Impact of SARS-CoV-2 vaccination in inflammatory bowel disease patients with different biological agents: a systematic review and meta-analysis

Background: There are concerns regarding the effect of biological agents on SARS-CoV-2 vaccination in patients with inflammatory bowel disease (IBD). A systematic review and meta-analysis was performed about the serological responses, breakthrough infections and clinical relapse of IBD patients treated with biological agents following SARS-CoV-2 vaccination. Methods: Electronic databases were searched to identify relevant studies. Primary outcomes were the pooled seroconversion rates, breakthrough infection rates and clinical relapse rates after SARS-CoV-2 vaccination in IBD patients treated with biological agents. Secondary outcomes were the comparison of seroconversion rates, breakthrough infection rates and clinical relapse rates in IBD patients treated with biological agents and control cohort after SARS-CoV-2 vaccination. Results: Thirty-five studies were included in this meta-analysis. A high percentage of seroconversion (96.6%, 99% and 99.2%) was achieved in IBD patients treated with anti-TNF-α therapy, vedolizumab and ustekinumab after SARS-CoV-2 vaccination, respectively. The pooled breakthrough infection rate was 2.5% and 3.9% in IBD patients treated with anti-TNF-α therapy and vedolizumab, respectively. The breakthrough infection rate in IBD patients treated with anti-TNF-α therapy was significantly lower than control cohort (RR 0.178, 95% CI 0.084–0.378). The pooled clinical relapse rate in IBD patients treated with anti-TNF-α therapy, vedolizumab and ustekinumab was 6.9%, 5.4% and 5.3%, respectively. Conclusion: The overall seroconversion rate after SARS-CoV-2 vaccination in IBD patients treated with biological agents is high. The overall breakthrough infection rate and clinical relapse rate in IBD patients treated with biological agents were low (AU)

Interchangeability of biosimilars: A study of expert views and visions regarding the science and substitution.

Healthcare systems have reached a critical point regarding the question of whether biosimilar substitution should become common practice. To move the discussion forward, the study objective was to investigate the views of experts from medicines agencies and the pharmaceutical industry on the science underpinning interchangeability of biosimilars. We conducted an empirical qualitative study using semi-structured interviews informed by a cross-disciplinary approach encompassing regulatory science, law, and pharmaceutical policy. In total 25 individuals with experience within biologics participated during September 2018-August 2019. Eight participants were EU national medicines authority regulators, and 17 had pharmaceutical industry background: five from two originator-only companies, four from two companies with both biosimilar and originator products, and eight from seven biosimilar-only companies. Two analysts independently conducted inductive content analysis, resulting in data-driven themes capturing the meaning of the data. The participants reported that interchangeability was more than a scientific question of likeness between biosimilar and reference products: it also pertained to regulatory practices and trust. Participants were overall confident in the science behind exchanging biosimilar products for the reference products via switching, i.e., with physician involvement. However, their opinions differed regarding the scientific risk associated with biosimilar substitution, i.e., without physician involvement. Almost all participants saw no need for additional scientific data to support substitution. Moreover, the participants did not believe that switching studies, as required in the US, were appropriate for obtaining scientific certainty due to their small size. It is unclear why biosimilar switching is viewed as scientifically safer than substitution; therefore, we expect greater policy debate on biosimilar substitution in the near future. We urge European and UK policymakers and regulators to clarify their visions for biosimilar substitution; the positions of these two frontrunners are likely to influence other jurisdictions on the future of biosimilar use.

Current treatment of recurrent pericarditis: safety considerations and future directions.

