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The Journal of Clinical Endocrinology... Sep 2014Thyroid-associated ophthalmopathy (TAO) is the component of Graves' disease characterized by orbital inflammation and connective tissue remodeling. The IGF-1 receptor...
CONTEXT
Thyroid-associated ophthalmopathy (TAO) is the component of Graves' disease characterized by orbital inflammation and connective tissue remodeling. The IGF-1 receptor (IGF-1R) and TSH receptor (TSHR) form a physical and functional complex in orbital fibroblasts. A subset of these fibroblasts is derived from infiltrating CD34(+) fibrocytes. Teprotumumab (RV 001, R1507) is a human monoclonal anti-IGF-1R blocking antibody currently undergoing a phase 2 clinical trial in patients with active TAO.
OBJECTIVE
To determine whether teprotumumab inhibits the induction by TSH of IL-6 and IL-8 in fibrocytes.
DESIGN
Fibrocytes were treated without or with teprotumumab in combination with IGF-1 or TSH.
MAIN OUTCOME MEASURES
IL-6 and IL-8 mRNA expression and protein production were analyzed by real-time PCR and Luminex, respectively. Phosphorylated Akt (S473) levels were analyzed by Western blot. TSHR and IGF-1R display was assessed by flow cytometry.
RESULTS
Fibrocyte display of IGF-1R and TSHR was reduced with teprotumumab, as were IGF-1- and TSH-dependent phosphorylated Akt levels. TSH induction of IL-6 and IL-8 mRNA and protein was also reduced by the monoclonal antibody.
CONCLUSIONS
Teprotumumab attenuates the actions of both IGF-1 and TSH in fibrocytes. Specifically, it blocks the induction of proinflammatory cytokines by TSH. These results provide, at least in part, the molecular rationale for interrogating the therapeutic efficacy of this antibody in TAO.
Topics: Antibodies, Blocking; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cells, Cultured; Fibroblasts; Graves Disease; Humans; Insulin-Like Growth Factor I; Interleukin-6; Interleukin-8; Protein Modification, Translational; Proto-Oncogene Proteins c-akt; RNA, Messenger; Receptor, IGF Type 1; Thyrotropin
PubMed: 24878056
DOI: 10.1210/jc.2014-1580 -
Stroke Jun 2019Background and Purpose- Our previous studies found that erythrocyte CD47 has a role in regulating hematoma resolution following experimental intracerebral hemorrhage...
Background and Purpose- Our previous studies found that erythrocyte CD47 has a role in regulating hematoma resolution following experimental intracerebral hemorrhage (ICH). The current study examined whether or not a CD47 blocking antibody enhances hematoma clearance in a mouse ICH. Methods- ICH was induced by intracaudate injection of autologous blood in adult C57BL/6 mice. Mice had an ICH or ICH with CD47 blocking antibody or IgG coinjection. In subgroups of CD47 blocking antibody-treated mice, clodronate (to deplete microglia/macrophages) or control liposomes were coinjected. The effects of CD47 blocking antibody on ICH-induced brain injury were also tested in both males and females. Mice had magnetic resonance imaging to examine clot volume, iron deposition, brain swelling, and brain tissue loss. Behavioral tests were performed in all mice, and brains were harvested for brain immunohistochemistry. Results- In male mice, CD47 blocking antibody speeded up hematoma/iron clearance by macrophages/microglia and reduced ICH-induced brain swelling, neuronal loss, and neurological deficits. In contrast, clodronate liposome-induced microglia/macrophage depletion caused more severe brain swelling, neuronal loss, and functional deficits. In addition, similar injury severity in males and females was found in IgG control group and CD47 blocking antibody was also effective in females. Conclusions- Blocking CD47 in the hematoma speeded hematoma clearance and reduced brain injury after ICH suggesting it could be a treatment for ICH patients with surgical clot removal.
