type 1 interferon
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Author(s):  
Elana R Shaw ◽  
Lindsey B Rosen ◽  
Aristine Cheng ◽  
Kerry Dobbs ◽  
Ottavia M Delmonte ◽  
...  

Abstract Binding levels and neutralization activity of anti-type 1 interferon (T1IFN) autoantibodies peaked during acute COVID-19 and markedly decreased thereafter. Most patients maintained some ability to neutralize T1IFN into convalescence despite lower levels of binding IgG. Identifying these autoantibodies in healthy individuals before they develop critical viral disease may be challenging.


2021 ◽  
Author(s):  
Elisha D.O. Roberson ◽  
Mary Carns ◽  
Li Cao ◽  
Kathleen Aren ◽  
Isaac A. Goldberg ◽  
...  

Systemic sclerosis (SSc) is characterized by immune activation, vasculopathy, and unresolving fibrosis in the skin, lungs, and other organs. We performed RNA-Seq analysis on skin biopsies and peripheral blood mononuclear cells (PBMCs) from SSc patients and controls to better understand SSc pathogenesis. We analyzed these data to 1) test for case-control differences, and 2) identify genes whose expression levels correlate with SSc severity as measured by local skin score, modified Rodnan skin score (MRSS), forced vital capacity (FVC), or diffusion capacity for carbon monoxide (DLCO). We found that PBMCs from SSc patients showed a strong type 1 interferon signature. This signal replicated in the skin, with additional signals for increased extracellular matrix (ECM) genes, classical complement pathway activation, and the presence of B cells. Notably, we observed a marked decrease in the expression of SPAG17, a cilia component, in SSc skin. We identified genes that correlated with MRSS, DLCO, and FVC in SSc PBMCs and skin using weighted gene co-expression analysis (WGCNA). These genes were largely distinct from the case/control differentially expressed genes. In PBMCs, type 1 interferon signatures negatively correlated with DLCO. In SSc skin, ECM gene expression positively correlated with MRSS. Network analysis of SSc skin genes correlated with clinical features identified the non-coding RNAs SOX9-AS1 and ROCR, both near the SOX9 locus, as highly connected,"hub-like" genes in the network. These results identify non-coding RNAs and SPAG17 as novel factors potentially implicated in SSc pathogenesis.


Author(s):  
Jiao Gao ◽  
Chonghui Li ◽  
Wenjing Li ◽  
Haotian Chen ◽  
Yurong Fu ◽  
...  

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1332-1332
Author(s):  
Wendy Cozen ◽  
Marta Epeldegui ◽  
David V. Conti ◽  
Amie E. Hwang ◽  
Jun Wang ◽  
...  

Abstract Background: We and others have demonstrated persistent differences in T cell function and cytokine responses in adolescent/ young adult Hodgkin lymphoma (AYAHL) survivors and their family members. To identify the transcription control pathways involved, we examined mRNA profiles from 17 pairs of long term AYA HL survivors and their unaffected twins. Methods: Blood samples were collected remotely from AYAHL survivors and their like-sex unaffected co-twin controls and shipped to the Epeldegui laboratory at UCLA. B and T cells were negatively separated using magnetic beads. RNA was extracted and sequenced using a high-efficiency mRNA-targeted assay system (Lexogen QuantSeq 3' FWD), with an average 6.7 million reads per sample mapped to the hg38 human transcriptome (99%) using the STAR aligner. Raw read counts for each gene transcript were normalized to transcripts per million total mapped reads and log2 transformed for analysis using linear statistical models including a random effect of twin pair. Analyses examined average expression of pre-specified sets of 17 genes in general immunologic activation (i.e., AP-1- and NF-kB-family transcripts) and 28 Type I IFN-responsive genes (e.g., IFI-, OAS-, and MX-family), as well as TELiS promoter-based bioinformatics analyses of all genes showing >2-fold empirical differences in gene expression (focusing on activation-induced transcription factors, NF-kB and AP-1, and Type 1 interferon-related IRF transcription factors). Body mass index, history of therapeutic radiation, zygosity, sex, age at diagnosis and age at blood collection were included in the model. Results: The average age at diagnosis was 25 years with blood collected 33 years post-diagnosis. In T-cells, AYAHL survivors showed marginally lower expression of 12 activation-induced genes (average 0.41-fold, p = .038) and markedly lower expression of 28 Type 1 interferon-related genes (average 0.33-fold, p < .001) relative to their unaffected co-twins. B cells showed similar reductions in activation-induced genes (0.33-fold, p < .001) but no difference in Type 1 interferon genes (1.02-fold, p =. 942). Promoter-based bioinformatics analyses of all 151 genes found to be differentially expressed by >2-fold in T cells between AYAHL survivors and their unaffected co-twin controls implicated IRF-family transcription factors in mediating observed differences, with IRF3 showing the most significant signal of decreased activity (0.68-fold, p = .059). We also identified marked up-regulation of multiple GATA family transcription factors (GATA3: p < .001; GATA1: p = .009; GATA2: p = .032). Conclusions: Transcriptional indicators of immunologic activation and Type 1 interferon activity show persistent down-regulation in T lymphocytes from long-term adult AYAHL survivors compared to their unaffected like-sex co-twin controls. Incidental findings also identified persistent activation of other gene regulatory pathways mediating T-cell differentiation (e.g., GATA family). We have previously demonstrated higher Epstein-Barr virus (EBV) copy number in AYAHL long-term survivors compared to their unaffected co-twin controls, as well as lower levels of circulating interleukin-12, consistent with a decrease in the ability to control viral replication. The GATA family plays a major role in commitment to T cell lineage (GATA3) and upregulation of the T-helper-type 2 response, and possibly in control of EBV viral infection (GATA2), processes relevant to AYAHL. These differences further support the premise that abnormalities in T-cells play a strong role in etiology, pathogenesis, and survivorship. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
Author(s):  
Gabrielle Sonigo ◽  
Charles Cassius ◽  
Maxime Battistella ◽  
Hélène Le Buanec ◽  
Martine Bagot ◽  
...  

