Pathogenic Role of B Cells in Anti-CD40-Induced Necroinflammatory Liver Disease

Kimura, Kiminori; Moriwaki, Hisataka; Nagaki, Masahito; Saio, Masanao; Nakamoto, Yasunari; Naito, Makoto; Kuwata, Kazuo; Chisari, Francis V.

doi:10.2353/ajpath.2006.050314

Cited by 30 publications

(35 citation statements)

References 44 publications

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“…This is consistent with studies by Joyce et al, which first demonstrated the exclusive binding capability of RGR-FITC molecules to angiogenic vessels in RIP-Tag tumors (4). Moreover, compared with unconjugated compounds, anti-CD40-RGR/IL-2-RGR treatment induced limited liver toxicity, as assessed by serum alanine aminotransferase and serum TNF-α ( Figure 1, E and F) (21) and reduced systemic immune responses ( Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI33201DS1). Our data thus demonstrate that vascular targeting is a viable approach to deliver immune-modulating, and otherwise systemically toxic, agents into tumors, which are not accessible by direct intratumoral injections.…”

Section: Peptide-mediated Homing Of Immune Stimulatory Agents Into Sosupporting

confidence: 79%

Vascular targeting of anti-CD40 antibodies and IL-2 into autochthonous tumors enhances immunotherapy in mice

Hamzah¹,

Nelson²,

Moldenhauer³

et al. 2008

J. Clin. Invest.

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Current anticancer therapy is a delicate balance between elimination of malignant cells and harmful side effects for the host. In this study, we used a tumor-homing peptide to engineer anti-CD40 agonist antibodies and recombinant IL-2 such that they were selectively delivered into spontaneously arising tumors in a transgenic mouse model of islet cell carcinogenesis. Intravenous injection of these agents, either separately or together, led to accumulation in the vicinity of tumor neovessels without toxic side effects. Although both molecules are critical for adaptive immunity, the most profound effects were seen in endothelial cells. Combined, local anti-CD40 and IL-2 therapy reduced tumor vascularity and significantly delayed tumor growth in mice. Remarkably, tumor-bearing mice remained disease-free long-term when targeted anti-CD40 and IL-2 were combined with transfers of preactivated antitumor immune cells. In this therapeutic setting, triggering of CD40 on endothelial cells induced an inflammatory response of the vessel wall and facilitated effector cell accumulation in the tumor parenchyma while IL-2 promoted antigen-specific immune cell persistence. We believe this is a novel and highly effective anticancer approach, whereby tumor stroma is "conditioned" for enhanced immune cell entry and survival, facilitating immune-mediated tumor destruction and leading to a sustained antitumor response.

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Section: Peptide-mediated Homing Of Immune Stimulatory Agents Into Sosupporting

confidence: 79%

Vascular targeting of anti-CD40 antibodies and IL-2 into autochthonous tumors enhances immunotherapy in mice

Hamzah¹,

Nelson²,

Moldenhauer³

et al. 2008

J. Clin. Invest.

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“…Inflammation and hypertrophy of lymphoid tissues follow, characterized by loss of normal follicular structure and co-localization of activated T cells and B cells in lymphocytic clusters (Peters et al, 2009). Pronounced infiltrates of B cells, NK cells, CD4 + T-cells, dendritic cells and macrophages occur in various organs, mainly the liver but also lung, pancreas and gastrointestinal tract (Kimura et al, 2006;Zhou et al, 2005). Furthermore, lymphadenopathy and splenomegaly occur due to myeloid cell hyperplasia and B-cell expansion.…”

Section: Including Tumor Necrosis Factor (Tnf) Interleukin-(il-) Il-mentioning

confidence: 99%

CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway

Cathomas

Fuertig

Sigrist

et al. 2015

Brain, Behavior, and Immunity

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The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immune-inflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxygenase (IDO) inhibitor blocked activation of the kynurenine pathway but was without effect on SBS and saccharin drinking. This study provides novel evidence that CD40-TNF activation induces deficits in saccharin drinking and Pavlovian fear learning and activates the kynurenine pathway, and that CD40-TNF activation of the kynurenine pathway is not necessary for induction of the acute or extended SBS effects. AbstractThe similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immuneinflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3 days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxyg...

