Immune Checkpoint Inhibitor-Related Cytokine Release Syndrome: Analysis of WHO Global Pharmacovigilance Database.

Immune checkpoint inhibitors (ICIs) have proven effective in the treatment of numerous cancers; however, they have been associated with immune-related adverse events (irAEs), among which cytokine release syndrome (CRS) has been reported in a few case reports. To describe the burden of ICI-related CRS and raise awareness of CRS as irAE, we queried VigiBase, the World Health Organization global database of spontaneously reported suspected adverse drug reactions (ADRs), and retrieved safety reports of suspected CRS associated with ICIs, gathered in the database through January 12th 2020. We assessed ICI-related CRS safety reports in terms of geographical and temporal patterns of reporting, patient demographics and clinical features, treatment characteristics, CRS clinical presentation, timing, seriousness, and outcome. We retrieved 58 cases of whom 43 (74%) reported CRS with anti-programmed death-1/anti-programmed death-ligand 1 agents. Melanoma (n=17, 29%) and hematologic malignancies (n=16, 28%) were the most common underlying cancers. ICIs were the solely suspected drugs in 37 (64%) cases. Typical signs and symptoms of CRS were reported in 25 (43%) patients. ICI-related CRS developed a median of 4 weeks after ICI initiation (IQR 1-18 weeks, n=9, 16%). Besides two fatal cases, CRS recovered/was recovering at the time of reporting in 35 (60%) cases. We observed differences in the geographical pattern of ICI-related CRS reporting, with a high proportion of ICI-related CRS cases in Australia and North America (0.14 and 0.10% respectively). Due to ICI expanding indications, clinicians should be aware that ICIs could contribute to CRS onset in cancer patients as pharmacological triggers.

The type 1 TNF receptor and its associated adapter protein, FAN, are required for TNFalpha-induced sickness behavior.

RATIONALE: During the course of an infection, the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) acts in the brain to trigger development of behavioral responses, collectively termed sickness behavior. Biological activities of TNFalpha can be mediated by TNF receptor type 1 (TNF-R1) and type 2 (TNF-R2). TNFalpha activates neutral sphingomyelinase through the TNF-R1 adapter protein FAN (factor associated with neutral sphingomyelinase activation), but a behavioral role of FAN in the brain has never been reported. OBJECTIVES: We hypothesized that TNFalpha-induced sickness behavior requires TNF-R1 and that FAN is a necessary component for this response. MATERIALS AND METHODS: We determined the role of brain TNF-R1 in sickness behavior by administering an optimal amount of TNFalpha intracerebroventricularly (i.c.v., 50 ng/mouse) to wild-type (WT), TNF-R1-, TNF-R2-, and FAN-deficient mice. Sickness was assessed by decreased social exploration of a novel juvenile, induction of immobility, and loss of body weight. RESULTS: TNF-R1-deficient mice were resistant to the sickness-inducing properties of i.c.v. TNFalpha, whereas both TNF-R2-deficient and WT mice were fully responsive. Furthermore, the complete absence of TNFalpha-induced sickness behavior in FAN-deficient mice provided in vivo evidence that FAN-dependent TNF-R1 signaling is critical for this central action of TNFalpha. CONCLUSIONS: This is the first report to demonstrate that TNFalpha-induced sickness behavior is fully mediated by TNF-R1 and that the adaptor protein FAN is a necessary intracellular intermediate for sickness behavior.

Systemic inflammation switches the inflammatory cytokine profile in CNS Wallerian degeneration.

Axon loss in the CNS is characteristic of many neurodegenerative diseases but the mechanisms of axon degeneration are poorly understood. In particular, we know little of the inflammatory response triggered by CNS axon degeneration with comparison to that provoked by death of the neuronal cell body. We show that Wallerian degeneration of the mouse optic nerve induces transcription of TGF-beta1 and TNF-alpha, but not pro-inflammatory cytokines IL-1beta and IL-6 and microglial activation. This atypical inflammatory response resembles macrophages that have phagocytosed apoptotic cells and prion-infected CNS. Significantly, peripheral endotoxin challenge after injury switched this profile by inducing IL-1beta, IL-6 transcripts, other inflammation-associated products and reducing neurofilament immunoreactivity. We propose that microglia are activated by Wallerian degeneration and persist in an atypical but "primed" state and can be switched by systemic inflammation to provoke a classical pro-inflammatory profile with potentially deleterious consequences.

TNFalpha-induced sickness behavior in mice with functional 55 kD TNF receptors is blocked by central IGF-I.

A variety of pathogenic insults cause synthesis of tumor necrosis factor (TNF)alpha in the brain, resulting in sickness behavior. Here we used TNF-receptor (TNF-R)2-deficient and wild-type mice to demonstrate that the reduction in social exploration of a novel juvenile, the increase in immobility and the loss of body weight caused by central TNFalpha (i.c.v., 50 ng/mouse) are blocked by central pre-treatment with the multifunctional peptide, insulin-like growth factor (IGF-I; i.c.v., 300 ng/mouse). These results establish that sickness behavior induced by central TNFalpha via the TNF-R1 (p55) is directly opposed by IGF-I in the brain.