INTRODUCTION: Recurrent pericarditis is one of the most troublesome complications of pericarditis affecting a substantial amount of patients and often severely impairing the quality of life. Current medical treatments range from non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids to biological agents (anti IL-1 agents, especially anakinra and rilonacept), intravenous immunoglobulins and immunosuppressive treatments. Safety is a major issue to deal with since the disease often affects relatively young or middle-aged patients. AREAS COVERED: The review is aimed at providing an update on the efficacy and safety of current medical therapies for recurrent pericarditis including most recent advances represented by anti IL-1 agents. EXPERT OPINION: Therapy of recurrent pericarditis has evolved over years leading to a more evidence-based and personalized treatment based on clinical presentation and pathophysiology. The main distinction is between patients with an inflammatory phenotype (e.g. fever, elevation of markers of inflammation, pericardial, and/or pleural effusion) vs. those without an inflammatory phenotype. Colchicine and anti IL-1 agents are especially efficacious and indicated for those with an inflammatory phenotype, while corticosteroids, azathioprine, and immunoglobulins seem more indicated for those without evidence of systemic inflammation.

Impact of Food-Derived Bioactive Compounds on Intestinal Immunity.

The gastrointestinal system is responsible for the digestion and the absorption of nutrients. At the same time, it is essentially involved in the maintenance of immune homeostasis. The strongest antigen contact in an organism takes place in the digestive system showing the importance of a host to develop mechanisms allowing to discriminate between harmful and harmless antigens. An efficient intestinal barrier and the presence of a large and complex part of the immune system in the gut support the host to implement this task. The continuous ingestion of harmless antigens via the diet requires an efficient immune response to reliably identify them as safe. However, in some cases the immune system accidentally identifies harmless antigens as dangerous leading to various diseases such as celiac disease, inflammatory bowel diseases and allergies. It has been shown that the intestinal immune function can be affected by bioactive compounds derived from the diet. The present review provides an overview on the mucosal immune reactions in the gut and how bioactive food ingredients including secondary plant metabolites and probiotics mediate its health promoting effects with regard to the intestinal immune homeostasis.

The Zebrafish Embryo as a Model to Test Protective Effects of Food Antioxidant Compounds.

The antioxidant activity of food compounds is one of the properties generating the most interest, due to its health benefits and correlation with the prevention of chronic disease. This activity is usually measured using in vitro assays, which cannot predict in vivo effects or mechanisms of action. The objective of this study was to evaluate the in vivo protective effects of six phenolic compounds (naringenin, apigenin, rutin, oleuropein, chlorogenic acid, and curcumin) and three carotenoids (lycopene B, ß-carotene, and astaxanthin) naturally present in foods using a zebrafish embryo model. The zebrafish embryo was pretreated with each of the nine antioxidant compounds and then exposed to tert-butyl hydroperoxide (tBOOH), a known inducer of oxidative stress in zebrafish. Significant differences were determined by comparing the concentration-response of the tBOOH induced lethality and dysmorphogenesis against the pretreated embryos with the antioxidant compounds. A protective effect of each compound, except ß-carotene, against oxidative-stress-induced lethality was found. Furthermore, apigenin, rutin, and curcumin also showed protective effects against dysmorphogenesis. On the other hand, ß-carotene exhibited increased lethality and dysmorphogenesis compared to the tBOOH treatment alone.

Risk of herpes zoster associated with biological therapies for psoriasis and psoriatic arthritis: A systematic review and meta-analysis.