Topics: Animals; Antibodies, Blocking; Brain; Brain Edema; CD47 Antigen; Cerebral Hemorrhage; Disease Models, Animal; Female; Hematoma; Magnetic Resonance Imaging; Male; Mice
PubMed: 31084334
DOI: 10.1161/STROKEAHA.118.024578 -
Clinical and Experimental Immunology Apr 2003Gene delivery has the potential to offer effective treatment to patients with life-threatening lung diseases such as cystic fibrosis, alpha1-antitrypsin deficiency and... (Review)
Review
Gene delivery has the potential to offer effective treatment to patients with life-threatening lung diseases such as cystic fibrosis, alpha1-antitrypsin deficiency and lung cancer. Phase I/II clinical trials have shown that, in principle, gene transfer to the lung is feasible and safe. However, gene expression from both viral and non-viral gene delivery systems has been inefficient. In addition to extra- and intracellular barriers, the host innate and acquired immune system represents a major barrier to successful gene transfer to the lung. Results from studies in experimental animals and clinical trials have shown that inflammatory, antibody and T cell responses can limit transgene expression duration and readministration of the gene transfer vector. We will review here how the development of pharmacological and/or immunological agents can modulate the host immune system and the limitations of these strategies. A better understanding of the immunological barriers which exist in the lung might allow for a more sustained expression of the transgene and importantly help overcome the problem of readministration of viral vectors.
Topics: Antibodies, Blocking; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Gene Expression; Genetic Therapy; Genetic Vectors; Humans; Immunosuppressive Agents; Inflammation; Lung; Lung Diseases; Macrophages; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper-Inducer; Treatment Failure
PubMed: 12653829
DOI: 10.1046/j.1365-2249.2003.02124.x -
Journal of Thrombosis and Haemostasis :... May 2018Acquired FXIII deficiencies caused by autoantibodies against FXIII subunits represent rare but very severe bleeding diatheses. Alloantibodies in FXIII-deficient patients... (Review)
Review
Acquired FXIII deficiencies caused by autoantibodies against FXIII subunits represent rare but very severe bleeding diatheses. Alloantibodies in FXIII-deficient patients also cause life-threatening bleeding complications, but they develop extremely rarely. In this review we provide an overview of the diagnosis and classification of anti-FXIII antibodies and analyze 48 patients with autoimmune FXIII deficiency and four additional FXIII-deficient patients who developed anti-FXIII alloantibody. The patients were collected from peer-reviewed publications from which relevant data could be extracted. With the exception of two cases the antibodies were directed against FXIII-A. The difficulties in the diagnosis of FXIII deficiency in the presence of anti-FXIII antibodies are discussed and a scheme for the functional classification of the anti-FXIII antibodies is recommended. The three main categories are neutralizing and non-neutralizing antibodies and antibodies with combined effect. The methods being used for detecting and quantifying the inhibitory effect on FXIII activation and on the transglutaminase activity of activated FXIII are summarized and techniques for the classification of neutralizing anti-FXIII antibodies are outlined. The importance of clearance studies in these cases is emphasized. Binding assays, useful for the identification of non-neutralizing and combined type antibodies, were collected from the literature and their informative power is demonstrated by examples. The most frequently occurring bleeding symptoms in patients with anti-FXIII antibodies were soft tissue bleeding; intracranial bleedings also occurred, but less frequently than in inherited FXIII deficiency. Treatment of such patients is extremely challenging; the main aim should be eradication of the antibody.
Topics: Animals; Antibodies, Blocking; Antibodies, Neutralizing; Autoantibodies; Factor VIII; Hemophilia A; Hemorrhage; Hemostasis; Humans; Isoantibodies; Predictive Value of Tests; Prognosis; Risk Factors; Severity of Illness Index
PubMed: 29460500
DOI: 10.1111/jth.13982 -
Journal of Virology Jul 2017The emergence of pandemic GII.4 norovirus (NoV) strains has been proposed to occur due to changes in receptor usage and thereby to lead to immune evasion. To address...
