scholarly journals Anti-GD2 IgA kills tumors by neutrophils without antibody-associated pain in the preclinical treatment of high-risk neuroblastoma

2021 ◽  
Vol 9 (10) ◽  
pp. e003163
Author(s):  
Mitchell Evers ◽  
Marjolein Stip ◽  
Kaylee Keller ◽  
Hanneke Willemen ◽  
Maaike Nederend ◽  
...  
Keyword(s):  
High Risk ◽  
Sensory Neurons ◽  
Complement System ◽  
Severe Pain ◽  
Neuroblastoma Cells ◽  
Antibody Therapy ◽  
Preclinical Treatment ◽  
The Complement System

BackgroundThe addition of monoclonal antibody therapy against GD2 to the treatment of high-risk neuroblastoma led to improved responses in patients. Nevertheless, administration of GD2 antibodies against neuroblastoma is associated with therapy-limiting neuropathic pain. This severe pain is evoked at least partially through complement activation on GD2-expressing sensory neurons.MethodsTo reduce pain while maintaining antitumor activity, we have reformatted the approved GD2 antibody ch14.18 into the IgA1 isotype. This novel reformatted IgA is unable to activate the complement system but efficiently activates leukocytes through the FcαRI (CD89).ResultsIgA GD2 did not activate the complement system in vitro nor induced pain in mice. Importantly, neutrophil-mediated killing of neuroblastoma cells is enhanced with IgA in comparison to IgG, resulting in efficient tumoricidal capacity of the antibody in vitro and in vivo.ConclusionsOur results indicate that employing IgA GD2 as a novel isotype has two major benefits: it halts antibody-induced excruciating pain and improves neutrophil-mediated lysis of neuroblastoma. Thus, we postulate that patients with high-risk neuroblastoma would strongly benefit from IgA GD2 therapy.

The Interaction of Liposomes with the Complement System: In Vitro and In Vivo Assays

2003 ◽  
pp. 136-154 ◽  
Author(s):  
Janos Szebeni ◽  
Lajos Baranyi ◽  
Sandor Savay ◽  
Janos Milosevits ◽  
Michael Bodo ◽  
...  
Keyword(s):  
Complement System ◽  
In Vivo Assays ◽  
The Complement System

Introduction to the complement system

1984 ◽  
Vol 306 (1129) ◽  
pp. 279-281 ◽  
Keyword(s):  
Humoral Immunity ◽  
Complement System ◽  
Bacterial Infections ◽  
Cross Linking ◽  
Complement Components ◽  
The Third ◽  
Effector Mechanism ◽  
The Complement System

Complement is the essential effector mechanism in humoral immunity to infection. Combination of antibody with antigen causes cross-linking, leading to precipitation of soluble antigens and agglutination of particular antigens, but no more. Unless complement is also present, agglutinated microorganisms can, in appropriate media in vitro grow out and form as lethal a culture as if not reacted with antibody. That this is also true in vivo is apparent from experience with patients with inherited deficiencies in complement components. The pattern is complex because of the presence of two pathways of activation, but in the rare cases of deficiency of the third component, C3, which is central to both pathways, the individuals are susceptible to repeated bacterial infections similar to aggammaglobulinaemics who are unable to synthesize antibodies. Both antibodies and complement are essential for effective humoral immunity.

scholarly journals KDM6B promotes oncogenic CDK4/6-pRB-E2F pathway via maintaining enhancer activation in high-risk neuroblastoma

2020 ◽  
Author(s):  
Alexandra D’Oto ◽  
Jie Fang ◽  
Hongjian Jin ◽  
Beisi Xu ◽  
Shivendra Singh ◽  
...  
Keyword(s):  
High Risk ◽  
Target Genes ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Gene Signature ◽  
Chromatin Accessibility ◽  
Chromatin Interaction ◽  
Pharmacologic Inhibition

ABSTRACTThe H3K27me2/me3 histone demethylase KDM6B is over-expressed in neuroblastoma and essential to neuroblastoma cell survival. While the KDM6B inhibitor, GSK-J4, has shown activity in in vitro and in vivo preclinical models, the mechanism of action remains poorly defined. We demonstrate that genetic and pharmacologic inhibition of KDM6B downregulate the pRB-E2F transcriptome and MYCN expression. Chemical genetics analyses show that a high E2F transcriptome is positively correlated with sensitivity of cancer cells to the KDM6 inhibitor GSK-J4. Mechanistically, inhibition of KDM6B activity reduces the chromatin accessibility of E2F target genes and MYCN. GSK-J4 alters distribution of H3K27me3 and broadly represses the enhancer mark H3K4me1, which may consequently disrupt the long-range chromatin interaction of E2F target genes. KDM6B inhibition phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout not only confers neuroblastoma cell resistance to palbociclib but also to GSK-J4. A gene signature targeted by KDM6B inhibition is associated with poor survival of patients with neuroblastoma regardless of the MYCN status. These data indicate that KDM6B activity promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.

