scholarly journals CSF-1R–Dependent Lethal Hepatotoxicity When Agonistic CD40 Antibody Is Given before but Not after Chemotherapy

2016 ◽  
Vol 197 (1) ◽  
pp. 179-187 ◽  
Author(s):  
Katelyn T. Byrne ◽  
Nathan H. Leisenring ◽  
David L. Bajor ◽  
Robert H. Vonderheide
Keyword(s):  
Agonistic Cd40 Antibody

Phenyl N-Tert-Butylnitrone (PBN) Protects Syngeneic Marrow Transplant Recipients from the Lethal Cytokine Syndrome Occurring after Agonistic CD40 Antibody Administration.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2128-2128
Author(s):  
William R. Drobyski ◽  
Nadine Halligan ◽  
Richard Komorowski ◽  
Brent Logan ◽  
William J. Murphy ◽  
...  
Keyword(s):  
Free Radical ◽  
Organ Damage ◽  
Marrow Transplant ◽  
Antitumor Effects ◽  
Free Radical Production ◽  
Radical Production ◽  
Gut Toxicity ◽  
Significant Difference ◽  
Ifn Γ ◽  
Agonistic Cd40 Antibody

Abstract Administration of agonistic monoclonal antibodies or recombinant cytokines is a potential approach to enhance antitumor immunity in bone marrow transplant (BMT) recipients, but is complicated by toxicity due to proinflammatory cytokine-mediated vital organ damage. Inflammatory cytokines are known to induce free radical production which we hypothesized might be the proximate cause of toxicity in this setting. Phenyl-tert-butylnitrone (PBN) is a spin trap inhibitor, that has been used in electron paramagnetic resonance (EPR) studies to trap free radicals so they can be visualized by EPR spectroscopy. To test whether PBN could mitigate cytokine-mediated organ damage, we employed a murine syngeneic transplant model in which administration of agonistic CD40 antibody to mice early post BMT results in lethality due to production of high levels of cytokines such as IL-12 and IFN-γ, leading to fatal gut toxicity. Lethally irradiated C57BL/6J (B6) mice were transplanted with B6 BM and then treated with either IgG or anti-CD40 antibody (7 μg) on days 1–4 post-BMT. Cohorts of anti-CD40-antibody-treated mice were then administered either DMSO or PBN (50 mg/kg BID) on days 0–5 post-BMT. Administration of PBN completely protected BMT recipients from anti-CD40 antibody-induced mortality (0% survival CD40/DMSO versus 100% survival CD40/PBN). This was attributable to a significant reduction in gut toxicity as determined using a pathological scoring system. To examine the mechanism by which mice were protected, cytokine and nitrate/nitrite levels were measured to determine whether PBN inhibited production of proinflammatory mediators. Administration of anti-CD40 antibody resulted in a significant increase in IL-12, IFN-γ,TNF-α, and nitrate/nitrite levels compared to IgG/PBN-treated control mice. However, there was no significant difference in serum measurements of these cytokines in CD40/PBN compared to CD40/DMSO-treated animals. These data demonstrated that the protective effects of PBN were not attributable to a reduction in cytokine mediators and suggested that the action of PBN occurred downstream of these inflammatory cytokine signaling pathways, through inhibition of free radical production. Cytokines, such as IL-12 and IFN-γ, are also important downstream mediators of the antitumor effects induced by agonistic CD40 antibody. Therefore to directly test whether PBN compromised these antitumor effects, B6 mice were intravenously administered 107 EL4 cells and then treated on days 3-6 with either rat IgG or anti-CD40 antibody. Since EL4 cells do not express CD40, tumor regression mediated by anti-CD40 antibody is attributable to augmentation of host immunity and has been shown to dependent upon IFN-γ. B6 mice were challenged with a lethal dose EL4 tumor cells and then treated with IgG or agonistic CD40 antibody (500 μg/day) in the presence or absence of PBN. IgG-treated control mice all died within 20 days. In contrast, CD40/DMSO and CD40/PBN-treated mice all survived >80 days after tumor challenge indicating that PBN did not compromise antitumor effects. We conclude that PBN administration may represent a novel approach for reduction of toxicity without compromise of antitumor effects resulting from administration of therapeutic antibodies in BMT recipients.

scholarly journals Fcγ Receptor Dependency of Agonistic CD40 Antibody in Lymphoma Therapy Can Be Overcome through Antibody Multimerization

2014 ◽  
Vol 193 (4) ◽  
pp. 1828-1835 ◽  
Author(s):  
Ann L. White ◽  
Lang Dou ◽  
H. T. Claude Chan ◽  
Vikki L. Field ◽  
C. Ian Mockridge ◽  
...  
Keyword(s):  
Fcγ Receptor ◽  
Agonistic Cd40 Antibody ◽  
Lymphoma Therapy

scholarly journals Local Activation of CD8 T Cells and Systemic Tumor Eradication without Toxicity via Slow Release and Local Delivery of Agonistic CD40 Antibody

2011 ◽  
Vol 17 (8) ◽  
pp. 2270-2280 ◽  
Author(s):  
Marieke F. Fransen ◽  
Marjolein Sluijter ◽  
Hans Morreau ◽  
Ramon Arens ◽  
Cornelis J.M. Melief
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Slow Release ◽  
Local Delivery ◽  
Local Activation ◽  
Agonistic Cd40 Antibody ◽  
Tumor Eradication

scholarly journals Stimulus-dependent Deacylation of Bacterial Lipopolysaccharide by Dendritic Cells

2003 ◽  
Vol 197 (12) ◽  
pp. 1745-1754 ◽  
Author(s):  
Mingfang Lu ◽  
Mei Zhang ◽  
Richard L. Kitchens ◽  
Susan Fosmire ◽  
Akira Takashima ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lipid A ◽  
Host Responses ◽  
Bacterial Protein ◽  
Cpg Oligodeoxynucleotides ◽  
Antibody Maturation ◽  
Acyl Chains ◽  
Acyloxyacyl Hydrolase ◽  
Lps Treatment ◽  
Agonistic Cd40 Antibody

We describe here a previously unrecognized property of dendritic cells (DCs), the ability to deacylate the lipid A moiety of gram-negative bacterial LPSs. Both immature DCs of the XS52 cell line and bone marrow–derived DCs produce acyloxyacyl hydrolase, an enzyme that detoxifies LPS by selectively removing the secondary acyl chains from lipid A. Acyloxyacyl hydrolase expression decreased when DCs were incubated with IL-4, IL-1β, TNFα, and an agonistic CD40 antibody (maturation cocktail), and increased after treatment with LPS, CpG oligodeoxynucleotides, or a gram-positive bacterium (Micococcus luteus). Maturation cocktail treatment also diminished, whereas LPS treatment enhanced or maintained the cells' ability to kill Escherichia coli, deacylate LPS, and degrade bacterial protein. Enzymatic deacylation of LPS is an intrinsic, regulated mechanism by which DCs may modulate host responses to this potent bacterial agonist.

scholarly journals Multivalent Porous Silicon Nanoparticles Enhance the Immune Activation Potency of Agonistic CD40 Antibody

2012 ◽  
Vol 24 (29) ◽  
pp. 3981-3987 ◽  
Author(s):  
Luo Gu ◽  
Laura E. Ruff ◽  
Zhengtao Qin ◽  
Maripat Corr ◽  
Stephen M. Hedrick ◽  
...  
Keyword(s):  
Porous Silicon ◽  
Immune Activation ◽  
Silicon Nanoparticles ◽  
Porous Silicon Nanoparticles ◽  
Agonistic Cd40 Antibody
Sign in / Sign up

Export Citation Format

Share Document