Influence of the course of brain inflammation on the endogenous IL-1beta/IL-1Ra balance in the model of brain delayed-type hypersensitivity response to bacillus Calmette-Guérin in Lewis rats.

Interleukin-1beta (IL-1beta) is a key player in the pathogenesis of acute and chronic inflammatory diseases at the periphery and in the brain. Its action is regulated by interleukin-1 receptor antagonist (IL-1Ra), the specific endogenous antagonist of IL-1 receptors. The ratio between local concentrations of IL-1Ra and IL-1beta is known to influence the initiation and progression of many inflammatory and autoimmune diseases at the periphery. In order to determine whether this is also the case in the brain, brain and plasma concentrations of IL-1beta and IL-1Ra were measured by ELISA in a model of chronic brain inflammation in Lewis rats, the hippocampal delayed-type hypersensitivity (DTH) response to bacillus Calmette-Guérin (BCG). Brain IL-1beta increased rapidly after intracerebral (i.c.) injection of BCG and came back to baseline concentrations 1 week later, whereas IL-1Ra increased gradually over time and remained elevated during the last 2 weeks post-BCG intracerebral injection. Following peripheral BCG challenge, brain IL-1beta increased at the site of the brain BCG and peaked 12 days later before decreasing on day 16 post-challenge. Brain IL-1Ra remained elevated during the first days post-challenge and then decreased from the 12th day post-challenge. The same temporal variations were observed in the plasma concentrations of IL-1beta and IL-1Ra. The increase in the IL-1beta/IL-1Ra ratio that was apparent from day 3 to day 12 post-challenge might be correlated with the invasion of peripheral inflammatory cells at the site of intracerebral injection. Besides showing that the course of inflammation alters the brain IL-1beta/IL-1Ra ratio, these findings point to the importance of monitoring plasma IL-1beta/IL-1Ra ratio to predict the course of brain inflammation.

Mechanisms involved in dual vasopressin/apelin neuron dysfunction during aging.

Normal aging is associated with vasopressin neuron adaptation, but little is known about its effects on the release of apelin, an aquaretic peptide colocalized with vasopressin. We found that plasma vasopressin concentrations were higher and plasma apelin concentrations lower in aged rats than in younger adults. The response of AVP/apelin neurons to osmotic challenge was impaired in aged rats. The overactivity of vasopressin neurons was sustained partly by the increased expression of Transient receptor potential vanilloid2 (Trpv2), because central Trpv blocker injection reversed the age-induced increase in plasma vasopressin concentration without modifying plasma apelin concentration. The morphofunctional plasticity of the supraoptic nucleus neuron-astrocyte network normally observed during chronic dehydration in adults appeared to be impaired in aged rats as well. IL-6 overproduction by astrocytes and low-grade microglial neuroinflammation may contribute to the modification of neuronal functioning during aging. Indeed, central treatment with antibodies against IL-6 decreased plasma vasopressin levels and increased plasma apelin concentration toward the values observed in younger adults. Conversely, minocycline treatment (inhibiting microglial metabolism) did not affect plasma vasopressin concentration, but increased plasma apelin concentration toward control values for younger adults. This study is the first to demonstrate dual vasopressin/apelin adaptation mediated by inflammatory molecules and neuronal Trpv2, during aging.

Interleukin-6 activates arginine vasopressin neurons in the supraoptic nucleus during immune challenge in rats.

The increase of plasma arginin-vasopressin (AVP) release, which translates hypothalamic AVP neuron activation in response to immune challenge, appears to occur independently of plasma osmolality or blood pressure changes. Many studies have shown that major inflammatory mediators produced in response to peripheral inflammation, such as prostaglandin (PG)-E(2) and interleukin (IL)-1beta, excite AVP neurons. However, in vivo electrical activation of AVP neurons was still not assessed in relation to plasma AVP release, osmolality, or blood pressure or to the expression and role of inflammatory molecules like PG-E(2), IL-1beta, IL-6, and tumor necrosis factor-alpha (TNFalpha). This study aims at elucidating those factors that underlie the activation of AVP neurons in response to immune stimulation mimicked by an intraperitoneal injection of lipopolysaccharide (LPS) in male Wistar rats. LPS treatment concomittanlty decreased diuresis and increased plasma AVP as well as AVP neuron activity in vivo, and these effects occurred as early as 30 min. Activation was sustained for more than 6 h. Plasma osmolality did not change, whereas blood pressure only transiently increased during the first hour post-LPS. PG-E(2), IL-1beta, and TNFalpha mRNA expression were raised 3 h after LPS, whereas IL-6 mRNA level increased 30 min post-LPS. In vivo electrophysiological recordings showed that brain IL-6 injection increased AVP neuron activity similarly to peripheral LPS treatment. In contrast, brain injection of anti-IL-6 antibodies prevented the LPS induced-activation of AVP neurons. Taken together, these results suggest that the early activation of AVP neurons in response to LPS injection is induced by brain IL-6.