The emergence of pandemic GII.4 norovirus (NoV) strains has been proposed to occur due to changes in receptor usage and thereby to lead to immune evasion. To address this hypothesis, we measured the ability of human sera collected between 1979 and 2010 to block glycan binding of four pandemic GII.4 noroviruses isolated in the last 4 decades. In total, 268 sera were investigated for 50% blocking titer (BT) values of virus-like particles (VLPs) against pig gastric mucin (PGM) using 4 VLPs that represent different GII.4 norovirus variants identified between 1987 and 2012. Pre- and postpandemic sera (sera collected before and after isolation of the reference NoV strain) efficiently prevented binding of VLP strains MD145 (1987), Grimsby (1995), and Houston (2002), but not the Sydney (2012) strain, to PGM. No statistically significant difference in virus-blocking titers was observed between pre- and postpandemic sera. Moreover, paired sera showed that blocking titers of ≥160 were maintained over a 6-year period against MD145, Grimsby, and Houston VLPs. Significantly higher serum blocking titers (geometric mean titer [GMT], 1,704) were found among IgA-deficient individuals than among healthy blood donors (GMT, 90.9) ( < 0.0001). The observation that prepandemic sera possess robust blocking capacity for viruses identified decades later suggests a common attachment factor, at least until 2002. Our results indicate that serum IgG possesses antibody-blocking capacity and that blocking titers can be maintained for at least 6 years against 3 decades of pandemic GII.4 NoV. Human noroviruses (NoVs) are the major cause of acute gastroenteritis worldwide. Histo-blood group antigens (HBGAs) in saliva and gut recognize NoV and are the proposed ligands that facilitate infection. Polymorphisms in HBGA genes, and in particular a nonsense mutation in (G428A), result in resistance to global dominating GII.4 NoV. The emergence of new pandemic GII.4 strains occurs at intervals of several years and is proposed to be attributable to epochal evolution, including amino acid changes and immune evasion. However, it remains unclear whether exposure to a previous pandemic strain stimulates immunity to a pandemic strain identified decades later. We found that prepandemic sera possess robust virus-blocking capacity against viruses identified several decades later. We also show that serum lacking IgA antibodies is sufficient to block NoV VLP binding to HBGAs. This is essential, considering that 1 in every 600 Caucasian children is IgA deficient.
Topics: Adult; Aged; Antibodies, Blocking; Caliciviridae Infections; Genotype; Humans; Middle Aged; Mucins; Norovirus; Virus Attachment
PubMed: 28468886
DOI: 10.1128/JVI.00567-17 -
PloS One 2022The kinetics and magnitude of antibody responses to different proteins of the SARS-CoV-2 virus in Sinopharm/BBIBP-CorV vaccinees has not been previously studied.... (Comparative Study)
Comparative Study
Comparison of the kinetics and magnitude of antibody responses to different SARS-CoV-2 proteins in Sinopharm/BBIBP-CorV vaccinees following the BNT162b2 booster or natural infection.
The kinetics and magnitude of antibody responses to different proteins of the SARS-CoV-2 virus in Sinopharm/BBIBP-CorV vaccinees has not been previously studied. Therefore, we investigated antibody responses to different SARS-CoV-2 proteins at 2 weeks, 3 months, and 6 months post-second dose in previously infected (n = 20) and uninfected (n = 20) Sinopharm/BBIBP-CorV vaccinees. The IgG antibodies to the S, S1 and S2 and N were several folds higher in those who had natural infection compared to uninfected individuals at all time points. We then compared the persistence of antibody responses and effect of natural omicron infection or BNT162b2 booster in Sinopharm/BBIBP-CorV vaccinees. We measured the total antibodies to the RBD, ACE2 blocking antibodies and antibody responses to different SARS-CoV-2 proteins in Sinopharm vaccinees at 7 months post second dose, including those who remained uninfected and not boosted (n = 21), or those who had previous infection and who did not obtain the booster (n = 17), those who were not infected, but who received a BNT162b2 booster (n = 30), or those who did not receive the booster but were infected with omicron (n = 29). At 7 months post second dose uninfected (no booster) had the lowest antibody levels to the RBD, while omicron infected vaccinees showed significantly higher anti-RBD antibody levels (p = 0.04) than vaccinees who received the booster. Only 3/21 cohort A (14.3%) had ACE2 blocking antibodies, while higher frequencies were observed in naturally infected individuals (100%), those who received the booster (18/21, 85.7%), and omicron infected individuals (100%). Pre-vaccination, naturally infected had the highest antibody levels to the N protein. These data suggest that those previously infected Sinopharm/BBIBP-CorV vaccinees have a robust antibody response, 7 months post vaccination, while vaccinees who were naturally infected with omicron had a similar immune response to those who received the booster. It will be important to investigate implications for subsequent clinical protection.
