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1.
Nat Commun ; 13(1): 1379, 2022 03 16.
Article in English | MEDLINE | ID: mdl-35296643

ABSTRACT

Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 - 27.5] vs 47.6 days [45.5 - 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 - 36.8] vs 58.0 days [55.0 - 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.


Subject(s)
COVID-19 , Inflammatory Bowel Diseases , Viral Vaccines , Antibodies, Monoclonal, Humanized/therapeutic use , BNT162 Vaccine , COVID-19 Vaccines , ChAdOx1 nCoV-19 , Humans , Inflammatory Bowel Diseases/drug therapy , Infliximab/therapeutic use , SARS-CoV-2 , T-Lymphocytes , Tumor Necrosis Factor Inhibitors
2.
J Immunol ; 186(1): 305-11, 2011 Jan 01.
Article in English | MEDLINE | ID: mdl-21106846

ABSTRACT

Aqueous humor (AqH) has been shown to have significant immunosuppressive effects on APCs in animal models. We wanted to establish whether, in humans, AqH can regulate dendritic cell (DC) function and to identify the dominant mechanism involved. Human AqH inhibited the capacity of human peripheral blood monocyte-derived DC to induce naive CD4(+) T cell proliferation and cytokine production in vitro, associated with a reduction in DC expression of the costimulatory molecule CD86. This was seen both for DC cultured under noninflammatory conditions (immature DC) and for DC stimulated by proinflammatory cytokines (mature DC). DC expression of MHC classes I/II and CD83 was reduced (mature DC only). Myeloid DC from peripheral blood were similarly sensitive to the effects of human AqH, but only under inflammatory conditions. The addition of α-melanocyte stimulating hormone and vasoactive intestinal peptide did not cause significant inhibition at physiological levels. However, the addition of exogenous cortisol at physiological levels recapitulated the AqH-induced reduction in CD86 and inhibition of DC-induced T cell proliferation, and blockade of cortisol in AqH partially reversed its suppressive effects. TGF-ß2 had an additional effect with cortisol, and although simultaneous blockade of cortisol and TGF-ß2 in AqH reduced its effectiveness, there was still a cortisol- and TGF-ß-independent component. In humans, AqH regulates DC maturation and function by the combined actions of cortisol and TGF-ß2, a pathway that is likely to contribute to the maintenance of immune privilege in the eye.


Subject(s)
Aqueous Humor/immunology , Dendritic Cells/immunology , Eye/immunology , Hydrocortisone/physiology , Immune Tolerance , Transforming Growth Factor beta2/physiology , Antigen Presentation/immunology , Aqueous Humor/metabolism , Cells, Cultured , Coculture Techniques , Dendritic Cells/cytology , Dendritic Cells/metabolism , Eye/metabolism , HLA Antigens/biosynthesis , Histocompatibility Antigens Class I/biosynthesis , Histocompatibility Antigens Class II/biosynthesis , Humans , Hydrocortisone/antagonists & inhibitors , Lymphocyte Activation/immunology , Signal Transduction/immunology , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Transforming Growth Factor beta2/antagonists & inhibitors
3.
Genes Chromosomes Cancer ; 48(11): 983-92, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19681120

ABSTRACT

Cervical cancer (CC) is the second most common cancer in women. Currently, no tractable molecular-based therapeutic targets exist for patients with invasive CC and no predictive markers of risk assessment for progression of precancerous lesions are identified. New molecular insights into CC pathogenesis are urgently needed. Towards this goal, we first determined the copy number alterations of chromosome 4 and then examined the role of PCDH10 mapped to 4q28 as a candidate tumor suppressor gene. We identified monosomy 4 in 47% of 81 invasive CC studied by SNP array and found that 91% of 130 invasive CC harboring methylation in the promoter region of the PCDH10 gene. We then showed that aberrant promoter hypermethylation of PCDH10 is associated with downregulation of gene expression and cell lines exposed to demethylating agent resulted in profound reactivated gene expression. We also showed that the promoter methylation in the PCDH10 gene occurs at an earliest identifiable stage of low-grade squamous intraepithelial lesion. Our studies demonstrate that inactivation of PCDH10 may be a critical event in CC progression and form a potentially useful therapeutic target for CC.


Subject(s)
Cadherins/genetics , DNA Methylation , Uterine Cervical Neoplasms/genetics , Cadherins/metabolism , Cell Line, Tumor , Chromosomes, Human, Pair 4 , DNA Copy Number Variations , DNA Mutational Analysis , Disease Progression , Epigenesis, Genetic , Female , Gene Dosage , Gene Expression , Humans , Monosomy , Oligonucleotide Array Sequence Analysis , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Protocadherins , Uterine Cervical Neoplasms/metabolism
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