BACKGROUND: Biological therapy is effective for the treatment of psoriasis and psoriatic arthritis; however, adverse effects related to immunosuppression, such as viral infections, have been reported. Amongst these infections, herpes zoster (HZ) is common. OBJECTIVE: To evaluate the risk of HZ in psoriasis and psoriatic arthritis patients treated with biological therapy. DATA SOURCES: A comprehensive literature search of PubMed, Embase, and Web of Science was performed using certain keywords until October 9, 2020. Nine studies were included after a detailed assessment. STUDY ELIGIBILITY CRITERIA: The eligibility criteria included randomized controlled trials (RCTs) and observational studies of patients with psoriasis or psoriatic arthritis treated with biological therapies; compared with non-biological therapies, non-biological systemic therapies, or controls; with the incidence of HZ reported in case and control groups. The Cochrane risk of bias tool and Newcastle-Ottawa scale were used to assess the quality of the RCTs and observational studies, respectively. Data were extracted from 9 eligible studies and then analyzed using Stata software (Version 12.0). RESULTS: The risk of HZ in biological therapies was higher than that in non-biological (odds ratios [OR]: 1.48; 95% confidence interval [CI]: 1.18-1.86; I2 = 0%) and non-biological systemic (OR: 1.32; 95% CI: 1.02-1.71; I2 = 0%) therapies. Furthermore, the risk of HZ associated with tumor necrosis factor-α inhibitors increased significantly (OR: 1.50; 95% CI: 1.11-2.02; I2 = 0%). Notably, infliximab (OR: 2.43; 95% CI: 1.31-4.50; I2 = 0%) and etanercept (OR: 1.65; 95% CI: 1.07-2.56; I2 = 0%) increased the risk of HZ, while adalimumab (OR: 1.21; 95% CI: 0.64-2.30; I2 = 0%), ustekinumab (OR: 2.20; 95% CI: 0.89-5.44; I2 = 0%), alefacept (OR: 1.46; 95% CI: 0.20-10.47; I2 = 0%), and efalizumab (OR: 1.58; 95% CI: 0.22-11.34; I2 = 0%) did not. LIMITATIONS: Few RCTs have reported HZ incidents; thus, our results require confirmation via large-scale RCTs. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Biological therapies, especially tumor necrosis factor-α inhibitors, may lead to the risk of HZ in psoriasis and psoriatic arthritis patients. Amongst these agents, infliximab and etanercept have been shown to significantly increase the risk of HZ. Additionally, younger age and female sex may be risk factors. SYSTEMATIC REVIEW REGISTRATION NUMBER: INPLASY202110027.

Effect of flaxseed on systemic inflammation and oxidative stress in diabetic rats with or without chronic kidney disease.

BACKGROUND: Diabetes mellitus (DM) and chronic kidney disease (CKD) are common causes of morbidity and mortality. Flaxseed contains several bioactive compounds that have been shown to possess anti-inflammatory and antioxidative properties. The aim of the present study was to investigate the possible effect of flaxseed in diabetic rats with adenine-induced CKD. METHODS: Male Wister rats (n = 48) were randomly divided into seven equal groups and treated for 33 consecutive days as follows: G1: control. G2 adenine, G3: streptozotocin (STZ), G4: flaxseed, G5: adenine+flaxseed, G6: STZ+flaxseed, G7: adenine+STZ+flaxseed). DM or CKD were experimentally induced by a single intraperitoneal injection of streptozotocin (STZ) or by adenine via oral gavage, respectively. RESULTS: Rats fed adenine alone exhibited several changes including decreased body weight, increased food and water intake and urine output, increased urinary albumin/creatinine ratio. They also showed an increase in plasma urea and, creatinine, indoxyl sulfate, neutrophil gelatinase-associated lipocalin and cystatin C, and a decrease in renalase activity. These were associated with significant changes in inflammatory and oxidative biomarkers, e.g., increase in 8-isoprostane, 8 -hydroxy -2-deoxy guanosine and decrease in antioxidant enzymes, as well as increase in interleukins 1ß and 6, and NF-κB, and a decrease in interlukin-10. Histopathologically, there was increased tubular necrosis and fibrosis. Concomitant administration of adenine and STZ further worsened the renal damage induced by adenine alone. Flaxseed significantly ameliorated the changes caused by adenine and STZ, given either singly or in combination. CONCLUSION: These findings suggest that flaxseed is a potential therapeutic agent in attenuating the progression of CKD in diabetes.

The therapeutic triad of extracellular vesicles: As drug targets, as drugs, and as drug carriers.

