Engineering immunosuppressive drug-resistant armored(IDRA)SARS-CoV-2 T cells for cell therapy

Solid organ transplant(SOT)recipients receive immunosuppressive drugs(ISDs)and are susceptible to developing severe COVID-19.Here,we analyze the Spike-specific T-cell response after 3 doses of mRNA vaccine in a group of SOT patients(n=136)treated with different ISDs.We demonstrate that a combination of a calcineurin inhibitor(CNI),mycophenolate mofetil(MMF),and prednisone(Pred)treatment regimen strongly suppressed the mRNA vaccine-induced Spike-specific cellular response.Such defects have clinical consequences because the magnitude of vaccine-induced Spike-specific T cells was directly proportional to the ability of SOT patients to rapidly clear SARS-CoV-2 after breakthrough infection.To then compensate for the T-cell defects induced by immunosuppressive treatment and to develop an alternative therapeutic strategy for SOT patients,we describe production of 6 distinct SARS-CoV-2 epitope-specific ISD-resistant T-cell receptor(TCR)-T cells engineered using the mRNA electroporation method with reactivity minimally affected by mutations occurring in Beta,Delta,Gamma,and Omicron variants.This strategy with transient expression characteristics marks an improvement in the immunotherapeutic field and provides an attractive and novel therapeutic possibility for immunosuppressed COVID-19 patients.

Pharmacogenetics of immunosuppressant drugs:A new aspect for individualized therapy

In recent years,pharmacogenetics has emerged as an important tool for choosing the right immunosuppressant drug and its appropriate dose.Indeed,pharmacogenetics may exert its action on immunosuppressant drugs at three levels.Pharmacogenetics identifies and studies the genes involved in encoding the proteins involved in drug pharmacokinetics and in encoding the enzymes involved in drug degradation.Pharmacogenetics is also relevant in encoding the enzymes and proteins involved in codifying the transmembrane proteins involved in transmembrane passage favoring the absorption and intracellular action of several immunosuppressants.Pharmacogenetics concern the variability of genes encoding the proteins involved as immunosuppressant triggers in the pharmacodynamic pathways.Of course,not all genes have been discovered and studied,but some of them have been clearly examined and their relevance together with other factors such as age and race has been defined.Other genes on the basis of relevant studies have been proposed as good candidates for future studies.Unfortunately,to date,clear conclusions may be drawn only for those drugs that are metabolized by CYP3A5 and its genotyping before kidney,heart and lung transplantation is recommended.The conclusions of the studies on the recommended candidate genes,together with the development of omics techniques could in the future allow us to choose the right dose of the right immunosuppressant for the right patient.

New Progress in the Treatment of Myasthenia Gravis

In recent decades, the treatment of myasthenia gravis has been extensively developed, but a standardized standard still needs to be used. Its treatment strategy is associated with patient prognosis, economic costs, and complications. This article reviews the pathogenesis, treatment methods, and complications of myasthenia gravis, providing new ideas for diagnosing and treating myasthenia gravis and fully embodies the principle of safety and precision.

''Minimizing tacrolimus' ' strategy and long-term survival after liver transplantation

AIM: To investigate the effect of the ‘‘minimizing tacrolimus' ' strategy on long-term survival of patients after liver transplantation(LT).METHODS: We conducted a retrospective study of 319 patients who received LT between January 2009 and December 2011 at the First Affiliated Hospital of Zhejiang University School of Medicine. Following elimination of ineligible patients, 235 patients were included in the study. The relationship between early tacrolimus(TAC)exposure and survival period was analyzed by Kaplan Meier curves. Adverse effects related to TAC were eval-uated by the χ2 test. Routine monitoring of blood TAC concentration(TC) was performed using the PRO-TracTM Ⅱ Tacrolimus Elisa Kit(Diasorin, United States). RESULTS: Of 235 subjects enrolled in the study, 124(52.8%) experienced adverse effects due to TAC. When evaluating mean TC, the survival time of patients with a mean TC < 5 ng/mL was significantly shorter than that in the other groups(911.3 ± 131.6 d vs 1381.1 ± 66.1 d, 911.3 ± 131.6 d vs 1327.3 ± 47.8 d, 911.3 ± 131.6 d vs 1343.2 ± 83.1 d, P < 0.05), while the survival times of patients with a mean TC of 5-7, 7-10 and 10-15 ng/mL were comparable. Adverse effects due to TAC in all four groups were not significantly different. When comparing the standard deviation(SD) of TC among the groups, the survival time of patients with a SD of 2-4 was significantly longer than that in the other groups(1388.8 ± 45.4 d vs 1029.6 ± 131.3 d, 1388.8 ± 45.4 d vs 1274.9 ± 57.0 d, P < 0.05), while in patients with a SD < 2 and SD > 4, the survival time was not statistically different. Adverse effects experienced in all three groups were not statistically different. In Cox regression analysis, male patients and those with a primary diagnosis of benign disease, mean TC > 5 ng/mL and TC SD 2-4 had better outcomes.CONCLUSION: The early ‘‘minimizing tacrolimus' ' strategy with a mean TC of 5-10 ng/mL and SD of 2-4 was beneficial in terms of long-term survival after LT.

