CD32 inhibition and high dose of rhFVIII suppress murine FVIII-specific recall response by distinct mechanisms in vitro

Vollack, Nadine; Friese, Julia; Bergmann, Sabine; Tiede, Andreas; Werwitzke, Sonja

doi:10.1160/th17-03-0201

Cited by 6 publications

(10 citation statements)

References 44 publications

(62 reference statements)

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“…Formation of FVIII‐specific ASCs was suppressed by AT128 in a dose‐dependent manner, and T cell stimulation was diminished at higher doses (Figure A). In comparison with the dual anti‐CD16/CD32 mAb, a five times higher concentration of AT128 was needed to suppress the FVIII‐specific recall response, probably reflecting its lower affinity for CD32 . Otherwise, results observed with this mAb were similar to those with anti‐CD16/CD32 mAb excluding major effects occurring from the additional blockade of CD16 .…”

Section: Discussionmentioning

confidence: 54%

“…Genetic deletion or inhibition of CD32 suppressed the FVIII‐specific recall response by inducing apoptosis in FVIII‐specific MBCs and reducing T cell stimulation by APCs . The receptor mechanisms preventing the FVIII‐specific recall response, however, remained unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Blockade of CD32 using the antagonistic mAb AT128 suppressed FVIII‐specific ASC formation and reduced secretion of key cytokines, IFN‐ γ and IL‐10. These data confirmed previous result with the antagonistic anti‐CD16/32 mAb . In contrast, activation of CD32 by agonistic mAbs AT130‐2 and AT130‐5 allowed the differentiation of FVIII‐specific ASCs and enabled normal cytokine release.…”

Section: Discussionmentioning

confidence: 99%

“…In comparison with the dual anti‐CD16/CD32 mAb, a five times higher concentration of AT128 was needed to suppress the FVIII‐specific recall response, probably reflecting its lower affinity for CD32 . Otherwise, results observed with this mAb were similar to those with anti‐CD16/CD32 mAb excluding major effects occurring from the additional blockade of CD16 . Taken together, these results confirm the importance of CD32 in the FVIII‐specific B cell response.…”

Section: Discussionmentioning

confidence: 99%

“…Consistently, CD32 deficiency or blockade with the dual anti‐CD16/32‐specific mAb suppresses the differentiation of murine FVIII‐specific memory B cells (MBCs) into antibody‐secreting cells (ASCs) in vitro . This suppression seems to be mediated by two distinct mechanisms: (I) induction of apoptosis in FVIII‐specific MBCs and (II) disturbed FVIII presentation by antigen‐presenting cells (APCs) . As anti‐CD16/32 mAb blocks IC binding to CD32 but also prevents the phosphorylation of its intracellular ITIM, it is unclear whether the suppression of FVIII‐specific ASC formation is triggered by the absence of inhibitory signalling or the blockade of F8‐ICs binding to CD32.…”

Section: Introductionmentioning

confidence: 99%

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Anti‐FcγRIIB (CD32) Antibodies Differentially Modulate Murine FVIII‐Specific Recall Response in vitro

