scholarly journals Probing the peripheral immune response in mouse models of oxaliplatin-induced peripheral neuropathy highlights their limited translatability

2021 ◽  
Vol 6 ◽  
pp. 68
Author(s):  
Zoe Lee Hore ◽  
Sara Villa-Hernandez ◽  
Franziska Denk
Keyword(s):  
Immune Response ◽  
Peripheral Neuropathy ◽  
Lymph Nodes ◽  
Myeloid Cell ◽  
Chemotherapeutic Agents ◽  
Mechanical Stimuli ◽  
Inguinal Lymph Nodes ◽  
Peripheral Immune Response ◽  
Repeated Dosing ◽  
Underlying Mechanisms

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of various chemotherapeutic agents, including oxaliplatin. It is highly prevalent amongst cancer patients, causing sensory abnormalities and pain. Unfortunately, as the underlying mechanisms remain poorly understood, effective therapeutics are lacking. Neuro-immune interactions have been highlighted as potential contributors to the development and maintenance of CIPN, however, whether this is the case in oxaliplatin-induced peripheral neuropathy (OIPN) is yet to be fully established. Methods: In this study we used flow cytometry to examine the peripheral immune response of male C57BL/6 mice following both single and repeated oxaliplatin administration. In animals exposed to repeated dosing, we also undertook mechanical and thermal behavioural assays to investigate how oxaliplatin alters phenotype, and conducted RT-qPCR experiments on bone marrow derived macrophages in order to further inspect the effects of oxaliplatin on immune cells. Results: In contrast to other reports, we failed to observe substantial changes in overall leukocyte, lymphocyte or myeloid cell numbers in dorsal root ganglia, sciatic nerves or inguinal lymph nodes. We did however note subtle, tissue-dependant alterations in several myeloid subpopulations following repeated dosing. These included a significant reduction in MHCII antigen presenting cells in the sciatic nerve and an increase in infiltrating cell types into the inguinal lymph nodes. Though repeated oxaliplatin administration had a systemic effect, we were unable to detect a pain-like behavioural phenotype in response to either cold or mechanical stimuli. Consequently, we cannot comment on whether the observed myeloid changes are associated with OIPN. Conclusions: Our discussion puts these results into the wider context of the field, advocating for greater transparency in reporting, alignment in experimental design and the introduction of more clinically relevant models. Only through joint concerted effort can we hope to increase our understanding of the underlying mechanisms of CIPN, including any immune contributions.

scholarly journals Probing the peripheral immune response in mouse models of oxaliplatin-induced peripheral neuropathy highlights their limited translatability

2021 ◽  
Vol 6 ◽  
pp. 68
Author(s):  
Zoe Lee Hore ◽  
Sara Villa-Hernandez ◽  
Franziska Denk
Keyword(s):  
Immune Response ◽  
Peripheral Neuropathy ◽  
Lymph Nodes ◽  
Myeloid Cell ◽  
Chemotherapeutic Agents ◽  
Mechanical Stimuli ◽  
Inguinal Lymph Nodes ◽  
Peripheral Immune Response ◽  
Repeated Dosing ◽  
Underlying Mechanisms

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of various chemotherapeutic agents, including oxaliplatin. It is highly prevalent amongst cancer patients, causing sensory abnormalities and pain. Unfortunately, as the underlying mechanisms remain poorly understood, effective therapeutics are lacking. Neuro-immune interactions have been highlighted as potential contributors to the development and maintenance of CIPN, however, whether this is the case in oxaliplatin-induced peripheral neuropathy (OIPN) is yet to be fully established. Methods: In this study we used flow cytometry to examine the peripheral immune response of male C57BL/6 mice following both single and repeated oxaliplatin administration. In animals exposed to repeated dosing, we also undertook mechanical and thermal behavioural assays to investigate how oxaliplatin alters phenotype, and conducted RT-qPCR experiments on bone marrow derived macrophages in order to further inspect the effects of oxaliplatin on immune cells. Results: In contrast to other reports, we failed to observe substantial changes in overall leukocyte, lymphocyte or myeloid cell numbers in dorsal root ganglia, sciatic nerves or inguinal lymph nodes. We did however note subtle, tissue-dependant alterations in several myeloid subpopulations following repeated dosing. These included a significant reduction in MHCII antigen presenting cells in the sciatic nerve and an increase in infiltrating cell types into the inguinal lymph nodes. Though repeated oxaliplatin administration had a systemic effect, we were unable to detect a pain-like behavioural phenotype in response to either cold or mechanical stimuli. Consequently, we cannot comment on whether the observed myeloid changes are associated with OIPN. Conclusions: Our discussion puts these results into the wider context of the field, advocating for greater transparency in reporting, alignment in experimental design and the introduction of more clinically relevant models. Only through joint concerted effort can we hope to increase our understanding of the underlying mechanisms of CIPN, including any immune contributions.

