramuscular route then boosted three weeks later with Ovalbumin plus: PCEP, Leptin, Curdlan, PCEP+Curdlan, Curdlan+Leptin, or saline. Mice vaccinated with OVA+PCEP and OVA+Curdlan+Leptin showed significantly higher frequency of antigen-specific CD4+ T cells secreting IL-17 relative to OVA-vaccinated mice. No formulation increased the frequency of CD4+ T cells secreting IL-4 or IFNγ. Since activation of innate immunity precedes the development of adaptive immunity, we wished to establish whether induction of Th17-type immunity could be predicted from in vitro experiments and/or from the local cytokine environment after immunization with adjuvants alone. Elevated IL-6 and TGFβ with reduced secretion of IL-12 is a cytokine milieu known to promote differentiation of Th17-type immunity. We injected the immunostimulants or saline buffer into murine thigh muscles and measured acute local cytokine production. PCEP induced significant production of IL-6 and reduced IL-12 production in muscle but it did not lead to elevated TGFβ production. Curdlan+Leptin injected into muscle induced significant production of TGFβ and IL-17 but not IL-6 or IL-12. We also stimulated splenocytes with media or PCEP, Leptin, Curdlan, PCEP+Curdlan, Curdlan+Leptin, PCEP+Leptin, and PCEP+Curdlan+Leptin and measured cytokine production. PCEP stimulation of splenocytes failed to induce significant production of IL-6, IL-12, TGFβ, or IL-17 and therefore ex vivo splenocyte stimulation failed to predict the increased frequency of Th17-type T cells in response to the vaccine. Curdlan-stimulated splenocytes produced Th1-type, inducing cytokine, IL-12. Curdlan+/-PCEP stimulated TGF-β production and Curdlan+Leptin+/- PCEP induced secretion of IL-17. We conclude that PCEP as well as Curdlan+Leptin are Th17-type vaccine adjuvants in mice but that cytokines produced in response to these adjuvants in muscle after injection or in ex vivo cultured splenocytes did not predict their role as a Th17-type adjuvant. Together, these data suggest that the cytokine environments induced by these immunostimulants did not predict induction of an antigen-specific Th17-type adaptive immune response. This is the first report of these adjuvants inducing a Th17-type adaptive immune response.

Contribution of Topical Agents to Wound Healing

The process of wound healing is often accompanied by bacterial infection or critical colonization, which leads to an extension of the inflammatory response phase and delayed epithelization. In the review of scientific articles, we found the description and mode of action of topical antiseptic agents, including silver and sodium hypochlorite solution, to control the spread of microorganisms. The value of hyaluronic acid for wound healing is described. Furthermore, a novel treatment option with microspheres is mentioned. Attachment of cells to microspheres establishes a local cytokine response that acts anti-inflammatory, cell attachment results also in morphological and functional cell changes that reactivate healing.

Changes to the cervicovaginal microbiota and cervical cytokine profile following surgery for cervical intraepithelial neoplasia

Persistent HPV infection associated with immune modulation may result in high-grade squamous intraepithelial lesions (CIN)2/3. Currently, there is little information on the cervicovaginal microbiome, local cytokine levels and HPV infection related to CIN. Follow-up of patients after local surgery provides an opportunity to monitor changes in the cervicovaginal environment. Accordingly, we undertook this longitudinal retrospective study to determine associations between HPV genotypes, cervicovaginal microbiome and local cytokine profiles in 41 Japanese patients with CIN. Cervicovaginal microbiota were identified using universal 16S rRNA gene (rDNA) bacterial primers for the V3/4 region by PCR of genomic DNA, followed by MiSeq sequencing. We found that Atopobium vaginae was significantly decreased (p < 0.047), whereas A. ureaplasma (p < 0.022) increased after surgery. Cytokine levels in cervical mucus were measured by multiplexed bead-based immunoassays, revealing that IL-1β (p < 0.006), TNF-α (p < 0.004), MIP-1α (p < 0.045) and eotaxin (p < 0.003) were significantly decreased after surgery. Notably, the level of eotaxin decreased in parallel with HPV clearance after surgery (p < 0.028). Thus, local surgery affected the cervicovaginal microbiome, status of HPV infection and immune response. Changes to the cervicovaginal microbiota and cervical cytokine profile following surgery for cervical intraepithelial neoplasia may be important for understanding the pathogenesis of CIN in future.