et al. 2017

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Fc gamma receptors (FcγRs) for IgG regulate adaptive immune responses by modulating activating and inhibitory signalling pathways within immune cells. Data from a haemophilia A mouse model demonstrate that genetic deletion or blockade of the inhibitory FcγR (CD32) suppresses the formation of antibody-secreting cells (ASCs) in vitro. Mechanisms preventing the FVIII-specific recall response, however, remain unclear. Here, the potential role of CD32 inhibition was studied by differentially modulating receptor activity with selected anti-CD32 monoclonal antibodies (mAbs). Splenocytes from immunized FVIII mice were restimulated with FVIII in the absence or presence of different anti-CD32 mAbs over 6 days. At day 6, cytokine release was quantified from cell culture supernatant and the formation of FVIII-specific ASCs assessed. Binding of FVIII-containing immune complexes (F8-ICs) to bone marrow-derived dendritic cells (BMdDCs) was also investigated. The antagonistic CD32 mAb AT128 suppressed the formation of FVIII-specific ASCs and reduced secretion of IFN-γ and IL-10. In contrast, the agonistic mAbs AT130-2 and AT130-5, and their F(ab') fragments, allowed the formation of FVIII-specific ASCs, even though the full IgG of AT130-2 reduced binding of F8-ICs to CD32. Data suggest that an inhibitory signal is transmitted when F8-ICs bind to CD32 and that this signal is required during memory B cell (MBC) activation to support formation of FVIII-specific ASCs. If the inhibitory signal is lacking due to CD32 deletion or blockade with antagonistic anti-CD32 mAbs, FVIII-specific T cell stimulation and ASC formation are suppressed, whereas agonistic stimulation of CD32 restores T cell stimulation and ASC formation.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anti‐FcγRIIB (CD32) Antibodies Differentially Modulate Murine FVIII‐Specific Recall Response in vitro

et al. 2017

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Identification of genes underlying the enhancement of immunity by a formula of lentinan, pachymaran and tremelia polysaccharides in immunosuppressive mice

Luo

Huang

Luo

et al. 2018

Sci Rep

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The efficacy of polysaccharides is widespread, especially in immune regulation. However, the genetic basis of the changes in polysaccharides regulating immunity is unclear. To obtain genome-wide insights into transcriptome changes and regulatory networks, we designed a polysaccharide formula, comprising lentinan, pachymaran and tremelia, to increase the availability of their optimized active sites. In this case, we focused on a model of immunosuppression to investigate genes by digital gene expression (DGE) tag profiling in T and B cells. These genes were further validated by qRT-PCR and Western blot experiments. Consequently, polysaccharide formula treatment helped to recover the expression of immune-related genes, including CADM1, CCR2, IGLL1, LIGP1, and FCGR3, FCGR2 in B cells, as well as S100A8, S100A9, ChIL3, MMP8 and IFITM3 in T cells. These results suggest that treatment with polysaccharides improves the immunity of immunosuppressive mice by regulating genes associated with T and B cell functions.

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Tolerogenic properties of the Fc portion of IgG and its relevance to the treatment and management of hemophilia

Blumberg

Lillicrap

2018

Blood

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Hemophilia, or inherited genetic deficiencies in coagulation factors, results in uncontrolled bleeding requiring replacement therapy with recombinant proteins given preventively or on demand. However, a major problem with these approaches is the potential for development of immune responses to the administered proteins due to the underlying genetic deficiency of the factor(s) throughout life. As such, there is great interest in developing strategies that avoid immunogenicity and induce immune tolerance. Recently, recombinant factor VIII (rFVIII) and rFIX fused to the crystallizable fragment (Fc) domain of immunoglobulin G (IgG) have been developed as therapeutic agents for hemophilia A and B, respectively. Although it is well known that the possession of an Fc domain confers IgG's longer-lasting circulating half-life, it is not generally appreciated that the Fc domain also confers immunoregulatory properties that are associated with the induction of tolerance. Here, we review some of the latest advances in our understanding of the tolerogenic abilities of IgG Fc and the impact of Fc-fusion proteins of rFVIII on the treatment of hemophilia.

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CD32 inhibition and high dose of rhFVIII suppress murine FVIII-specific recall response by distinct mechanisms in vitro

Cited by 6 publications

References 44 publications

Anti‐FcγRIIB (CD32) Antibodies Differentially Modulate Murine FVIII‐Specific Recall Response in vitro

Anti‐FcγRIIB (CD32) Antibodies Differentially Modulate Murine FVIII‐Specific Recall Response in vitro

Identification of genes underlying the enhancement of immunity by a formula of lentinan, pachymaran and tremelia polysaccharides in immunosuppressive mice

Tolerogenic properties of the Fc portion of IgG and its relevance to the treatment and management of hemophilia

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