scholarly journals Immune Complex Formation Is Associated With Loss of Tolerance and an Antibody Response to Both Drug and Target

2021 ◽  
Vol 12 ◽  
Author(s):  
Mark A. Kroenke ◽  
Troy E. Barger ◽  
Jenny Hu ◽  
Mieke Jill Miller ◽  
Kevin Kalenian ◽  
...  
Keyword(s):  
T Cell ◽  
Antibody Response ◽  
Immune Complexes ◽  
T Cell Epitopes ◽  
Necrosis Factor Alpha ◽  
Cell Assays ◽  
Factor Alpha ◽  
Loss Of Tolerance ◽  
Necrosis Factor

AMG 966 is a bi-specific, heteroimmunoglobulin molecule that binds both tumor necrosis factor alpha (TNFα) and TNF-like ligand 1A (TL1A). In a first-in-human clinical study in healthy volunteers, AMG 966 elicited anti-drug antibodies (ADA) in 53 of 54 subjects (98.1%), despite a paucity of T cell epitopes observed in T cell assays. ADA were neutralizing and bound to all domains of AMG 966. Development of ADA correlated with loss of exposure. In vitro studies demonstrated that at certain drug-to-target ratios, AMG 966 forms large immune complexes with TNFα and TL1A, partially restoring the ability of the aglycosylated Fc domain to bind FcγRIa and FcγRIIa, leading to the formation of ADA. In addition to ADA against AMG 966, antibodies to endogenous TNFα were also detected in the sera of subjects dosed with AMG 966. This suggests that the formation of immune complexes between a therapeutic and target can cause loss of tolerance and elicit an antibody response against the target.

scholarly journals HLA-B*35-Restricted CD8+-T-Cell Epitope in Mycobacterium tuberculosis Rv2903c

2002 ◽  
Vol 70 (2) ◽  
pp. 981-984 ◽  
Author(s):  
Michèl R. Klein ◽  
Abdulrahman S. Hammond ◽  
Steve M. Smith ◽  
Assan Jaye ◽  
Pauline T. Lukey ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Epitope ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Mycobacterial Antigens ◽  
Necrosis Factor

ABSTRACT Few human CD8+ T-cell epitopes in mycobacterial antigens have been described to date. Here we have identified a novel HLA-B*35-restricted CD8+ T-cell epitope in Mycobacterium tuberculosis Rv2903c based on a reverse immunogenetics approach. Peptide-specific CD8 T cells were able to kill M. tuberculosis-infected macrophages and produce gamma interferon and tumor necrosis factor alpha.

Tumour necrosis factor alpha blockade impairs dendritic cell survival and function in rheumatoid arthritis

2009 ◽  
Vol 69 (6) ◽  
pp. 1200-1207 ◽  
Author(s):  
Helen M Baldwin ◽  
Toshiko Ito-Ihara ◽  
John D Isaacs ◽  
Catharien M U Hilkens
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Dendritic Cell ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Tumour Necrosis Factor Alpha ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor

ObjectivesTumour necrosis factor alpha (TNFα) blockade is an effective therapy for rheumatoid arthritis (RA). The immunomodulatory effects of TNFα antagonists are thought to contribute to their therapeutic action. This study investigated whether anti-TNFα therapeutics exerted their immunoregulatory effects through modulation of dendritic cell (DC) function.MethodsTwo complementary approaches were taken: in the first ‘in vitro’ approach monocyte-derived DC from healthy donors were matured with lipopolysaccharide and treated with TNFα antagonists in vitro for 48 h. In the second ‘ex vivo’ approach monocyte-derived DC were generated from RA patients before and 8–12 weeks into anti-TNFα treatment. DC were analysed for survival, phenotype, cytokine production and T-cell stimulatory capacity.ResultsTNFα blockade during DC maturation in vitro induced approximately 40% of DC to undergo apoptosis. Importantly, the surviving DC displayed a semimature phenotype with reduced levels of HLA-DR, CD80, CD83, CD86 and CCR7, and their production of IL-10 was enhanced compared with DC matured without TNFα antagonists. Furthermore, anti-TNFα-treated DC were poor stimulators of T-cell proliferation and polarised T-cell development towards a higher IL-10/lower IFNγ cytokine profile. Similarly, DC derived from RA patients after anti-TNFα treatment showed impaired upregulation of CD80 and CD86 upon lipopolysaccharide activation and displayed poor T-cell stimulatory activity.ConclusionsThe data show that TNFα blockade has profound effects on DC function with downstream, potentially immunoregulatory, effects on T cells. These data provide an interesting new insight into the potential mechanism by which anti-TNFα drugs contribute to the restoration of immunoregulation in RA patients.

scholarly journals Suppression of tumor necrosis factor-alpha-induced neutrophil adherence responses by essential oils

2003 ◽  
Vol 12 (6) ◽  
pp. 323-328 ◽  
Author(s):  
Shigeru Abe ◽  
Naho Maruyama ◽  
Kazumi Hayama ◽  
Hiroko Ishibashi ◽  
Shigeharu Inoue ◽  
...  
Keyword(s):  
Essential Oils ◽  
Tumor Necrosis ◽  
Neutrophil Activation ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Neutrophil Adherence ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor

Background:In aromatherapy, essential oils are used as anti-inflammatory remedies, but experimental studies on their action mechanisms are very limited.Aims:To assess their anti-inflammatory activities, effects of essential oils on neutrophil activation were examinedin vitro.Methods:Neutrophil activation was measured by tumor necrosis factor-alpha (TNF-α)-induced adherence reaction of human peripheral neutrophils.Results:All essential oils tested at 0.1% concentration suppressed TNF-α-induced neutrophil adherence, and, in particular, lemongrass, geranium and spearmint oils clearly lowered the reaction even at 0.0125%. Similar inhibitory activities for the neutrophil adherence were obtained by their major constituent terpenoids: citral, geraniol, citronellol and carvone. In contrast, very popular essential oils, tea tree oil and lavender oil, did not display the inhibitory activity at the concentration.Conclusion:Thus, some essential oils used as anti-inflammatory remedies suppress neutrophil activation by TNF-α at a low concentration (0.0125-0.025%)in vitro.

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