Mannose receptor expression specifically reveals perivascular macrophages in normal, injured, and diseased mouse brain.

Perivascular macrophages are believed to have a significant role in inflammation in the central nervous system (CNS). They express a number of different receptors that point toward functions in both innate immunity, through pathogen-associated molecular pattern recognition, phagocytosis, and cytokine responsiveness, and acquired immunity, through antigen presentation and co-stimulation. We are interested in the receptors that are differentially expressed by perivascular macrophages and microglia in both the normal CNS as well as in neuroinflammation and neurodegeneration. In this article we report the use of a well-characterized monoclonal antibody, 5D3, to localize the expression of the mannose receptor to perivascular macrophages in the normal CNS and in various models of brain pathology. Mannose receptor expression was limited to perivascular, meningeal, and choroid plexus macrophages in normal, inflamed, injured, and diseased CNS. In particular, activated microglia and invading hematogenous leukocytes were mannose receptor negative while expressing the F4/80 antigen, macrosialin (CD68), FcRII (CD32), scavenger receptor (CD204), and CR3 (CD11b/CD18). Since the perivascular macrophages expressing the mannose receptor are known to be the only constitutively phagocytic cells in the normal CNS, we injected clodronate-loaded liposomes intracerebroventricularly in control mice to deplete these cells. In these mice, there was no detectable mannose receptor expression in perivascular spaces after immunocytochemistry with the 5D3 monoclonal antibody. This finding underlines the value of the monoclonal antibody 5D3 as a tool to study murine perivascular macrophages selectively. Mannose receptor expression by macrophages located at blood-brain (perivascular), brain-cerebrospinal fluid (CSF) (meningeal), and CSF-blood (choroid plexus) interfaces supports a functional role of these cells in responding to external stimuli such as infection.

Interleukin-1beta mediates the memory impairment associated with a delayed type hypersensitivity response to bacillus Calmette-Guérin in the rat hippocampus.

Interleukin-1beta (IL-1beta) plays a major role in the initiation and exacerbation of brain inflammation, and its action is limited by the natural antagonist of IL-1 receptors, IL-1Ra. The aim of the present study was to test the hypothesis that IL-1beta mediates the functional consequences of inflammation during the course of delayed-type hypersensitivity response to bacillus Calmette-Guérin (BCG) in the hippocampus of Lewis rats. Animals were primed with an injection of BCG in the right hippocampus and challenged 4 weeks later with BCG administered subcutaneously. Concentrations of IL-1beta and IL-1Ra were measured by ELISA in the BCG injected hippocampus and compared to those measured in the contralateral hippocampus during the first 2 weeks post-challenge. IL-1beta levels increased in response to BCG challenge and peaked 12 days after challenge. The same variations appeared in the contralateral hippocampus but to a lesser extent. Hippocampal IL-1Ra levels increased in response to intrahippocampal injection of BCG. They further increased at days 6 and 9 post-challenge and decreased from day 12 back to baseline values on day 16. The increase in IL-1beta levels and the decline in IL-1Ra levels were associated with an impairment in spatial memory in a Y-maze on day 16 post-challenge, that was abrogated by chronic administration of IL-1Ra via a subcutaneously implanted osmotic minipump geared to deliver 7 mg IL-1Ra/day. These results show that overexpression of IL-1beta in the brain during the course of a chronic inflammation has deleterious consequences on cognitive processes, that are reversed by blockade of IL-1 receptors.

Conditioned taste aversion with lipopolysaccharide and peptidoglycan does not activate cytokine gene expression in the spleen and hypothalamus of mice.

Several reports show that behavioural and physiological components of the acute phase reaction can be conditioned. However, the mechanisms responsible for these effects remain obscure. The underlying assumption that the changes observed in conditioned animals are dependent on a conditioned production of cytokines has never been demonstrated. In the present study, the possibility of conditioning the production of cytokines or molecules implicated in their signalling pathways was tested by submitting mice to conditioned taste aversion with a new saccharin taste paired with intraperitoneal (i.p.) injections of lipopolysaccharide (LPS, 0.83 microg/g) or peptidoglycan (PGN, 20 microg/g). After two conditioning sessions, conditioned mice developed a clear aversion to saccharine that was not associated with activation of genes of the cytokine network either at the periphery, or in the hypothalamus, as demonstrated by a macroarray approach and confirmed by real time RT-PCR. In contrast, there was an activation of the genes coding for nuclear factor kappa B (NFkappaB) and mitogen activated protein kinase (MAPK) signalling pathways in the spleen and to a lesser extent in the hypothalamus. This modulation of the NFkappaB and MAPK signalling pathways is interpreted in terms of a possible conditioned sensitisation of the immune system.