Suppression of Fcγ-Receptor-Mediated Antibody Effector Function during Persistent Viral Infection

Yamada, Douglas H.; Elsaesser, Heidi; Lux, Anja; Timmerman, John M.; Morrison, Sherie L.; Torre, Juan Carlos de la; Nimmerjahn, Falk; Brooks, David G.

doi:10.1016/j.immuni.2015.01.005

Cited by 59 publications

(73 citation statements)

References 50 publications

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“…A similar effect on viral replication in tissues was also observed (Fig 1C). Development of neutralizing antibody titers are delayed after cl13 infection, non-neutralizing antibodies may be important(9, 13, 14) (data not shown) defective FcR function impairs viral control during cl13 infection(15, 16). Thus, non-neutralizing functions of T-bet dependent antibody or B cell responses may play a role in chronic LCMV infection.…”

Section: Resultsmentioning

confidence: 98%

Cutting Edge: B Cell–Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection

Barnett

Staupe

Odorizzi

et al. 2016

The Journal of Immunology

155

177

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The role of antibody and B cells in preventing infection is established. In contrast, the role of B cell responses in containing chronic infections remains poorly understood. IgG2a (IgG1 in humans) can prevent acute infections and T-bet promotes IgG2a isotype switching. However, whether IgG2a and B cell-expressed T-bet influence the host-pathogen balance during persisting infections is unclear. Here we demonstrate that B cell specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells not only controlled IgG2a production, but also mucosal localization, proliferation, glycosylation, and a broad transcriptional program. T-bet controlled a broad antiviral program in addition to IgG2a since T-bet in B cells was important even in the presence of virus-specific IgG2a. Our data supports a model in which T-bet is a universal controller of antiviral immunity across multiple immune lineages.

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Section: Resultsmentioning

confidence: 98%

Cutting Edge: B Cell–Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection

Barnett

Staupe

Odorizzi

et al. 2016

The Journal of Immunology

155

177

View full text Add to dashboard Cite

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“…Opsonization of antigen can also lead to increases in DC migration from peripheral tissues to the draining lymph nodes (41). Alternatively, Ab may neutralize peptide, or excess IC can interfere with antigen uptake and presentation (42). However, in light of the positive association with clinical outcome, we hypothesize that in this setting the Abs are supporting antitumor immunity.…”

Section: Discussionmentioning

confidence: 99%

Vaccination with Melanoma Helper Peptides Induces Antibody Responses Associated with Improved Overall Survival

Reed¹,

Cresce²,

Mauldin³

et al. 2015

Clin Cancer Res

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Purpose A melanoma vaccine incorporating six peptides designed to induce helper T cell responses to melanoma antigens has induced Th1-dominant CD4+ T cell responses in most patients, and induced durable clinical responses or stable disease in 24% of evaluable patients. The present study tested whether this vaccine also induced antibody (Ab) responses to each peptide, and whether Ab responses were associated with T cell responses and with clinical outcome. Patients and Methods Serum samples were studied from 35 patients with stage III–IV melanomas vaccinated with 6 melanoma helper peptides (6MHP). IgG Ab responses were measured by ELISA. Associations with immune response and overall survival were assessed by log-rank test and Chi square analysis of Kaplan-Meier data. Results Ab responses to 6MHP were detected by week 7 in 77% of patients, and increased to peak 6 weeks after the last vaccine and persisted to 6 months. Ab responses were induced most frequently to longer peptides. Of those with T cell responses, 82% had early Ab responses. Survival was improved for patients with early Ab response (p = 0.0011) or with early T cell response (p < 0.006), and was best for those with both Ab and T cell responses (p = 0.0002). Conclusion Vaccination with helper peptides induced both Ab responses and T cell responses, associated with favorable clinical outcome. Such immune responses may predict favorable clinical outcome to guide combination immunotherapy. Further studies are warranted to understand mechanisms of interaction of these Abs, T cell responses, and tumor control.

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“…Although the mechanisms by which GB4542 mediated enhanced B cell killing at lower concentrations are readily understandable, the means by which it induced FcgR-dependent inhibition at higher concentrations are less clear and are likely pleiotropic. Several recent studies demonstrate that soluble immune complexes (ICs) effectively mitigate defined types of autoimmunity in mice (18) and that high amounts of IC formation during persistent viral infection interfere with Ab effector functions by competition for FcgRs (31,32). Our studies demonstrated that GB4542 likely mimics the effects of naturally occurring IC by competing for FcgRs and inhibiting FcFcgR-dependent effector functions.…”

Section: Discussionmentioning

confidence: 64%

“…effectively bind low-affinity FcgRs in the absence of Ag, a fact that limits their ability to induce secondary FcgR-mediated and complement-mediated tolerance (31,32).…”

Section: Discussionmentioning

confidence: 99%

Anti-CD20 Antibody with Multimerized Fc Domains: A Novel Strategy To Deplete B Cells and Augment Treatment of Autoimmune Disease

Zhang

Olsen

Chen

et al. 2016

The Journal of Immunology

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We developed a fully recombinant anti-CD20 protein derived from cDNA encoding one Fab domain, two IgG1 Fc regions, the IgG2 hinge, and an isoleucine zipper. This protein, called GB4542, contained both the homodimer and higher-order multimers. Binding studies revealed that GB4542 preferentially bound CD20+ cells yet also recognized CD20−FcγR+ PBMC. In contrast, a control mAb containing the identical Fab region, GB4500, failed to bind CD20−FcγR+ PBMC. Consistent with these findings, interactions between GB4542 and the canonical FcγRs had substantially lower KD values than correlate interfaces between GB4500 and these receptors. At low concentrations, GB4542 showed enhanced Ab-dependent cellular cytotoxicity, Ab-dependent cellular phagocytosis, and complement-dependent cytotoxicity compared with GB4500. However, at higher concentrations, an Fc analog of GB4542 inhibited anti-CD20 mAb–mediated B cell clearance through direct blocking of both Fc–FcγR interactions and C1q deposition on target cells. Furthermore, the higher-order multimer fraction of GB4542 demonstrated greater binding avidity with the canonical FcγRs and was associated with inhibitory effects observed in Ab-dependent cellular phagocytosis and complement-dependent cytotoxicity assays. These data suggest that GB4542 might have utility in the treatment of autoimmune diseases by combining both mAb-mediated B cell depletion and multimerized Fc-mediated tolerogenic effects.

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Suppression of Fcγ-Receptor-Mediated Antibody Effector Function during Persistent Viral Infection

Cited by 59 publications

References 50 publications

Cutting Edge: B Cell–Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection

Cutting Edge: B Cell–Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection

Vaccination with Melanoma Helper Peptides Induces Antibody Responses Associated with Improved Overall Survival

Anti-CD20 Antibody with Multimerized Fc Domains: A Novel Strategy To Deplete B Cells and Augment Treatment of Autoimmune Disease

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