Rapidly growing interest in the study of extracellular vesicles (EVs) has led to the accumulation of evidence on their critical roles in various pathologies, as well as opportunities to design novel therapeutic EV-based applications. Efficiently exploiting the constantly expanding knowledge of the biology and function of EVs requires a deep understanding of the various possible strategies of using EVs for therapeutic purposes. Accordingly, in the present work, we have narrowed the broad therapeutic potential of EVs and consider the similarities and differences of various strategies as we articulate three major aspects (i.e., a triad) of their therapeutic uses: (i) EVs as drug targets, whereby we discuss therapeutic targeting of disease-promoting EVs; (ii) EVs as drugs, whereby we consider the natural medicinal properties of EVs and the available options for their optimization; and (iii) EVs as drug carriers, whereby we highlight the advantages of EVs as vehicles for efficacious drug delivery of natural compounds. Finally, after conducting a comprehensive review of the latest literature on each of these aspects, we outline opportunities, limitations, and potential solutions.

COVID-19 prevalence and outcomes in patients receiving biologic therapies at an infusion center in New York City.

To better understand COVID-19 infection in patients receiving biologic and immunomodulatory therapies, we evaluated prevalence and outcomes for symptomatic cases of COVID-19 at a large therapeutic infusion center in New York City during the height of the pandemic. 2074 patients received treatment with biologic infusions at our center between March and May 2020, and 34 patients developed symptomatic COVID-19 infection, for an overall low rate of 1.64%. The majority of infections and deaths were in a small subset of patients with a primary immunodeficiency. Patients with inflammatory or autoimmune conditions requiring biologic therapies tended to have mild cases. Higher inflammatory responses were observed in patients who died.

Multiphysics Modeling and Simulation of Subcutaneous Injection and Absorption of Biotherapeutics: Sensitivity Analysis.

PURPOSE: A multiphysics simulation model was recently developed to capture major physical and mechanical processes of local drug transport and absorption kinetics of subcutaneously injected monoclonal antibody (mAb) solutions. To further explore the impact of individual drug attributes and tissue characteristics on the tissue biomechanical response and drug mass transport upon injection, sensitivity analysis was conducted and reported. METHOD: Various configurations of injection conditions, drug-associated attributes, and tissue properties were simulated with the developed multiphysics model. Simulation results were examined with regard to tissue deformation, porosity change, and spatiotemporal distributions of pressure, interstitial fluid flow, and drug concentration in the tissue. RESULTS: Injection conditions and tissue properties were found influential on the mechanical response of tissue and interstitial fluid velocity to various extents, leading to distinct drug concentration profiles. Intrinsic tissue porosity, lymphatic vessel density, and drug permeability through the lymphatic membrane were particularly essential in determining the local absorption rate of an mAb injection. CONCLUSION: The sensitivity analysis study may shed light on the product development of an mAb formulation, as well as on the future development of the simulation method.

Lower incidence of COVID-19 in patients with inflammatory bowel disease treated with non-gut selective biologic therapy.

BACKGROUND AND AIM: Since the outbreak of COVID-19, concerns have been raised as to whether inflammatory bowel disease (IBD) patients under biologic therapy may be more susceptible to the disease. This study aimed to determine the incidence and outcomes of COVID-19 in a large cohort of IBD patients on biologic therapy. METHODS: This observational retrospective multicenter study collected data about COVID-19 in IBD patients on biologic therapy in Italy, between February and May 2020. The main end-points were (i) to assess both the cumulative incidence and clinical outcome of COVID-19, according to different biologic agents and (ii) to compare them with the general population and a cohort IBD patients undergoing non-biologic therapies. RESULTS: Among 1816 IBD patients, the cumulative incidence of COVID-19 was 3.9 per 1000 (7/1816) with a 57% hospitalization rate and a 29% case-fatality rate. The class of biologic agents was the only risk factor of developing COVID-19 (P = 0.01). Non-gut selective agents were associated with a lower incidence of COVID-19 cases, related symptoms, and hospitalization (P < 0.05). Compared with the general population of Lombardy, an overall lower incidence of COVID-19 was observed (3.9 vs 8.5 per 1000, P = 0.03). Compared with 565 IBD patients on non-biologic therapies, a lower rate of COVID-19 symptoms was observed in our cohort (7.5% vs 18%, P < 0.001). CONCLUSIONS: Compared with the general population, IBD patients on biologic therapy are not exposed to a higher risk of COVID-19. Non-gut selective agents are associated with a lower incidence of symptomatic disease, supporting the decision of maintaining the ongoing treatment.

