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Nature May 2023Microbial organisms have key roles in numerous physiological processes in the human body and have recently been shown to modify the response to immune checkpoint...
Microbial organisms have key roles in numerous physiological processes in the human body and have recently been shown to modify the response to immune checkpoint inhibitors. Here we aim to address the role of microbial organisms and their potential role in immune reactivity against glioblastoma. We demonstrate that HLA molecules of both glioblastoma tissues and tumour cell lines present bacteria-specific peptides. This finding prompted us to examine whether tumour-infiltrating lymphocytes (TILs) recognize tumour-derived bacterial peptides. Bacterial peptides eluted from HLA class II molecules are recognized by TILs, albeit very weakly. Using an unbiased antigen discovery approach to probe the specificity of a TIL CD4 T cell clone, we show that it recognizes a broad spectrum of peptides from pathogenic bacteria, commensal gut microbiota and also glioblastoma-related tumour antigens. These peptides were also strongly stimulatory for bulk TILs and peripheral blood memory cells, which then respond to tumour-derived target peptides. Our data hint at how bacterial pathogens and bacterial gut microbiota can be involved in specific immune recognition of tumour antigens. The unbiased identification of microbial target antigens for TILs holds promise for future personalized tumour vaccination approaches.
Topics: Humans; Antigens, Neoplasm; Bacterial Proteins; Cancer Vaccines; CD4-Positive T-Lymphocytes; Cell Line, Tumor; Gastrointestinal Microbiome; Glioblastoma; Histocompatibility Antigens Class II; HLA Antigens; Lymphocytes, Tumor-Infiltrating; Peptide Fragments; Symbiosis; Bacteria
PubMed: 37198490
DOI: 10.1038/s41586-023-06081-w -
Frontiers in Immunology 2022This study aimed to explore the shared mechanism and candidate drugs of multiple sclerosis (MS) and Sjögren's syndrome (SS).
OBJECTIVE
This study aimed to explore the shared mechanism and candidate drugs of multiple sclerosis (MS) and Sjögren's syndrome (SS).
METHODS
MS- and SS-related susceptibility genes and differentially expressed genes (DEGs) were identified by bioinformatics analysis based on genome-wide association studies (GWAS) and transcriptome data from GWAS catalog and Gene Expression Omnibus (GEO) database. Pathway enrichment, Gene Ontology (GO) analysis, and protein-protein interaction analysis for susceptibility genes and DEGs were performed. The drugs targeting common pathways/genes were obtained through Comparative Toxicogenomics Database (CTD), DrugBank database, and Drug-Gene Interaction (DGI) Database. The target genes of approved/investigational drugs for MS and SS were obtained through DrugBank and compared with the common susceptibility genes.
RESULTS
Based on GWAS data, we found 14 hub common susceptibility genes (, , , , , , , , , , , , , and ), with 8 drugs targeting two or more than two genes, and 28 common susceptibility pathways, with 15 drugs targeting three or more than three pathways. Based on transcriptome data, we found 3 hub common DEGs (, , ) with 3 drugs and 10 common risk pathways with 435 drugs. "JAK-STAT signaling pathway" was included in common susceptibility pathways and common risk pathways at the same time. There were 133 overlaps including JAK-STAT inhibitors between agents from GWAS and transcriptome data. Besides, we found that and , identified as hub common susceptibility genes, were the targets of daclizumab and glatiramer that were used for MS, indicating that daclizumab and glatiramer may be therapeutic for SS.
CONCLUSION
We observed the shared mechanism of MS and SS, in which JAK-STAT signaling pathway played a vital role, which may be the genetic and molecular bases of comorbidity of MS with SS. Moreover, JAK-STAT inhibitors were potential therapies for MS and SS, especially for their comorbidity.
Topics: Computational Biology; Daclizumab; Genome-Wide Association Study; Glatiramer Acetate; HLA-DRB1 Chains; Humans; Multiple Sclerosis; Sjogren's Syndrome; Transcriptome
PubMed: 35356004
DOI: 10.3389/fimmu.2022.857014 -
Revista de Neurologia Apr 2018Daclizumab is a monoclonal antibody directed against the CD25 subunit of the interleukin-2 receptor, investigated as a disease-modifying therapy in relapsing-remitting... (Review)
Review
INTRODUCTION
Daclizumab is a monoclonal antibody directed against the CD25 subunit of the interleukin-2 receptor, investigated as a disease-modifying therapy in relapsing-remitting multiple sclerosis. The present review addresses how the drug was developed, the known mechanism of action of the drug and the up-to-date data of efficacy and safety.
