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1.
Cell Rep ; 39(13): 110989, 2022 06 28.
Article in English | MEDLINE | ID: covidwho-1906847

ABSTRACT

The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon ß (IFNß) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNß as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNß-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNß in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection.


Subject(s)
Interferon-beta , Interleukin-12 , Toll-Like Receptor 4 , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Cytokines/immunology , Cytokines/metabolism , Humans , Interferon-beta/immunology , Interferon-beta/metabolism , Interleukin-12/immunology , Interleukin-12/metabolism , Lipopolysaccharides/pharmacology , Proteomics , SARS-CoV-2/immunology
2.
Expert Opin Drug Saf ; 21(1): 1-8, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1735444

ABSTRACT

INTRODUCTION: Ustekinumab is a human IgG1 kappa monoclonal antibody that targets the p40 subunit of interleukin (IL)-12 and IL-23 and blocks the binding of these cytokines to the IL-12Rß1 chain of their receptors. Ustekinumab is approved for treating moderate-to-severe ulcerative colitis (UC). AREAS COVERED: We reviewed the mechanism of action, pharmacokinetics, efficacy, and safety of ustekinumab. Future challenges for optimizing UC treatment with ustekinumab are discussed. EXPERT OPINION: Ustekinumab has favorable clinical efficacy and safety profiles for moderately-to-severely active UC. Ustekinumab is the first biologic for targeting IL-12/IL-23 pathways. Therefore, ustekinumab can be a therapeutic option following the failure of other biologics, including anti-tumor necrosis factor-α antagonists and anti-α4ß7 integrin antagonists. However, the positioning of ustekinumab in the therapeutic strategy for UC remains unclear. The efficacy of combinations of ustekinumab and immunomodulators over ustekinumab monotherapy has not been supported in studies. Ustekinumab is a human immunoglobulin G monoclonal antibody with low immunogenicity. Therefore, ustekinumab monotherapy, which should be safe, could be sufficient for treating UC. Further studies are required to understand the efficacy and safety of ustekinumab in patients with UC, particularly in special situations, and to optimize UC treatment with ustekinumab.


Subject(s)
Colitis, Ulcerative/drug therapy , Immunologic Factors/administration & dosage , Ustekinumab/administration & dosage , Animals , Colitis, Ulcerative/immunology , Colitis, Ulcerative/physiopathology , Humans , Immunologic Factors/adverse effects , Interleukin-12/immunology , Interleukin-23/immunology , Severity of Illness Index , Ustekinumab/adverse effects
3.
J Infect Dis ; 223(7): 1145-1149, 2021 04 08.
Article in English | MEDLINE | ID: covidwho-1174909

ABSTRACT

Most patients with coronavirus disease 2019 (COVID-19) experience asymptomatic disease or mild symptoms, but some have critical symptoms requiring intensive care. It is important to determine how patients with asymptomatic or mild COVID-19 react to severe acute respiratory syndrome coronavirus 2 infection and suppress virus spread. Innate immunity is important for evasion from the first virus attack, and it may play an important role in the pathogenesis in these patients. We measured serum cytokine levels in 95 patients with COVID-19 during the infection's acute phase and report that significantly higher interleukin 12 and 2 levels were induced in patients with asymptomatic or mild disease than in those with moderate or severe disease, indicating the key roles of these cytokines in the pathogenesis of asymptomatic or mild COVID-19.


Subject(s)
COVID-19/immunology , Immunity, Innate , Interleukin-12/blood , Interleukin-2/blood , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Asymptomatic Infections , COVID-19/blood , COVID-19/diagnosis , COVID-19/virology , COVID-19 Nucleic Acid Testing , Case-Control Studies , Female , Healthy Volunteers , Humans , Interleukin-12/immunology , Interleukin-2/immunology , Male , Middle Aged , RNA, Viral/isolation & purification , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Severity of Illness Index , Young Adult
4.
BMJ Case Rep ; 14(3)2021 Mar 22.
Article in English | MEDLINE | ID: covidwho-1146828

ABSTRACT

Active inflammatory bowel disease (IBD), combined immunosuppression and corticosteroid therapy have all been identified as risk factors for a poor outcome in COVID-19 infection. The management of patients with both COVID-19 infection and active IBD is therefore complex. We present the case of a 31-year-old patient with Crohn's disease, on dual immunosuppression with infliximab and mercaptopurine presenting with inflammatory small bowel obstruction and COVID-19 infection. The case highlights the use of nutritional therapy, which remains underused in the management of adults with IBD, to manage his flare acutely. Following negative SARS-CoV-2 PCR testing and SARS-CoV-2 IgG testing confirming an antibody response, ustekinumab (anti-interleukin 12/23) was prescribed for long-term maintenance.


Subject(s)
COVID-19/complications , Crohn Disease/immunology , Crohn Disease/therapy , Enteral Nutrition , Immunocompromised Host , Adult , Crohn Disease/complications , Crohn Disease/diagnostic imaging , Humans , Immunosuppressive Agents/therapeutic use , Interleukin-12/immunology , Interleukin-23/immunology , Male , SARS-CoV-2 , Tomography, X-Ray Computed , Treatment Outcome , Ustekinumab/therapeutic use
5.
Eur Rev Med Pharmacol Sci ; 24(23): 12536-12544, 2020 12.
Article in English | MEDLINE | ID: covidwho-995014

ABSTRACT

OBJECTIVE: We aimed to study the dynamics of cytokines and lymphocyte subsets and their correlation with the prognosis of patients with severe COVID-19. PATIENTS AND METHODS: The lymphocyte subsets and cytokines of 31 patients with severe COVID-19 (7 deaths and 24 survivals) were longitudinally analyzed. RESULTS: The mean age of enrolled patients was 64 years, 24 (77.4%) patients were men, and 23 (74.2%) patients had comorbidities. Compared with survival group, the death group showed significant and sustained increases in the levels of IL-6, IL-8, and IL-10 from baseline to 28 days after admission (all p<0.05). No significant differences were observed in the levels of TNF-α, IL-1b, IL-2, IL-4, IL-5, IL-12P70, IL-17, IFN-α, and IFN-γ between the death group and survival group during the follow-up (all p>0.05). The absolute counts of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD45+ T cells were lower in both survival group and death group patients from hospital admission to 3 days after admission, and gradually recovered in 4 to 35 days in the survival group, but continually stayed at low levels in the death group during the follow-up. CONCLUSIONS: The kinetic changes of cytokines and lymphocyte subsets are related with the prognosis of patients with severe COVID-19.


Subject(s)
COVID-19/immunology , Cytokines/immunology , T-Lymphocyte Subsets/immunology , Aged , Aged, 80 and over , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/blood , COVID-19/mortality , COVID-19/therapy , Female , Humans , Interferon-alpha/immunology , Interleukin-10/immunology , Interleukin-12/immunology , Interleukin-17/immunology , Interleukin-1beta/immunology , Interleukin-2/immunology , Interleukin-4/immunology , Interleukin-5/immunology , Interleukin-6/immunology , Interleukin-8/immunology , Leukocyte Common Antigens/immunology , Longitudinal Studies , Lymphocyte Count , Male , Middle Aged , Prognosis , SARS-CoV-2 , Severity of Illness Index , Tumor Necrosis Factor-alpha/immunology
6.
J Allergy Clin Immunol Pract ; 8(6): 1798-1801, 2020 06.
Article in English | MEDLINE | ID: covidwho-72194
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