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“…Several human 2,4 and animal [24][25][26][27] studies using CD40 agonists report elevated levels of circulating hepatocyte enzymes ALT and AST, indicative of liver damage. To examine the severity of hepatocellular damage with monotherapy versus combination therapy, we measured plasma levels of ALT and AST in mice after vaccination ( Figure 5A,B).…”

Section: ␣Cd40-induced Hepatocellular Injury Is Reduced By Coadministmentioning

confidence: 99%

Enhanced efficacy and reduced toxicity of multifactorial adjuvants compared with unitary adjuvants as cancer vaccines

Ahonen

Wasiuk

Fuse

et al. 2008

Blood

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Identification of Toll-like receptors (TLRs)and their ligands, and tumor necrosis factor-tumor necrosis factor receptor (TNF-TNFR) pairs have provided the first logical, hypothesis-based strategies to molecularly concoct adjuvants to elicit potent cell-mediated immunity via activation of innate and adaptive immunity. However, isolated activation of one immune pathway in the absence of others can be toxic, ineffective, and detrimental to long-term, protective immunity. Effective engineered vaccines must include agents that trigger multiple immunologic pathways. Here, we report that combinatorial use of CD40 and TLR agonists as a cancer vaccine, compared with monotherapy, elicits high frequencies of selfreactive CD8 ؉ T cells, potent tumorspecific CD8 ؉ memory, CD8 ؉ T cells that efficiently infiltrate the tumor-burdened target organ; therapeutic efficacy; heightened ratios of CD8 ؉ T cells to FoxP3 ؉ cells at the tumor site; and reduced hepatotoxicity. These findings provide intelligent strategies for the formulation of multifactorial vaccines to achieve maximal efficacy in cancer vaccine trials in hu IntroductionThe molecular identification of Toll-like receptors (TLRs) and their ligands, as well as tumor necrosis factor (TNF)-tumor necrosis factor receptor (TNFR) pairs that control adaptive immunity, has provided the first logical, hypothesis-based strategies to molecularly concoct adjuvants that elicit potent cell-mediated immunity. Paralleling TLRs in mobilizing the innate immune response, CD40 and its ligand represent the primary ligand-receptor pair essential for development of the adaptive immune response. Individually, TLR agonists 1 and CD40 agonists 2-4 have entered clinical trials as adjuvants for eliciting protective immune responses to cancer. Inherent in these monotherapeutic approaches are limited induction of immunity, lack of clinical efficacy and, in some cases, hepatotoxicity. 3,4 TLRs are widely expressed on both hematopoietic and nonhematopoietic cells and elicit proinflammatory responses upon receptor engagement. Indeed, use of TLR agonists as solitary adjuvants triggers dendritic cell (DC) maturation, leukocyte migration, and release of chemokines and cytokines, and enhances immunity. 5,6 Studies in which TLR agonists have been scrutinized for their ability to induce cross-presentation and antigen-specific CD8 ϩ responses in vivo 7 show some level of activity that is minimal compared with that observed when combined with a CD40 agonist. 8,9 TLR agonists as unitary adjuvants in murine tumor models have demonstrated marginal efficacy, as reviewed, 10 but have proven effective when combined with other vaccine modalities. [11][12][13] Finally, clinical use of a TLR9 agonist in lung cancer trials has been recently suspended due to lack of clinical response. 1Studies from animal models underscore the utility of anti-CD40 (␣CD40) as a unitary adjuvant. 14,15 We previously demonstrated that the magnitude of immune responses elicited by TLR or CD40 agonists alone is minimal compared with the magnit...

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Pathogenic Role of B Cells in Anti-CD40-Induced Necroinflammatory Liver Disease

Cited by 30 publications

References 44 publications

Vascular targeting of anti-CD40 antibodies and IL-2 into autochthonous tumors enhances immunotherapy in mice

Vascular targeting of anti-CD40 antibodies and IL-2 into autochthonous tumors enhances immunotherapy in mice

CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway

Enhanced efficacy and reduced toxicity of multifactorial adjuvants compared with unitary adjuvants as cancer vaccines

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