DEVELOPMENT
Daclizumab has shown superiority in prevention of relapses against placebo and low-dose interferon beta-1a at a level that puts it on par with the rest of current first-line drugs. The effect on the progression of the disease and on neurodegeneration parameters, however, is not clear. On the other hand, it presents safety problems (mainly risk of autoimmunity phenomena including fulminant hepatopathy and encephalitis) that have supposed eventually its withdrawn from marketing. Daclizumab introduces a new mechanism of action through the blocking of a key interleukin in immune regulation and its effect on a population of cells with regulatory ability, such as the NK CD56(bright) cells.
CONCLUSIONS
Daclizumab has shown efficacy in slowing the inflammatory process of multiple sclerosis, although the appearance of potentially serious side effects has not allowed its use to significantly impact current clinical practice. The development of new drugs in multiple sclerosis must be contingent on maintaining or improving the risk-benefit profile with respect to those already in use.
Topics: Abnormalities, Drug-Induced; Antibodies, Monoclonal, Humanized; Autoimmune Diseases; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Daclizumab; Drug Eruptions; Encephalitis; Female; Humans; Immunosuppressive Agents; Interferon beta-1a; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Killer Cells, Natural; Models, Immunological; Multicenter Studies as Topic; Multiple Sclerosis; Pregnancy; Pregnancy Complications; Safety-Based Drug Withdrawals; T-Lymphocyte Subsets
PubMed: 29645071
DOI: No ID Found -
The Cochrane Database of Systematic... Jan 2024Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015.
OBJECTIVES
To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS.
SEARCH METHODS
CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS.
DATA COLLECTION AND ANALYSIS
Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach.
MAIN RESULTS
We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence).
AUTHORS' CONCLUSIONS
We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.
Topics: Adult; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Glatiramer Acetate; Interferon beta-1a; Fingolimod Hydrochloride; Natalizumab; Interferon beta-1b; Cladribine; Alemtuzumab; Dimethyl Fumarate; Daclizumab; Network Meta-Analysis; Immunologic Factors; Recurrence
PubMed: 38174776
DOI: 10.1002/14651858.CD011381.pub3 -
Cold Spring Harbor Perspectives in... May 2019Daclizumab is a humanized monoclonal antibody that prevents formation of high-affinity interleukin (IL)-2 receptor (IL-2R). Because activated T cells up-regulate... (Review)
Review
Daclizumab is a humanized monoclonal antibody that prevents formation of high-affinity interleukin (IL)-2 receptor (IL-2R). Because activated T cells up-regulate high-affinity IL-2R and IL-2 is used to grow activated T cells in vitro, daclizumab was envisioned to selectively inhibit activated T cells. However, the mechanism of action (MOA) of daclizumab is surprisingly broad and it includes many unanticipated effects on innate immunity. Specifically, daclizumab modulates the development of innate lymphoid cells, leading to expansion of immunoregulatory CD56 natural killer (NK) cells. Activated CD56 NK cells migrate to the intrathecal compartment in multiple sclerosis (MS) and regulate autoreactive T cells via cytotoxicity. Finally, daclizumab also restricts initial steps of T-cell activation by blocking -presentation of IL-2 by dendritic cells to antigen-specific T cells. In conclusion, daclizumab has complex immunomodulatory effects with resultant inhibition of central nervous system inflammation in MS.
Topics: Clinical Trials as Topic; Daclizumab; Humans; Immunoglobulin G; Immunosuppressive Agents; Killer Cells, Natural; Lymphocyte Activation; Multiple Sclerosis; T-Lymphocytes
PubMed: 29661806
DOI: 10.1101/cshperspect.a034470 -
American Journal of Transplantation :... Nov 2017Despite the abundance of information on cutaneous malignancies associated with solid organ transplantation in the transplant literature, there is limited information... (Review)
Review
Despite the abundance of information on cutaneous malignancies associated with solid organ transplantation in the transplant literature, there is limited information regarding nonmalignant skin changes after transplantation. There are numerous skin toxicities secondary to immunosuppressive and other transplant-related medications that can vary in presentation, severity, and prognosis. To limit associated morbidity and mortality, solid organ transplant recipient care providers should effectively identify and manage cutaneous manifestations secondary to drug toxicity. Toxicities from the following transplant-related medications will be discussed: antithymocyte globulins, systemic steroids, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, mammalian target of rapamycin inhibitors sirolimus and everolimus, basiliximab and daclizumab, belatacept, and voriconazole.
Topics: Humans; Immunosuppressive Agents; Organ Transplantation; Skin Diseases
PubMed: 28452165
DOI: 10.1111/ajt.14337 -
Hospital Pharmacy Dec 2016Each month, subscribers to receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to...
Each month, subscribers to receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of publishes selected reviews in this column. For more information about , contact Wolters Kluwer customer service at 866-397-3433. The December 2016 monograph topics are ozenoxacin cream, ocrelizumab, naldemedine, eteplirsen, and abaloparatide. The Safety MUE is on buprenorphine buccal.
PubMed: 28057953
DOI: 10.1310/hpj5111-928