The neuroprotection of deproteinized calf blood extractives injection against Alzheimer's disease via regulation of Nrf-2 signaling.

Alzheimer's disease (AD) is characterized by cognitive decline due to the accumulation of extracellular ß-amyloid (Aß) plaques and neurofibrillary tangles in the brain, which impair glutamate (Glu) metabolism. Deproteinized Calf Blood Extractive Injection (DCBEI) is a biopharmaceutical that contains 17 types of amino acids and 5 types of nucleotides. In this study, we found that DCBEI pretreatment reduced L-Glu-dependent neuroexcitation toxicity by maintaining normal mitochondrial function in HT22 cells. DCBEI treatment also reduced the expression of pro-apoptosis proteins and increased the expression of anti-apoptosis proteins. Furthermore, DCBEI attenuated AD-like behaviors (detected via the Morris water maze test) in B6C3-Tg (APPswePSEN1dE9)/Nju double transgenic (APP/PS1) mice; this effect was associated with a reduction in the amount of Aß and neurofibrillary tangle deposition and the concomitant reduction of phospho-Tau in the hippocampus. Metabonomic profiling revealed that DCBEI regulated the level of neurotransmitters in the hippocampus of APP/PS1 mice. Label-free proteomics revealed that DCBEI regulated the expression of Nrf-2 and its downstream targets, as well as the levels of phospho-protein kinase B and mitogen-activated protein kinase. Together, these data show that DCBEI can ameliorate AD symptoms by upregulating Nrf2-mediated antioxidative pathways and thus preventing mitochondrial apoptosis.

Molecularly targeted therapy for advanced gastrointestinal noncolorectal cancer treatment: how to choose? Past, present, future.

Gastrointestinal cancer is a leading cause of death worldwide. Conventional cytotoxic chemotherapy has been the backbone of advanced gastrointestinal cancer treatment for decades and still represents a key element of the therapeutic armamentarium. However, only small increments in survival outcomes have been reached. New clinical trials are designed, including classic chemotherapy in association with either small-molecule inhibitors or mAb. During the past few years, remarkable progress in molecular biology of gastrointestinal noncolorectal cancers, the discovery of specific targets and the resulting development of systemic drugs that block critical kinases and several molecular pathways have all contributed to progress. New biological agents with molecularly targeted therapies are now available or currently included in clinical trials (EGFR inhibitors (i), antiangiogenic agents, c-METi, IDHi, FGFR2i, BRAFi, Pi3Ki/AKTi/mTORi, NTRKi). When we focus on the current state of precision medicine for gastrointestinal malignancies, it becomes apparent that there is a mixed history of success and failure. The aim of this review is to focus on the studies that have been completed to date with target therapies and to understand which of these are currently the accepted choice in clinical practice and which need further confirmation and approval for inclusion in guidelines. All these findings will enable to guide clinical practice for oncologists in the design of the next round of clinical trials.

Perspectives on the pharmacological management of psoriasis in pediatric and adolescent patients.

INTRODUCTION: Psoriasis affects about 0.5% of children and adolescents, it has a high impact of social life. Management can be difficult. The beginning of the 21st century has been an interesting period for the management of pediatric psoriasis, with access to new topical and systemic treatments including several biotherapies. AREAS COVERED: Herein, we analyze the current therapeutic strategies for managing psoriasis in young patients, ranging from infants to adolescents, in a holistic approach. Usual treatment but also new galenics, new topical associations, and biological (anti-TNF-alpha, anti-interleukin 12/23, anti-interleukin 17) recently developed are presented. Results from clinical trials are detailed, but also real-world evaluations, and recent guidelines. Practical tips for day-to-day management are finally proposed. EXPERT OPINION: Currently, we have a wide range of treatments, which we can adapt to all types of psoriasis, depending on the demands of the child and his parents. The near future also looks promising with new topical combinations, new oral therapies (apremilast) and biologics (anti-interleukin 23), as well as genetically targeted therapies for pustular psoriasis.