Topics: Angiotensin-Converting Enzyme 2; Antibodies, Blocking; Antibodies, Viral; Antibody Formation; BNT162 Vaccine; COVID-19; Humans; Immunoglobulin G; SARS-CoV-2
PubMed: 36227884
DOI: 10.1371/journal.pone.0274845 -
Scientific Reports Jun 2017Vaccine development efforts have recently focused on enabling strong immune responses to poorly immunogenic antigens, via display on multimerisation scaffolds or virus...
Vaccine development efforts have recently focused on enabling strong immune responses to poorly immunogenic antigens, via display on multimerisation scaffolds or virus like particles (VLPs). Typically such studies demonstrate improved antibody titer comparing monomeric and nano-arrayed antigen. There are many such studies and scaffold technologies, but minimal side-by-side evaluation of platforms for both the amount and efficacy of antibodies induced. Here we present direct comparison of three leading platforms displaying the promising malaria transmission-blocking vaccine (TBV) target Pfs25. These platforms encompass the three important routes to antigen-scaffold linkage: genetic fusion, chemical cross-linking and plug-and-display SpyTag/SpyCatcher conjugation. We demonstrate that chemically-conjugated Qβ VLPs elicited the highest quantity of antibodies, while SpyCatcher-AP205-VLPs elicited the highest quality anti-Pfs25 antibodies for transmission blocking upon mosquito feeding. These quantative and qualitative features will guide future nanoassembly optimisation, as well as the development of the new generation of malaria vaccines targeting transmission.
Topics: Animals; Antibodies, Blocking; Antibodies, Protozoan; Female; Malaria Vaccines; Mice; Mice, Inbred BALB C; Nanoparticles; Protozoan Proteins; Vaccines, Virus-Like Particle
PubMed: 28630474
DOI: 10.1038/s41598-017-03798-3 -
BMC Biology Mar 2020Immune checkpoint inhibitor (ICPI) can augment the anti-tumour response by blocking negative immunoregulators with monoclonal antibodies. The anti-cytotoxic T...
BACKGROUND
Immune checkpoint inhibitor (ICPI) can augment the anti-tumour response by blocking negative immunoregulators with monoclonal antibodies. The anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibody is the first ICPI which has shown remarkable benefits in the clinical treatment of cancers. However, the increased activity of the immune system also causes some side effects called immune-related adverse events (irAEs). Colitis is one of the most common irAEs related to anti-CTLA-4 immunotherapy.
RESULTS
We identified that CD4 T cells were the primary responders in CTLA-4 blockade and that the expansion of gut-homing CD4 T cells by anti-CTLA-4 therapy was independent of CD103. We used dextran sulfate sodium (DSS)-induced colitis mice as our model and tested the possibility of using a trafficking-blocking antibody to treat anti-CTLA-4 antibody-induced irAEs. We found that blocking T cell homing increased colitis severity in the context of CTLA-4 blockade and that gut-trafficking blockade had different effects on different Th subsets and could facilitate the proliferation of Th17 cells in the lamina propria (LP).
CONCLUSIONS
Our data reveals the fundamental mechanism underlying trafficking-blocking antibody therapy for CTLA-4 blockade-induced colitis and provide a caution in regard to apply trafficking-blocking antibody treatment under CTLA-4 blockade condition.