scholarly journals Sequential Changes in the Mesenteric Lymph Node Microbiome and Immune Response during Cirrhosis Induction in Rats

mSystems ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Alba Santiago ◽  
Elisabet Sanchez ◽  
Allison Clark ◽  
Marta Pozuelo ◽  
Miguel Calvo ◽  
...  
Keyword(s):  
Immune Response ◽  
Lymph Nodes ◽  
Cytokine Production ◽  
Decompensated Cirrhosis ◽  
Mesenteric Lymph Nodes ◽  
Fecal Microbiome ◽  
Mesenteric Lymph ◽  
Systemic Cytokine Production ◽  
Underlying Mechanisms ◽  
Microbial Groups

ABSTRACT Whether the interaction between the gut microbiota and the immune response influences the evolution of cirrhosis is poorly understood. We aimed to investigate modifications of the microbiome and the immune response during the progression of cirrhosis. Rats were treated with carbon tetrachloride (CCl4) to induce cirrhosis. We then assessed microbiome load and composition in stool, ileocecal contents (ICCs), mesenteric lymph nodes (MLNs), blood, and ascitic fluids (AFs) at 6, 8, and 10 weeks or ascites production and measured cytokine production in MLNs and blood. The microbiome of MLN, blood, and AF showed a distinct composition compared to that of stool and ICCs. Betaproteobacteria (Sutterella) were found associated with the appearance of a decompensated state of cirrhosis. Microbial load increased and showed a positive correlation with the relative abundance of pathobionts in the MLN of decompensated rats. Among several genera, Escherichia and “Candidatus Arthromitus” positively correlated with elevated levels of systemic proinflammatory cytokines. “Candidatus Arthromitus,” a segmented filamentous bacteria, was detected in ICC, MLN, and AF samples, suggesting a possible translocation from the gut to the AF through the lymphatic system, whereas Escherichia was detected in ICC, MLN, AF, and blood, suggesting a possible translocation from the gut to the AF through the bloodstream. In the present study, we demonstrate that microbiome changes in distinct intestinal sites are associated with microbial shifts in the MLNs as well as an increase in cytokine production, providing further evidence of the role the gut-liver-immunity axis plays in the progression of cirrhosis. IMPORTANCE Cirrhosis severity in patients was previously shown to be associated with progressive changes in the fecal microbiome in a longitudinal setting. Recent evidence shows that bacterial translocation from the gut to the extraintestinal sites could play a major role in poor disease outcome and patient survival. However, the underlying mechanisms involving the microbiota in the disease progression are not well understood. Here, using an animal model of cirrhosis in a longitudinal and multibody sites setting, we showed the presence of a distinct composition of the microbiome in mesenteric lymph nodes, blood, and ascitic fluid compared to that in feces and ileocecal content, suggesting compartmentalization of the gut microbiome. We also demonstrate that microbiome changes in intestinal sites are associated with shifts in specific microbial groups in the mesenteric lymph nodes as well as an increase in systemic cytokine production, linking inflammation to decompensated cirrhosis in the gut-liver-immunity axis.

Radiation synovectomy of the knee joint

2006 ◽  
Vol 45 (01) ◽  
pp. 57-61
Author(s):  
M. Puille ◽  
D. Steiner ◽  
R. Bauer ◽  
R. Klett
Keyword(s):  
Knee Joint ◽  
Lymph Nodes ◽  
Geometric Mean ◽  
Radiation Synovectomy ◽  
Real Activity ◽  
Anterior View ◽  
Inguinal Lymph Nodes ◽  
The Real ◽  
Therapeutic Modalities ◽  
Real Value

Summary Aim: Multiple procedures for the quantification of activity leakage in radiation synovectomy of the knee joint have been described in the literature. We compared these procedures considering the real conditions of dispersion and absorption using a corpse phantom. Methods: We simulated different distributions of the activity in the knee joint and a different extra-articular spread into the inguinal lymph nodes. The activity was measured with a gammacamera. Activity leakage was calculated by measuring the retention in the knee joint only using an anterior view, using the geometric mean of anterior and posterior views, or using the sum of anterior and posterior views. The same procedures were used to quantify the activity leakage by measuring the activity spread into the inguinal lymph nodes. In addition, the influence of scattered rays was evaluated. Results: For several procedures we found an excellent association with the real activity leakage, shown by an r² between 0.97 and 0.98. When the real value of the leakage is needed, e. g. in dosimetric studies, simultaneously measuring of knee activity and activity in the inguinal lymph nodes in anterior and posterior views and calculation of the geometric mean with exclusion of the scatter rays was found to be the procedure of choice. Conclusion: When measuring of activity leakage is used for dosimetric calculations, the above-described procedure should be used. When the real value of the leakage is not necessary, e. g. for comparing different therapeutic modalities, several of the procedures can be considered as being equivalent.

