Immunomodulatory Therapy In Patients Research Articles

T regulatory lymphocytes and FoxP3 nuclear translocation in various adipose tissue depots in patients with coronary artery disease

T regulatory lymphocytes (Treg) are present is adipose tissue. Their frequency, as well as the level of FoxP3 nuclear translocation, in epicardial and thymus adipose tissue remains unexplored. Properties of adiposeresident Tregs may be of high significance in patients with coronary artery disease as potential pathophysiological factor in the development of atherosclerosis. The aim of the study was to compare frequency of FoxP3+Tregs and FoxP3 nuclear translocation in epicardial, thymus, subcutaneous adipose tissue and peripheral blood in patients with coronary artery disease. A pilot study was conducted in 11 patients with coronary artery disease scheduled for the coronary artery bypass graft surgery after prior selective coronary angiography. Frequency of CD4+CD25hiFoxP3+ and CD4+CD25loFoxP3+ lymphocytes and FoxP3 nuclear translocation were evaluated by imaging flow cytometry in peripheral blood and in stromal vascular fraction of epicardial, subcutaneous and thymus adipose tissue. Frequencies of CD4+CD25hiFoxP3+ and CD4+CD25loFoxP3+ lymphocytes were higher in epicardial adipose tissue compared to blood (3 and 5 times higher, p = 0.020); CD4+CD25loFoxP3+ cells frequency in subcutaneous adipose tissue was 4 times higher than in blood (p = 0.028). The level of FoxP3 nuclear translocation was the highest in blood and decreased in epicardial, subcutaneous and thymus adipose tissue (p = 0.020 both for CD4+CD25hiFoxP3+ and CD4+CD25loFoxP3+ lymphocytes). Frequency of CD4+CD25loFoxP3+ cells was directly related to age in thymus (rs = 0.818; p = 0.002), and inversely in epicardial adipose tissue (rs = -0.618; p = 0.043). Frequencies of CD4+CD25hiFoxP3+ and CD4+CD25loFoxP3+ with FoxP3 nuclear translocation in subcutaneous adipose tissue negatively correlated with age (rs = -0.827; p = 0.002 and rs = -0.648; p = 0.031, respectively). Frequency of CD4+CD25loFoxP3+ cells with FoxP3 nuclear translocation in thymus adipose tissue negatively correlated with waist-to-hip ratio (rs = -0.700; p = 0.016). The severity of atherosclerosis was related only to the frequency of CD4+CD25loFoxP3+ cells in subcutaneous adipose tissue (rs = -0.655; p = 0.029). Thus, epicardial and subcutaneous adipose tissue are enriched with Tregs, but factors that influence Treg accumulation and FoxP3 nuclear translocation in these fat depots may be different. The obtained results may further be used for personalized immunomodulatory therapy in patients with atherosclerosis.

CD73 Inhibition Reverses Immunosuppression and Has Potential As an Immunomodulatory Therapy in Patients with Multiple Myeloma

CD73 Inhibition Reverses Immunosuppression and Has Potential As an Immunomodulatory Therapy in Patients with Multiple Myeloma

Abstract 2074: ORIC-533, a small molecule CD73 inhibitor with best-in-class properties, reversesimmunosuppression and has potential as an immunomodulatory therapy in patients with multiple myeloma