scholarly journals Infection with an H2 recombinant herpes simplex virus vector results in expression of MHC class I antigens on the surfaces of human neuroblastoma cells in vitro and mouse sensory neurons in vivo

2000 ◽  
Vol 81 (10) ◽  
pp. 2375-2383 ◽  
Author(s):  
Allison Abendroth ◽  
Anthony Simmons ◽  
Stacey Efstathiou ◽  
Rosemarie A. Pereira
Keyword(s):  
Cell Surface ◽  
Sensory Neurons ◽  
Neuroblastoma Cells ◽  
Primary Sensory Neurons ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma ◽  
Mhc I ◽  
Simplex Virus

The majority of neurons in herpes simplex virus (HSV)-infected murine sensory ganglia are transiently induced to express MHC-I antigens at the cell surface, whereas only a minority are themselves productively infected. The aim of the current work was to determine whether MHC-I antigens can be expressed on the surfaces of infected neurons in addition to their uninfected neighbours. To address this aim a recombinant HSV type 1 strain, S-130, was used to deliver a mouse H2Kd gene, under control of the HCMV IE-1 promoter/enhancer, into human neuroblastoma cells in vitro and mouse primary sensory neurons in vivo. S-130 expressed H2Kd antigens on the surfaces of IMR-32 cells, a human neuroblastoma cell line that expresses very low levels of MHC-I constitutively. In K562 cells, which do not express MHC-I constitutively, H2Kd and β2-microglobulin (β2m) were shown to be co-expressed at the cell surface following S-130 infection. This observation was taken as evidence that class I heavy chain (αC) molecules encoded by the expression cassette in the HSV genome were transported to the cell surface as stable complexes with β2m. Significantly, after introduction of S-130 into flank skin, H2Kd antigens were detected on the surfaces of primary sensory neurons in ganglia innervating the inoculation site. Our data show that HSV-infected murine primary sensory neurons and human neuroblastoma cells are capable of expressing cell-surface MHC-I molecules encoded by a transgene. From this, we infer that up-regulation of αC expression is, in principle, sufficient to overcome potential impediments to neuronal cell surface expression of MHC-I complexes.

Anticancer efficacy of p -dodecylaminophenol against high-risk and refractory neuroblastoma cells in vitro and in vivo

2017 ◽  
Vol 27 (20) ◽  
pp. 4664-4672 ◽  
Author(s):  
Noriko Takahashi ◽  
Shunpei Koyama ◽  
Shinya Hasegawa ◽  
Masahiro Yamasaki ◽  
Masahiko Imai
Keyword(s):  
High Risk ◽  
Neuroblastoma Cells ◽  
Anticancer Efficacy

The Role of Membrane Bound Complement in the Aggregation of Mammalian Platelets by Collagen

1975 ◽  
Author(s):  
B. V. Chater
Keyword(s):  
Electron Microscope ◽  
Light Microscopy ◽  
Complement System ◽  
Membrane Bound ◽  
The Complement System ◽  
Adhesion Of Platelets ◽  
Collagen Stimulation

It has been observed in dogs decomplemented with purified Cobra Venom Factor, that their platelets lose the ability to aggregate in response to collagen stimulation. Further investigation of the effect of CVF in vitro in man, dog and rabbit, and in vivo in dog, reveals that in each case CVF abolishes the collagen response of platelets, and that this effect is dose related. Resuspension of CVF inactivated platelets in plasma containing complement, results in a total return of sensitivity to collagen. Examination of CVF inactivated platelets with the electron microscope, fails to show any marked difference from control platelets. Serotonin granules are still present and the platelets retain a discoid appearance. Incubation of platelets with antibodies to Cl, C3 and C5, results in inhibition of the collagen response, this effect also being dose related. Light microscopy studies indicate that CVF does not affect the adhesion of platelets to collagen but appears to prevent subsequent aggregation. It is suggested that the complement system is involved in the induction of release by collagen, and that inhibition by CVF and anti-complement antibodies is the result of a blocking of the release reaction.

Charge and Size Heterogeneity of C3d following in vivo and in vitro Activation of the Complement System

Complement ◽  
1984 ◽  
Vol 1 (1) ◽  
pp. 36-43 ◽  
Author(s):  
B. Teisner ◽  
J. Hau ◽  
J. Folkersen ◽  
H.H. Jepsen
Keyword(s):  
Complement System ◽  
In Vitro Activation ◽  
Size Heterogeneity ◽  
The Complement System
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