Topics: Animals; Antibodies, Blocking; CTLA-4 Antigen; Colitis; Dextran Sulfate; Female; Mice; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes
PubMed: 32183814
DOI: 10.1186/s12915-020-00765-9 -
The Journal of Allergy and Clinical... Apr 2023Although previous studies described the production of IgG antibodies in a subgroup of patients with common variable immunodeficiency (CVID) following messenger RNA...
BACKGROUND
Although previous studies described the production of IgG antibodies in a subgroup of patients with common variable immunodeficiency (CVID) following messenger RNA vaccinations with BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (CVID responders), the functionality of these antibodies in terms of avidity as measured by the dissociation rate constant (k) and the antibody response to booster immunization has not been studied.
OBJECTIVE
We sought to analyze in CVID responders and healthy individuals, the avidity of anti-SARS-CoV-2 serum antibodies and their neutralization capacity as measured by surrogate virus-neutralizing antibodies in addition to IgG-, IgM-, and IgA-antibody levels and the response of circulating (peripheral blood) follicular T-helper cells after a third vaccination with BNT162b2 SARS-CoV-2 messenger RNA vaccine.
METHODS
Binding IgG, IgA, and IgM serum levels were analyzed by ELISA in patients with CVID responding to the primary vaccination (CVID responders, n = 10) and healthy controls (n = 41). The binding avidity of anti-spike antibodies was investigated using biolayer interferometry in combination with biotin-labeled receptor-binding-domain of SARS-CoV-2 spike protein and streptavidin-labeled sensors. Antigen-specific recall T-cell responses were assessed by measuring activation-induced markers by flow cytometry.
RESULTS
After the third vaccination with BNT162b2, IgG-, IgM-, and IgA-antibody levels, surrogate virus-neutralizing antibody levels, and antibody avidity were lower in CVID responders than in healthy controls. In contrast, anti-SARS-CoV-2 spike protein avidity was comparable in CVID responders and healthy individuals following primary vaccination. Follicular T-helper cell response to booster vaccination in CVID responders was significantly reduced when compared with that in healthy individuals.
CONCLUSIONS
Impaired affinity maturation during booster response provides new insight into CVID pathophysiology.
Topics: Humans; BNT162 Vaccine; Common Variable Immunodeficiency; Antibody Formation; COVID-19; SARS-CoV-2; Spike Glycoprotein, Coronavirus; COVID-19 Vaccines; Antibodies, Blocking; Antibodies, Viral; Immunoglobulin A; Immunoglobulin M
PubMed: 36463978
DOI: 10.1016/j.jaci.2022.11.013 -
Cell Reports Aug 2021Cancer immunotherapies often modulate macrophage effector function by introducing either targeting antibodies that activate Fcγ receptors (FcγRs) or blocking...
Cancer immunotherapies often modulate macrophage effector function by introducing either targeting antibodies that activate Fcγ receptors (FcγRs) or blocking antibodies that disrupt inhibitory SIRPα-CD47 engagement. However, how these competing signals are integrated is poorly understood, raising questions about how to effectively titrate immune responses. Here, we find that macrophage phagocytic decisions are regulated by the ratio of activating ligand to inhibitory ligand over a broad range of absolute molecular densities. Using both endogenous and chimeric receptors, we show that activating:inhibitory ligand ratios of at least 10:1 are required to promote phagocytosis of model antibody-opsonized CD47-inhibited targets and that lowering that ratio reduces FcγR phosphorylation because of inhibitory phosphatases recruited to CD47-bound SIRPα. We demonstrate that ratiometric signaling is critical for phagocytosis of tumor cells and can be modified by blocking SIRPα, indicating that balancing targeting and blocking antibodies may be important for controlling macrophage phagocytosis in cancer immunotherapy.
Topics: Animals; Antibodies; Antibodies, Blocking; CD47 Antigen; Carrier Proteins; Neoplasms; Phagocytosis; Phosphorylation; Receptors, IgG
PubMed: 34433055
DOI: 10.1016/j.celrep.2021.109587