Abstract Adenosine accumulation within the tumor microenvironment can severely limit antitumor immunity by promoting the expansion of immunosuppressive cell types and impairing immune cell function, including T cells, natural killer cells and dendritic cells. The generation of adenosine from adenosine monophosphate (AMP) requires the activity of a cell surface ecto-5’-nucleotidase, CD73, expressed on the surface of various cell types including immune cells. CD73 overexpression is observed in many tumor types and correlates with unfavorable clinical outcomes. Given the essential role of CD73 in generating adenosine, inhibition of CD73 is a promising therapeutic strategy. Recent clinical proof of concept data demonstrated a significant improvement in progression free survival for non-small cell lung cancer patients upon targeting CD73 with the oleclumab anti-CD73 antibody in combination with anti-PDL1, relative to anti-PDL1 checkpoint inhibitor treatment alone.We developed ORIC-533, a potent, orally bioavailable, AMP-competitive, small molecule inhibitor of CD73, that is highly selective for CD73 and exhibits picomolar potency in biochemical assays, completely blocking adenosine production from AMP. In ex vivo assays, ORIC-533 displayed greater potency in restoring immunosuppressed CD8+ T cell proliferation and activation compared to oleclumab, as well as greater potency versus small molecule inhibitors of CD73 and the adenosine receptor. In multiple myeloma (MM) patients, elevated adenosine levels in the bone marrow (BM) niche correlate with progression of multiple myeloma through a CD73-mediated pathway. Moreover, we recently reported a functional role of CD73 signaling in BM of MM patients, indicating that CD73 inhibition may represent a unique vulnerability and treatment strategy for MM (Ray et al., abstract #2675, ASH 2021). We tested the impact of CD73 inhibition in bone marrow aspirates from patients with relapsed or refractory MM, using an autologous ex vivo assay system comprised of the multiple myeloma BM microenvironment. CD73 inhibition stimulated the activation of plasmacytoid dendritic cells and T cell activation in the context of the MM BM milieu. Moreover, ORIC CD73 inhibitor as a single agent overcame immune suppression and triggered significant lysis and cell death of multiple myeloma cells by autologous T-cells in the bone marrow microenvironment. Taken together, these results demonstrate that the ORIC CD73 inhibitor potently inhibits the adenosine pathway, which restores anti-tumor immunity and therefore holds potential for patients with MM. Based upon these data, ORIC-533 is being studied as a single agent in a Phase 1 clinical trial in patients with relapsed or refractory multiple myeloma. Citation Format: Melissa R. Junttila, Arghya Ray, Robert Warne, Xi Chen, Ting Du, Dena Sutimantanapi, Jae H. Chang, Brian Blank, Jared Moore, Chudi O. Ndubaku, Tatiana Zavorotinskaya, Pratik Multani, Omar Nadeem, Dharminder Chauhan, Kenneth C. Anderson, Lori S. Friedman. ORIC-533, a small molecule CD73 inhibitor with best-in-class properties, reversesimmunosuppression and has potential as an immunomodulatory therapy in patients with multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2074.

Phase I study of epacadostat in combination with sirolimus in advanced malignancy.

2575 Background: Epacadostat (E) is an inhibitor of Indoleamine 2,3 dioxygenase-1 (IDO1) which is a rate-limiting enzyme in the catabolism of tryptophan to kynurenine. The inhibition of IDO1 leads to increase tryptophan and reversal of immunosuppression by increasing the proliferation of T cells, suppression of regulatory T cells (Tregs) and activation of mTOR which suppresses autophagy. Sirolimus (S) can reverse the mTOR activation induced by E, suppress the expression of PD-L1 and function of Tregs. We initiated a phase I trial to test the safety and tolerability of SE combination in patients with advanced solid tumors, with plans for an expansion phase II study in patients with advanced recurrent lung cancer once maximum tolerated dose (MTD) was defined. Methods: The phase I trial portion of the study used a modified 3+3 design in which the dose transition rule was similar to standard 3+3 design with the modification based on sirolimus PK data. S had a lead-in of 3mg/day(d) at day -7 followed by 1mg/d with E added on day 1 of Cycle 1 starting at 300mg bid in a 28d cycle at dose level 1; then S is escalated to 6mg/d followed by 2mg/d maintenance with E at 300mg bid at level 2. An additional level 3 was added with S at 6mg/d followed by 2mg/day with E at 400 bid based on results of E at 400-600 mg bid in combination with a checkpoint inhibitor with improved control of peripheral kynurenine and intra-tumoral kynurenine reductions. Enrollment continued until Dose limiting toxicity (DLT) which was defined as grade 3 hematologic toxicities or grade 3 or 4 non-hematologic toxicities up to Cycle 2 day 1. MTD was defined as DLT not exceeding 33% of subjects. Results: The phase I study enrolled 15 patients, with 9 patients evaluable. The types of cancers were non-small cell lung ca (1), colorectal (5), esophagus (1), gallbladder (1) and sarcoma (1). DLT was not observed up to level 3. Adverse events attributed to SE were Grade 1 Diarrhea (2), stomach pain (1); elevated liver enzymes (ELE) (1), decreased white blood cell (1), anorexia (1), hypokalemia (1), dizziness (1), skin rash (1); Grade 2 ELE (1), Anemia (1), Vertigo (1), Constipation (1), Nausea (2); Grade 3: Diarrhea (1), serotonin syndrome (1), dyspnea (1). The best response observed was stable disease in 3 patients, 5 patients had disease progression and 1 patient was not assessable for response due treatment discontinuation related to side effect of serotonin syndrome. The Expansion Cohort (Part 2) did not proceed since the sponsor decided to discontinue further development of E. Conclusions: The combination of SE is feasible, tolerable with mostly grade 1 and 2 toxicities. There were few grades 3 toxicities. SE produced stable disease as best response in 33% of patients. Research using the combination of SE as an immunomodulatory therapy in patients with lung cancer resistant to checkpoint inhibitor is worth additional exploration. Clinical trial information: NCT03217669.