COVID-19: Considerations about immune suppression and biologicals at the time of SARS-CoV-2 pandemic

The extent of the profound immunological and nonimmunological responses linked to severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection is currently being investigated worldwide due to the large burden associated with death due to SARS-CoV-2 and the short-term consequences of coronavirus disease 2019(COVID-19).It has been hypothesized that patients on immunosuppressive treatments,including biologics,may have an augmented risk of being infected by SARS-CoV-2;however,there are currently no definitive data about biological drugs and COVID-19 in immune-mediated inflammatory diseases.Current epidemiological models developed to understand how long the COVID-19 epidemic may last are not conclusive and range from sustained epidemics to complete elimination.Nevertheless,even in the best-case scenario of apparent elimination,there is concordance about a possible contagion resurgence as late as 2024.Therefore,knowledge of the impact of SARS-CoV-2 on immunemediated diseases and among patients treated with biologicals,together with the results of novel and promising COVID-19 treatment strategies targeting the virus and the host immune response(or both),will help us to best manage our patients during this pandemic over the next few years.

Hydradenitis suppurativa and inflammatory bowel disease: An unusual, but existing association

Inflammatory bowel disease (IBD) could be associated with several extra-intestinal manifestations (EIMs) involving musculoskeletal, hepatopancreatobiliary, ocular, renal, and pulmonary systems, as well as the skin. In the last years, hidradenitis suppurativa (HS) is acquiring an increasing interest. IBD, especially Crohn&#x02019;s disease (CD), is among the most reported associated diseases in HS patients. The aim of this paper is to give a brief overview of data showing a possible epidemiologic and pathogenetic association between IBD and HS. We performed a pooled-data analysis of four studies and pooled prevalence of HS in IBD patients was 12.8%, with a 95%CI of 11.7%-13.9%. HS was present in 17.3% of subjects with CD (95%CI: 15.5%-19.1%) and in 8.5% of UC patients (95%CI: 7.0%-9.9%). Some items, especially altered immune imbalance, are generally involved in IBD pathogenesis as well as invoked by HS. Smoking is one of the most relevant risk factors for both disorders, representing a predictor of their severity, despite, actually, there being a lack of studies analyzing a possible shared pathway. A role for inheritance in HS and CD pathogenesis has been supposed. Despite a genetic susceptibility having been demonstrated for both diseases, further studies are needed to investigate a genetic mutual route. Although the pathogenesis of IBD and HS is generally linked to alterations of the immune response, recent findings suggest a role for intestinal and skin microbiota, respectively. In detail, the frequent finding of Staphylococcus aureus and coagulase-negative staphylococci on HS cutaneous lesions suggests a bacterial involvement in disease pathogenesis. Moreover, microflora varies in the different cutaneous regions of the body and, consequently, two different profiles of HS patients have been identified on these bases. On the other hand, it is well-known that intestinal microbiota may be considered as &#x0201c;the explosive mixture&#x0201d; at the origin of IBD despite the exact relationship having not been completely clarified yet. A better comprehension of the role that some bacterial species play in the IBD pathogenesis may be essential to develop appropriate management strategies in the near future. A final point is represented by some similarities in the therapeutic management of HS and IBD, since they may be controlled by immunomodulatory drugs. In conclusion, an unregulated inflammation may cause the lesions typical of both HS and IBD, particularly when they coexist. However, this is still a largely unexplored field.

Severe progression of autoimmune hepatitis in a young COVID-19 adult patient: A case report

Rationale:The impact of COVID-19 in patients with autoimmune liver disease treated with immunosuppressive therapy has not been described so far.This case report describes the clinical course of a patient with autoimmune hepatitis(AIH)who developed COVID-19 and the features of cytokine syndrome leading to its deterioration in our intensive care unit.Patient’s Concern:A 28-year-old male presented with generalized anasarca for two weeks and chronic liver disease for 8 months.Diagnosis:AIH and Covid-19 with features of cytokine storm syndrome.Interventions:Intravenous furosemide,mannitol,syrup lactulose,steroids(prednisolone 40 mg),azathioprine 1 mg/kg body weight,rifaximin,vitamin K,and blood products.Outcomes:The patient had hepatic encephalopathy and AIH and died on the 10th day after admission despite ventilatory support,sustained low-efficiency hemodialysis,and resuscition.Lessons:The dramatic release of cytokines and the inflammatory‐immune responses not only alter the pathophysiology but also affects the onset and severity of disease progression in patients with AIH.