Edible Microalgae and Their Bioactive Compounds in the Prevention and Treatment of Metabolic Alterations.

Marine and freshwater algae and their products are in growing demand worldwide because of their nutritional and functional properties. Microalgae (unicellular algae) will constitute one of the major foods of the future for nutritional and environmental reasons. They are sources of high-quality protein and bioactive molecules with potential application in the modern epidemics of obesity and diabetes. They may also contribute decisively to sustainability through carbon dioxide fixation and minimization of agricultural land use. This paper reviews current knowledge of the effects of consuming edible microalgae on the metabolic alterations known as metabolic syndrome (MS). These microalgae include Chlorella, Spirulina (Arthrospira) and Tetraselmis as well as Isochrysis and Nannochloropsis as candidates for human consumption. Chlorella biomass has shown antioxidant, antidiabetic, immunomodulatory, antihypertensive, and antihyperlipidemic effects in humans and other mammals. The components of microalgae reviewed suggest that they may be effective against MS at two levels: in the early stages, to work against the development of insulin resistance (IR), and later, when pancreatic -cell function is already compromised. The active components at both stages are antioxidant scavengers and anti-inflammatory lipid mediators such as carotenoids and -3 PUFAs (eicosapentaenoic acid/docosahexaenoic acid; EPA/DHA), prebiotic polysaccharides, phenolics, antihypertensive peptides, several pigments such as phycobilins and phycocyanin, and some vitamins, such as folate. As a source of high-quality protein, including an array of bioactive molecules with potential activity against the modern epidemics of obesity and diabetes, microalgae are proposed as excellent foods for the future. Moreover, their incorporation into the human diet would decisively contribute to a more sustainable world because of their roles in carbon dioxide fixation and reducing the use of land for agricultural purposes.

Biologic and advanced immunomodulating therapeutic options for sarcoidosis: a clinical update.

Introduction: Sarcoidosis is a multi-organ disease with a wide range of clinical manifestations and outcomes. A quarter of sarcoidosis patients require long-term treatment for chronic disease. In this group, corticosteroids and cytotoxic agents be insufficient to control diseaseAreas covered: Several biologic agents have been studied for treatment of chronic pulmonary and extra-pulmonary disease. A review of the available literature was performed searching PubMed and an expert opinion regarding specific therapy was developed.Expert opinion: These agents have the potential of treating patients who have progressive disease. Many of these agents have different mechanisms of action, response rates, and toxicity profiles.

Use of medications during pregnancy and breastfeeding for Crohn's disease and ulcerative colitis.

Introduction: The peak age of diagnosis of inflammatory bowel disease (IBD) occurs during childbearing years, therefore management of IBD during pregnancy is a frequent occurrence. Maintenance of disease remission is crucial to optimize pregnancy outcomes, and potential maternal or fetal toxicity from medications must be balanced against the risks of untreated IBD.Areas covered: This review summarizes the literature on safety and use of medications for IBD during pregnancy and lactation.Expert opinion: 5-aminosalicylates, corticosteroids and thiopurines are safe for use during pregnancy, while methotrexate and tofacitinib should only be used with extreme caution. Anti-TNF agents (except certolizumab), vedolizumab, ustekinumab and tofacitinib readily traverse the placenta via active transport, therefore theoretically may affect fetal development. Certolizumab only undergoes passive transfer across the placenta, thus has markedly lower cord blood levels making it likely the safest biologic agent for infants. There is reasonable evidence to support the safety of anti-TNF monotherapy and combination therapy during pregnancy and lactation. Vedolizumab and ustekinumab are also thought to be safe in pregnancy and lactation, while tofacitinib is generally avoided due to teratogenic effects in animal studies.