Reasons for switching immunomodulatory therapy in patients with relapsing-remitting multiple sclerosis

Aim: The aim of the study was to assess switching disease-modifying therapy in patients with relapsing-remitting multiple sclerosis. Materials and methods: This observational single-centre study involved a retrospective evaluation of data of patients with relapsing-remitting multiple sclerosis receiving disease-modifying therapy under drug programmes reimbursed by the National Health Fund. Demographic data, the level of disability, disease activity and treatment methods were analysed with a particular emphasis on the reasons for switching the therapy. Results: Data were collected from patients with a mean age of 39.6 years, with women accounting for 68%. Therapy was switched in 32% (n = 118) of patients. In this group, 72% (n = 85) of patients modified their first-line treatment, and 28% (n = 33) required switching to a second-line drug. Treatment failure (52.5%, n = 62), followed by treatment intolerance (47.5%, n = 56) were the main reasons for switching. Patients on first line-treatment mostly required switching from interferon beta-1a, which was usually replaced with dimethyl fumarate and glatiramer acetate. The most common adverse events included skin reactions and needle fatigue, which were the most common reasons for switching treatment due to intolerance. Conclusions: The currently used immunomodulatory treatment is relatively well tolerated, and its failure is a more frequent reason for therapy switching. This indicates the need for diseasemodifying treatments that are highly effective, safe and well tolerated.

Multiple sclerosis immunomodulatory therapies tested for effectiveness in COVID-19.

The global pandemic of COVID-19 began in Wuhan, China in December 2019. Research into effective therapies has been conducted worldwide. Currently, there is no antiviral treatment and many patients develop a severe course of the disease, including severe respiratory failure. Due to similar pathomechanisms of inflammation in multiple sclerosis (MS) and COVID-19, immunomodulatory drugs that are registered for the treatment of MS are under study in the SARS-CoV-2 infection in clinical trials. Using clinicaltrials.gov, we found information related to ongoing clinical studies on potential drugs for COVID-19 which are also used in MS therapy. The outcomes of several trials were published on pubmed.ncbi.nlm.nih.gov. There were 18 clinical trials evaluating the effectiveness and safety of interferon-β, fingolimod, or leflunomide in COVID-19. Some trial outcomes available at pubmed.ncbi.nlm.nih.gov suggested an association of these drug treatments with improvements in signs and symptoms, and the disease course. The administration of immunomodulatory drugs in COVID-19 may result in potential beneficial effects probably associated with their anti-inflammatory and antiviral properties. Further research is warranted to confirm the long-term effects of immunomodulatory therapies in patients with COVID-19.