Clinical spectrum and currently available treatment of typeⅠinterferonopathy Aicardi-Goutières syndrome

Background Aicardi-Goutières syndrome(AGS)is a genetically determined disorder with a variable phenotype.Since the original description of AGS,advances in gene sequencing techniques have resulted in a significant broadening of the phenotypic spectrum associated with AGS genes,and new clinical pictures have emerged beyond the classic presentation.The aim of this review is to provide a comprehensive analysis of the clinical spectrum of AGS and report currently available treatments and new immunosuppressive strategies.Data sources Literature reviews and original research articles were collected from databases,including PubMed and Clini-calTrials.gov.Relevant articles about AGS were included.Results The involvement of the nervous system certainly represents the major cause of mortality and morbidity in AGS patients.However,other clinical manifestations,such as chilblains,hepatosplenomegaly,and hematological disturbances,may lead to the diagnosis and considerably impact the prognosis and overall quality of life of these patients.Therapeutic approaches of AGS are limited to interventions aimed at specific symptoms and the management of multiple comorbidities.However,advances in understanding the pathogenesis of AGS could open new and more effective therapies.Conclusions The over-activation of innate immunity due to upregulated interferon production plays a critical role in AGS,leading to multi-organ damage with the main involvement of the central nervous system.To date,there is no specific and effective treatment for AGS.New drugs specifically targeting the interferon pathway may bring new hope to AGS patients.

Henoch-Schönlein purpura nephritis in children:incidence,pathogenesis and management

Background:Henoch-Schönlein purpura(HSP)is one of the most common vasculitides in children.It is manifested by skin purpura,arthritis,abdominal pain,renal involvement,etc.Typically,HSP is considered to be self-limiting,although renal involvement(HSP purpura nephritis,HSPN)is the principal cause of morbidity from this disease.For this reason,it is important to clarify the mechanism of onset and clinical manifestations of HSPN and to ascertain the most appropriate treatment for HSPN.In this article,we review the updated pathophysiology and treatment strategies for HSPN.Data sources:We searched databases including PubMed,Elsevier and Wanfang for the folowing key words:Henoch-Schönlein purpura,nephritis,mechanism and treatment,and we selected those publications written in English that we judged to be relevant to the topic of this review.Results:Based on the data present in the literature,we reviewed the following topics:1)the possible pathogenesis of HSPN:several studies suggest that immunoglobulin A immune complexes deposit in the mesangium and induce renal injury;2)multiple-drug treatment for HSPN:although there have been few evidence-based treatment strategies for HSPN,several studies have suggested that immunosuppressive drugs and multiple drug combination therapy were effective in ameliorating proteinuria and histological severity.Conclusions:HSPN is a severe disease of childhood.To better understand this disease,detailed investigations into the pathogenesis of HSPN and prospective randomized controlled treatment studies on children with severe HSPN are needed.

Effect of everolimus on the immunomodulation of the human neutrophil inflammatory response and activation

The primary cause of mortality at 5 years following a cardiac transplantation is the development of atherosclerosis, termed coronary allograft vasculopathy （CAV）. This pathology is characterized by diffused intimal hyperplasia and emanates from coronary arterial injuries caused by immune inflammatory cells. Neutrophils play an important role in this inflammatory process; however, their potential participation in the pathogenesis of CAV is poorly understood. Despite their essential contribution to the prevention of graft rejection, immunosuppressive drugs could have detrimental effects owing to their pro-inflammatory activities. Thus, we investigated the impact of different immunosuppressive drugs on the inflammatory response of neutrophils isolated from the blood of healthy volunteers. Under basal conditions, mammalian target of rapamycin （mTOR） inhibitors （sirolimus and everolimus） had the most potent anti-inflammatory effect, decreasing both IL-8 release （≈-80%） and vascular endothelial growth factor （VEGF） release （≈-65%） and preserving the release of the anti-inflammatory cytokine interleukin-1 receptor antagonist （IL-1RA）. In TNF-α-treated neutrophils, pre-incubation with everolimus provided the most potent effect, simultaneously reducing the release of both VEGF and IL-8 while doubling the release of IL-1RA. This latter effect of everolimus was maintained even when administered in combination with other immunosuppressive drugs. Sirolimus and everolimus decreased the tumor necrosis factor （TNF）-α-induced adhesion of neutrophils to human endothelial cells and human extracellular matrix. This effect was largely dependent on the ability of these compounds to alter P2-integrin/CD18 activation. Our results suggest a potential mechanism for the beneficial effect of everolimus in the prevention of CAV in heart transplant recipients.