Author(s):  
John M Magenau ◽  
Daniel C. Peltier ◽  
Mary Riwes ◽  
Attaphol Pawarode ◽  
Brian Parkin ◽  
...  

A potent graft-versus-leukemia (GVL) response is crucial in preventing relapse, the major impediment to successful allogeneic hematopoietic cell transplantation (HCT). In preclinical studies, Type-1 interferon (IFNα) enhanced cross-presentation of leukemia specific antigens by CD8α dendritic cells (DCs) and amplified GVL. This observation was translated into a proof-of-concept phase I/II clinical trial with long-acting IFNα (pegIFNα) in patients undergoing HCT for high-risk acute myeloid leukemia (AML). Patients with treatment resistant AML not in remission or poor risk leukemia were administered four dosages of pegIFNα every 14 days beginning at day -1 before HCT. Dose selection was established by adaptive design that continuously assessed the probability of dose limiting toxicities throughout the trial. Efficacy was evaluated by determining the six-month incidence of relapse at the maximum tolerated dose (MTD). Thirty-six patients (median age of 60 years) received pegIFNα treatment. Grade 3 or greater SAEs occurred in 25% of patients establishing 180mcg as the MTD. In phase II, the incidence of relapse was 39% at six-months, which was sustained through one-year post HCT. The incidence of transplant-related mortality was 13% and severe grade III-IV acute GVHD occurred in 11%. Paired blood samples from donors and recipients after HCT indicated elevated levels of Type-1 IFN with cellular response, persistence of cross-presenting DCs and circulating leukemia antigen specific T cells. These data suggest that prophylactic administration of pegIFNα is feasible in the peri-HCT period. In high-risk AML, increased toxicity was not observed with preliminary evidence for reduction in leukemia relapse after HCT.


Vaccines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 982
Author(s):  
Shakoora A. Sabree ◽  
Caitlin D. Lemke-Miltner ◽  
Sue E. Blackwell ◽  
Chaobo Yin ◽  
Aaron Bossler ◽  
...  

Vidutolimod, also known as CMP-001, is a virus-like particle composed of the Qβ bacteriophage coat protein encasing a TLR9 agonist. Vidutolimod injected intratumorally is showing promise in early phase clinical trials based on its ability to alter the tumor microenvironment and induce an anti-tumor immune response. We previously demonstrated that the in vivo efficacy of vidutolimod is dependent on the presence of anti-Qβ antibodies that enhance opsonization and uptake of vidutolimod by TLR9-expressing plasmacytoid dendritic cells (pDCs). Here, we evaluated the effect of immune complexes, including anti-Qβ-coated vidutolimod, on induction of Type 1 Interferon production by peripheral blood mononuclear cells in response to vidutolimod and soluble TLR9 agonists. Immune complexes, including but not limited to anti-Qβ-coated vidutolimod, indirectly suppressed TLR9-mediated Type 1 Interferon production by pDCs in a monocyte-dependent manner. These findings indicate that anti-Qβ-coated vidutolimod has effects in addition to those mediated by TLR9 that could have important clinical implications for understanding the mechanism of action of this exciting new approach to in situ immunization and cancer immunotherapy.


eJHaem ◽  
2021 ◽  
Author(s):  
Emaan Madany ◽  
June Lee ◽  
Chelsea Halprin ◽  
Jina Seo ◽  
Nicole Baca ◽  
...  

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1227
Author(s):  
Yu-Min Choi ◽  
Hyein Jeong ◽  
Uni Park ◽  
Nam-Hyuk Cho ◽  
Bum-Joon Kim

The current COVID-19 pandemic has highlighted the urgent need to develop effective therapeutic strategies. We evaluated the in vitro antiviral effect against SARS-CoV-2 of a hepatitis B virus (HBV) hexamer peptide, Poly6, which is capable of eliciting an antiviral effect against human immunodeficiency virus -1 (HIV-1), as a novel HIV-1 integrase inhibitor, and a strong anticancer immune response in an IFN-I-dependent manner, as a novel potential adjuvant in anticancer immunotherapy. Here, we report that Poly6 exerts an anti-SARS-CoV-2 effect, with an estimated 50% inhibitory concentration of 2.617 µM, in the human bronchial epithelial cell line, Calu-3 but not in Vero-E6 cells, which are deficient in type 1 interferon (IFN-I) signaling. We proved via assays based on mRNA profiles, inhibitors, or blocking antibodies that Poly6 can exert an anti-SARS-CoV-2 effect in an IFN-I-dependent manner. We also found that Poly6 inhibits IL-6 production enhanced by SARS-CoV-2 in infected Calu-3 cells at both the transcription and the translation levels, mediated via IL-10 induction in an IFN-I-dependent manner. These results indicate the feasibility of Poly6 as an IFN-I-inducing COVID-19 drug with potent antiviral and anti-inflammatory activities.


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