POS1210 PREVALENCE OF COVID-19 AMONG PATIENTS WITH RHEUMATIC DISEASES: AN OBSERVATIONAL SURVEY DURING THE TWO WAVES IN ITALY

Background:The new coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) is a source of concern for the management of patients suffering from rheumatic and musculoskeletal diseases (RMDs) treated with immunomodulatory therapies (1).Objectives:We aimed to analyze the prevalence of SARS-CoV-2 infection in patients with RMDs living in Italy.Methods:During the first wave (March-May 2020) and during the second wave (October-December 2020) of COVID-19, we conducted a survey to investigate the incidence of SARS-CoV-2 infection in patients with RMDs followed at the Rheumatology Unit of the University of Campania, Italy. The demographic data, medication use, the frequency of respiratory symptoms and the incidence of COVID-19 confirmed by nasopharyngeal swab were collected with questionnaires administered by phone. The prevalence of COVID-19 of our cohort was compared to that of the general population (2).Results:During the first wave, we collected data from 900 patients with RMDs (Table 1): 320 patients with rheumatoid arthritis (RA), 295 patients with spondyloarthropathies (SpA), 283 patients with systemic lupus erythematosus (SLE), 2 patients with vasculitis. 546 (60%) were treated with bDMARD/tsDMARDs. Overall, a total of 11/900 (1%) cases were tested for COVID-19 due to compatible symptoms. 2 (0.2%) adult patients treated with bDMARDs were registered as swab test positive by PCR for COVID-19. 2 patients without confirmed COVID-19 developed pneumonia that required admission to hospital. No deaths occurred among the patients with confirmed COVID-19.During the second wave, data were collected from 470 patients who accepted to take part of the study (Table 1). 49 presented with symptoms that were compatible with COVID-19. 139 patients were tested whereas 30 patients (6%) had a swab confirmation of SARS-CoV-2 infection. Among them, 16 (53%) were treated with bDMARDs and a patient was treated with tofacitinib. we found no increase in COVID-19 prevalence in patients treated with bDMARD/tsDMARDs (p>0.05). A patient with SLE developed pneumonia that required admission to hospital and died.Lacking distinct prevalence data between first and second waves, we found no differences in total COVID-19 prevalence between general population living in Campania (215.752/5.802.000; 3.7%) and patients with RMDs (32/900; 3.5%). However, we had a significant increase in COVID-19 prevalence in our cohort during the second wave compared to the first. Nevertheless, no increase in mortality or hospitalization was recorded, confirming the safety of immunomodulatory therapies in patients with RMDs.Conclusion:In this cohort of patients with RMDs in a geographical region with a high prevalence of COVID-19, the risk of SARS-CoV-2 infection does not appear different from that observed in the general population.

Nintedanib and immunomodulatory therapies in progressive fibrosing interstitial lung diseases

BackgroundIn the INBUILD trial in patients with chronic fibrosing interstitial lung diseases (ILDs) and a progressive phenotype, nintedanib reduced the rate of ILD progression with adverse events that were manageable for most patients. We investigated the potential impact of immunomodulatory therapies on the efficacy and safety of nintedanib.MethodsSubjects with fibrosing ILDs other than idiopathic pulmonary fibrosis, who had shown progression of ILD within the prior 24 months despite management in clinical practice, were randomized to receive nintedanib or placebo. Certain immunomodulatory therapies were restricted for the first 6 months. We analyzed post-hoc the rate of decline in forced vital capacity (FVC) over 52 weeks in subgroups by glucocorticoid use at baseline and in analyses excluding subjects or FVC measurements taken after initiation of restricted immunomodulatory or antifibrotic therapies.ResultsOf 663 subjects, 361 (54.4%) were taking glucocorticoids at baseline (353 at a dose of ≤ 20 mg/day). In the placebo group, the adjusted rate of decline in FVC (mL/year) over 52 weeks was numerically greater in subjects taking than not taking glucocorticoids at baseline (− 206.4 [SE 20.2] vs − 165.8 [21.9]). The difference between the nintedanib and placebo groups was 133.3 (95% CI 76.6, 190.0) mL/year in subjects taking glucocorticoids at baseline and 76.1 (15.0, 137.2) mL/year in subjects who were not (interaction P = 0.18). The effect of nintedanib on reducing the rate of FVC decline in analyses excluding subjects or measurements taken after initiation of restricted immunomodulatory or antifibrotic therapies was similar to the primary analysis. The adverse event profile of nintedanib was similar between subjects who did and did not use prohibited or restricted therapies at baseline or during treatment with trial drug.ConclusionsIn patients with progressive fibrosing ILDs, the effect of nintedanib on reducing FVC decline was not influenced by the use of immunomodulatory therapies. Nintedanib can be used in combination with immunomodulatory therapies in patients with progressive fibrosing ILDs.Trial registration ClinicalTrials.gov, NCT02999178. Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178