Is There a Role for Therapeutic Drug Monitoring in Patients with Hidradenitis Suppurativa on Tumor Necrosis Factor-α Inhibitors?

Tumor necrosis factor-α inhibitors, adalimumab and infliximab, are at the forefront of biologic therapy for the management of moderate-to-severe hidradenitis suppurativa, with adalimumab as currently the only approved medication for this condition. In treating patients, primary or secondary lack of response (also termed suboptimal response) is a major burden for both patients and healthcare systems and is a challenge with biologics in part owing to the development of anti-drug antibodies following treatment. To overcome this, therapeutic drug monitoring may be conducted proactively or reactively to a patient's suboptimal response guided by measurements of trough serum drug concentrations and levels of anti-drug antibodies. While strong evidence to support the utility of therapeutic drug monitoring exists in patients with inflammatory bowel disease, current information is limited in the context of hidradenitis suppurativa. We sought to summarize the available evidence and to present the role of therapeutic drug monitoring and other dose optimization strategies in improving clinical response in patients with hidradenitis suppurativa treated with tumor necrosis factor-α inhibitors.

Ultrafiltration and Injection of Islet Regenerative Stimuli Secreted by Pancreatic Mesenchymal Stromal Cells.

The secretome of mesenchymal stromal cells (MSCs) is enriched for biotherapeutic effectors contained within and independent of extracellular vesicles (EVs) that may support tissue regeneration as an injectable agent. We have demonstrated that the intrapancreatic injection of concentrated conditioned media (CM) produced by bone marrow MSC supports islet regeneration and restored glycemic control in hyperglycemic mice, ultimately providing a platform to elucidate components of the MSC secretome. Herein, we extend these findings using human pancreas-derived MSC (Panc-MSC) as "biofactories" to enrich for tissue regenerative stimuli housed within distinct compartments of the secretome. Specifically, we utilized 100 kDa ultrafiltration as a simple method to debulk protein mass and to enrich for EVs while concentrating the MSC secretome into an injectable volume for preclinical assessments in murine models of blood vessel and islet regeneration. EV enrichment (EV+) was validated using nanoscale flow cytometry and atomic force microscopy, in addition to the detection of classical EV markers CD9, CD81, and CD63 using label-free mass spectrometry. EV+ CM was predominately enriched with mediators of wound healing and epithelial-to-mesenchymal transition that supported functional regeneration in mesenchymal and nonmesenchymal tissues. For example, EV+ CM supported human microvascular endothelial cell tubule formation in vitro and enhanced the recovery of blood perfusion following intramuscular injection in nonobese diabetic/severe combined immunodeficiency mice with unilateral hind limb ischemia. Furthermore, EV+ CM increased islet number and ß cell mass, elevated circulating insulin, and improved glycemic control following intrapancreatic injection in streptozotocin-treated mice. Collectively, this study provides foundational evidence that Panc-MSC, readily propagated from the subculture of human islets, may be utilized for regenerative medicine applications.

Immunogenicity-unwanted immune responses to biological drugs - can we predict them?

INTRODUCTION: Biological agents (BAs) target molecules involved in disease mechanisms and have modified the natural history of several immune-mediated disorders. All BAs are immunogenic, resulting in the formation of antidrug antibodies (ADAs), which can neutralize drug activity leading to loss of response and potential relapse, or serious adverse events such as infusion hypersensitivity reactions. The production of ADAs is the result of a specific adaptive immune response in which T and B cells are involved. AREAS COVERED: Factors conditioning the immunogenicity of BAs, including drug-, treatment- and patient-related factors are currently the subject of many studies. Among them, a lot of attention is dedicated to define the impact of BAs structure, the effect of targeting (soluble or membrane) molecules, the impact of interruption of therapy as well as the role of genetic (HLA and non-HLA) predisposing factors and disease activity. EXPERT OPINION: Knowledge of factors capable of influencing the immunogenicity of BAs may help to understand, in a predictive manner and at the single patient level, the presence of risk factors influencing the production of ADAs and their impact on clinical outcomes.