Risk factors of mortality and contribution of treatment in patients infected with COVID-19: a retrospective propensity score matched study

Background Coronavirus disease 2019 (COVID-19) has now brought major challenges to public health and the economy globally since December 2019, which requires effective treatment and prevention strategies to adapt to the impact of the pandemic. We, therefore, explored the prognostic factors for patients with COVID-19 and the contribution of immunomodulatory therapy on COVID-19 outcome. Methods From 1 February to 16 March 2020, consecutive cases with COVID-19 were analyzed in the West Campus of Wuhan Union Hospital, a tertiary care center that is designated to care for patients with COVID-19 in Wuhan, China. The observation was based on follow-up until in-hospital death or discharge. Logistic regressions were performed for prognostic factors associated with in-hospital death. Furthermore, a propensity score-matched analysis was done using a multivariable logistic regression model to analyze the contributions of multiple treatments on COVID-19 death. Results Three hundred and seventeen patients with COVID-19 were enrolled, of whom 269 were discharged and 48 died in hospital. After propensity score matching based on age, gender, symptoms and comorbidities, multivariable logistic regression was performed with the adjustment of other variables that were significant risk factors in the univariate regression. Treatments with glucocorticoids, immunoglobulin, thymosin, and ammonium glycyrrhizinate were significantly associated with a higher rate of COVID-19 death. Conclusions For in-hospital patients with COVID-19 of all severity levels, a high risk for fatal outcome was observed in those treated with glucocorticoids, immunoglobulin, thymosin, and ammonium glycyrrhizinate. The results of this study do not support immunomodulatory therapy in patients admitted to the hospital with COVID-19. Further prospective studies are essential to clarify our findings, especially for non-critically ill patients.

COVID-19/SARS-CoV-2 Infection: Lysosomes and Lysosomotropism Implicate New Treatment Strategies and Personal Risks.

In line with SARS and MERS, the SARS-CoV-2/COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide. SARS-CoV-2 infection/COVID-19 provides numerous therapeutic targets, each of them promising, but not leading to the success of therapy to date. Neither an antiviral nor an immunomodulatory therapy in patients with SARS-CoV-2 infection/COVID-19 or pre-exposure prophylaxis against SARS-CoV-2 has proved to be effective. In this review, we try to close the gap and point out the likely relationships among lysosomotropism, increasing lysosomal pH, SARS-CoV-2 infection, and disease process, and we deduce an approach for the treatment and prophylaxis of COVID-19, and cytokine release syndrome (CRS)/cytokine storm triggered by bacteria or viruses. Lysosomotropic compounds affect prominent inflammatory messengers (e.g., IL-1B, CCL4, CCL20, and IL-6), cathepsin-L-dependent viral entry of host cells, and products of lysosomal enzymes that promote endothelial stress response in systemic inflammation. As supported by recent clinical data, patients who have already taken lysosomotropic drugs for other pre-existing conditions likely benefit from this treatment in the COVID-19 pandemic. The early administration of a combination of antivirals such as remdesivir and lysosomotropic drugs, such as the antibiotics teicoplanin or dalbavancin, seems to be able to prevent SARS-CoV-2 infection and transition to COVID-19.

Identification of Circulating microRNA Signatures As Potential Noninvasive Biomarkers for Prediction to Response to Extracorporeal Photoapheresis in Patients with Graft Versus Host Disease

INTRODUCTION: Extracorporeal photoapheresis (ECP) is an immunomodulatory therapy for patients with acute or chronic graft-versus-host disease (aGVHD/cGVHD). So far, few studies have explored the molecular regulation of GVHD, and to date no studies have addressed how specific is miRNA expression change during ECP, and whether selected miRNA profiles might be predictive of clinical responses to ECP. OBJECTIVE: The aim of the study was to analyze the expression profile of miRNAs in plasma of patients with GVHD candidates for ECP, and their changes in responding and non-responding patients to this therapy. PATIENTS AND METHODS: Patients with GVHD underwent ECP therapy by off-line methods according to internal protocols. Peripheral blood samples were drawn pre-ECP and after 6 months of treatment. Data on patient characteristics, medical therapies and responses were obtained from medical records. We included the following study cohorts: 1) Initial cohort of 10 GVHD patients (7 cGVHD, 3 aGVHD) and 3 controls; 2) Internal validation cohort with 21 GVHD patients (14 cGVHD, 7 aGVHD) and 10 controls; and 3) External validation cohort (Policlinico S. Matteo, Pavia) composed of 24 GVHD patients (17 cGVHD, 7 aGVHD) and 12 controls. Additionally, samples from 12 patients undergoing ECP due to lung transplantation were also included. Plasma miRNAs were purified with NucleoSpin miRNA Plasma (Macherey-Nagel). In the initial cohort, we analyzed 178 miRNAs, using the Plasma focus miRNAs PCR array (Exiqon). In the validation cohorts we quantified, by qRT-PCR, candidate miRNAs using miRcury LNA RT miRNA PCR (Exiqon) and specific Exiqon primers. RESULTS: In the initial cohort, 4 miRNAs (miR-22-5p, miR-34a-5p, miR-148a-3p, and miR-505-3p) showed higher expression in patients with GVHD compared to controls (p<0.05), which significantly decreased to values similar to healthy individuals at 6 months post-ECP (Fig. 1A). In the validation study with the groups of both the internal and external cohorts, only miR-34-5p and miR-148a-3p were significantly increased in GVHD patients before ECP treatment compared to controls, and those levels significantly decreased with this therapy. This effect was not an intrinsic change associated with ECP, since this pattern was not observed in patients undergoing ECP for lung transplantation (data not shown). We explored the ability of these 2 miRNAs to predict clinical responses to ECP at 6 months: responders showed higher pre-ECP levels of miR-34a-5p and lower miR-148a-3p compared to non-responders (p=0.009, and p=0.003, respectively) (Fig. 1B). The ROC curves showed an area under the curve (AUC) of 0.82 for miR-34a-5p and 0.89 for miR-148a-3p. The ability to identify patients who respond to ECP was improved (p<0.01) by combining both markers (AUC=0.96) (Fig. 1C). CONCLUSION: This study identifies miR-34a-5p and miR-148a-3p as potential biomarkers to predict responses to ECP in patients with GVHD. The combinatorial function of these miRNAs can provide a more informative outlook on the pathophysiology of the disease by identifying potential target genes being inhibited and the pathways involved, both in the development of GVHD and following responses to ECP. Overall, this information would enable the implementation of more personalized patient treatment strategies, and likely lead to significant advances in the management of GVHD patients. Disclosures Lozano: Amgen: Consultancy; Terumo S.A.: Consultancy; Grifols S.A.: Consultancy; Novartis: Consultancy; Macopharma: Consultancy.

Prévalence et caractéristiques de l’auto-immunité sérique chez les patientes suivies pour infertilité au CHU de Grenoble

Fertility disorders in autoimmune diseases are well described. However, little is known about the presence of a humoral serum autoimmunity in case of infertility (antinuclear antibodies, ACAN or antiphospholipid, APL) without criteria of autoimmune disease. We studied the prevalence, associated factors, and efficacy of immunomodulatory therapy in patients with unexplained infertility. Two groups were created retrospectively among patients followed in medically assisted procreation (PMA) for infertility: a group with serum autoimmunity (AI+) (ACAN, APL or anti-thyroperoxidase antibodies) and a group without serum autoimmunity (HAVE-). Clinical, biological, and therapeutic data were collected. The prevalence of autoimmunity was 33% among consultant patients. One hundred patients were seen in internal medicine consultation, 70 were included in the AI+ group and 30 in the AI- group. In the AI+ group, 76% had ACANs, 29% had anti-TPOs and 23% had APLs. There was a significant correlation between ACAN level and the presence of endometriosis (P=0.048). Immunomodulatory therapy was introduced for 68 of the 70 women in the AI+ group; pregnancy occurred in 28 patients (40%) during the treatment period, compared with 7 in the "AI-" group (23%), with a tendency to significance (P=0.09). In conclusion, there is an increased prevalence of serum autoimmunity in patients with fertility disorders, possibly with the efficacy of an immunomodulatory treatment to confront prospective therapeutic studies.

Have We Hit The Mark Yet? Biomarkers of Activity of Immunomodulatory Therapies in Patients with Metastatic Melanoma

Have We Hit The Mark Yet? Biomarkers of Activity of Immunomodulatory Therapies in Patients with Metastatic Melanoma

Influence of Vitamin D on Islet Autoimmunity and Beta-Cell Function in Type 1 Diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease leading to immune-mediated destruction of pancreatic beta cells, resulting in the need for insulin therapy. The incidence of T1D is increasing worldwide, thus prompting researchers to investigate novel immunomodulatory strategies to halt autoimmunity and modify disease progression. T1D is considered as a multifactorial disease, in which genetic predisposition and environmental factors interact to promote the triggering of autoimmune responses against beta cells. Over the last decades, it has become clear that vitamin D exerts anti-inflammatory and immunomodulatory effects, apart from its well-established role in the regulation of calcium homeostasis and bone metabolism. Importantly, the global incidence of vitamin D deficiency is also dramatically increasing and epidemiologic evidence suggests an involvement of vitamin D deficiency in T1D pathogenesis. Polymorphisms in genes critical for vitamin D metabolism have also been shown to modulate the risk of T1D. Moreover, several studies have investigated the role of vitamin D (in different doses and formulations) as a potential adjuvant immunomodulatory therapy in patients with new-onset and established T1D. This review aims to present the current knowledge on the immunomodulatory effects of vitamin D and summarize the clinical interventional studies investigating its use for prevention or treatment of T1D.

The effect of psychological gender on adherence to immunomodulatory therapy in patients with multiple sclerosis

To study the association between psychological gender and adherence to immunomodulatory therapy in patients with multiple sclerosis. Thirty-four patients (25 women and 9 men) with the diagnosis of multiple sclerosis were examined. The following methods were used: MMSE, The Bem Sex Role Inventory adapted in Russia, Beck Depression Inventory, State-Trait Anxiety Inventory. During three months patients reported the first and the last immunomodulator injections dates from every new pack. Then the patients' self-reports systematization and analysis were performed, drug-taking compliance and timing compliance were calculated. Twenty-eight patients had an androgynous type of psychological gender and six persons were feminine. The association was determined between high compliance and such psychological gender peculiarities as a significantly large number of feminine traits than masculine ones and the low number of masculine characteristics in men.

Cumulative exposure to biological therapy and risk of cancer in patients with psoriasis: a meta-analysis of Psonet studies from Israel, Italy, Spain, the U.K. and Republic of Ireland.

Cancer risk following long-term exposure to systemic immunomodulatory therapies in patients with psoriasis is possible. To assess a dose-response relationship between cumulative length of exposure to biological therapy and risk of cancer. Four national studies (a healthcare database from Israel, and prospective cohorts form Italy, Spain and the U.K. and Republic of Ireland) collaborating through Psonet (European Registry of Psoriasis) participated in these nested case-control studies, including nearly 60 000 person-years of observation. 'Cases' were patients who developed an incident cancer. Patients with previous cancers and benign or in situ tumours were excluded. Four cancer-free controls were matched to each case on year of birth, sex, geographic area and registration year. Follow-up for controls was censored at the date of cancer diagnosis for the matched case. Conditional logistic regression was performed by each registry. Results were pooled using random-effects meta-analysis. A total of 728 cases and 2671 controls were identified. After matching, differences between cases and controls were present for the Charlson Comorbidity Index in all three registries, and in the prevalence of previous exposure to psoralen-ultraviolet A and smoking (the British Association of Dermatologists Biologic Interventions Register only). The risk of first cancers was not significantly associated with cumulative exposure to biologics (adjusted odds ratio per year of exposure 1·02, 95% confidence interval 0·92-1·13). Results were similar if squamous and basal cell carcinomas were included in the outcome. Cumulative length of exposure to biological therapies in patients with psoriasis in real-world clinical practice does not appear to be linked to a higher risk of cancer after several years of use.

APOE GENE POLYMORPHISM: THE IMPACT OF APOE4 ALLELE ON SYSTEMIC INFLAMMATION AND ITS ROLE IN THE PATHOGENESIS OF ALZHEIMER’S DISEASE

ApoE is a member of lipoprotein family. It is the most common lipoprotein in the central nervous system (CNS), secreted by astrocytes, microglia, neurons and immunocompetent cells, including lymphocytes, monocytes and macrophages. According to recent data, it has endotheliotropic and immunomodulatory functions, regulating inflammatory activation of mononuclear phagocytes and antigen-induced lymphocyte proliferation. APOE4 allele is a major genetic risk factor of Alzheimer’s disease, with prevalence 3-12 times higher in those who have this allele. Mechanisms that predispose carriers of the allele to earlier clinical presentation of neurodegeneration include changes in lipid metabolism in the CNS, in the buildup of neurotoxic amyloid-beta oligomers, in the clearance of amyloid-beta peptides from the CNS and in regulation of immune response. In this review the functions of ApoE protein in central nervous and immune system and changes in functional activity of the protein in APOE4 carriers are discussed. The impact of APOE4 allele on monocyte phenotype and inflammatory activation of monocytes, on specific cell-mediated immune response to amyloid-beta antigens and on effectiveness of immunomodulatory therapy in patients with Alzheimer’s disease summarized, as well as the possible role of changes in the immune response characteristic for APOE4 carriers in the increased risk of Alzheimer’s disease.

Endometriosis as a pathology of regulatory mechanisms

The article represents the author’s original definition of genital endometriosis, emphasizing the main pathogenetic feature of the disease — violation of regulatory mechanisms, underlying in its development and characterizing diversity of its pathogenetic and clinical forms. The hierarchy of regulatory mechanisms is given, general ideas concerning approaches to the study of this illness and approaches to drug therapy are described. Special attention is paid to immunomodulatory therapy in patients with endometriosis, critical analysis of its advantages and disadvantages is given, and prospects of this direction are demonstrated.

Endogenous Brucella endophthalmitis: A case report

Brucellosis may be associated with a wide range of ophthalmic manifestations including endophthalmitis, which is a sight-threatening condition that needs to be rapidly recognized and treated to avoid permanent visual loss. A 26-year-old female with a 6-month history of vision loss in the left eye was treated with high dose systemic corticosteroids and azathioprine with an initial misdiagnosis elsewhere. A dense vitreous haze with opacities at the posterior hyaloid and a wide area of retinochoroiditis led to the diagnosis of endogenous endophthalmitis at presentation to us. The vitreous sample and blood cultures demonstrated growth of Brucella melitensis. She received 6months of systemic antibiotherapy, which resulted in resolution of inflammation; however, visual acuity remained poor due to irreversible damage. Infectious etiology, including brucellosis in endemic countries, has to be considered in the differential diagnosis before administering immunomodulatory therapy in patients with panuveitis of unknown origin.

First steps towards a targeted immunomodulatory therapy in patients with recurrent miscarriage and elevated natural killer cells

First steps towards a targeted immunomodulatory therapy in patients with recurrent miscarriage and elevated natural killer cells