The Therapeutic Potential of Chemokines in the Treatment of Chemotherapy- Induced Peripheral Neuropathy

2020 ◽  
Vol 21 (3) ◽  
pp. 288-301 ◽  
Author(s):  
Lin Zhou ◽  
Luyao Ao ◽  
Yunyi Yan ◽  
Wanting Li ◽  
Anqi Ye ◽  
...  
Keyword(s):  
Nervous System ◽  
Neuropathic Pain ◽  
Immune System ◽  
Peripheral Neuropathy ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Chemotherapeutic Agents ◽  
Cell Trafficking ◽  
Mediated Communication ◽  
Novel Therapeutic Strategies

Background: Some of the current challenges and complications of cancer therapy are chemotherapy- induced peripheral neuropathy (CIPN) and the neuropathic pain that are associated with this condition. Many major chemotherapeutic agents can cause neurotoxicity, significantly modulate the immune system and are always accompanied by various adverse effects. Recent evidence suggests that cross-talk occurs between the nervous system and the immune system during treatment with chemotherapeutic agents; thus, an emerging concept is that neuroinflammation is one of the major mechanisms underlying CIPN, as demonstrated by the upregulation of chemokines. Chemokines were originally identified as regulators of peripheral immune cell trafficking, and chemokines are also expressed on neurons and glial cells in the central nervous system. Objective: In this review, we collected evidence demonstrating that chemokines are potential mediators and contributors to pain signalling in CIPN. The expression of chemokines and their receptors, such as CX3CL1/CX3CR1, CCL2/CCR2, CXCL1/CXCR2, CXCL12/CXCR4 and CCL3/CCR5, is altered in the pathological conditions of CIPN, and chemokine receptor antagonists attenuate neuropathic pain behaviour. Conclusion: By understanding the mechanisms of chemokine-mediated communication, we may reveal chemokine targets that can be used as novel therapeutic strategies for the treatment of CIPN.

Beneficial Effects of Fingolimod on Social Interaction, CNS and Peripheral Immune Response in the BTBR Mouse Model of Autism

Neuroscience ◽  
2020 ◽  
Vol 435 ◽  
pp. 22-32
Author(s):  
Roberta De Simone ◽  
Alessia Butera ◽  
Monica Armida ◽  
Antonella Pezzola ◽  
Monica Boirivant ◽  
...  
Keyword(s):  
Immune Response ◽  
Social Interaction ◽  
Mouse Model ◽  
Beneficial Effects ◽  
Btbr Mouse ◽  
Peripheral Immune Response

scholarly journals Mechanisms of Venoarteriolar Reflex in Type 2 Diabetes with or without Peripheral Neuropathy

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 333
Author(s):  
Cécile Reynès ◽  
Antonia Perez-Martin ◽  
Houda Ennaifer ◽  
Henrique Silva ◽  
Yannick Knapp ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Peripheral Neuropathy ◽  
Spectral Power ◽  
Blood Perfusion ◽  
Doppler Flowmetry ◽  
Relative Contribution ◽  
Total Spectral Power ◽  
Underlying Mechanisms ◽  
Endothelial Nitric Oxide

The aim of this study is to investigate the underlying mechanisms of the venoarteriolar reflex (VAR) in type 2 diabetes mellitus (T2DM), with and without peripheral neuropathy. Laser Doppler flowmetry (LDF) recordings were performed on the medial malleus and dorsal foot skin, before and during leg dependency in healthy controls, in persons with obesity, in those with T2DM, in those with T2DM and subclinical neuropathy, and in those with T2DM and confirmed neuropathy. LDF recordings were analyzed with the wavelet transform to evaluate the mechanisms controlling the flowmotion (i.e., endothelial nitric oxide-independent and -dependent, neurogenic, myogenic, respiratory and cardiac mechanisms). Skin blood perfusion decreased throughout leg dependency at both sites. The decrease was blunted in persons with confirmed neuropathy compared to those with T2DM alone and the controls. During leg dependency, total spectral power increased in all groups compared to rest. The relative contribution of the endothelial bands increased and of the myogenic band decreased, without differences between groups. Neurogenic contribution decreased in controls, in persons with obesity and in those with T2DM, whereas it increased in subclinical- and confirmed neuropathy. In conclusion, this study provides evidence that confirmed diabetic neuropathy alters the VAR through the neurogenic response to leg dependency.

scholarly journals Melittin, a honeybee venom derived peptide for the treatment of chemotherapy-induced peripheral neuropathy

2021 ◽  
Vol 38 (5) ◽  
Author(s):  
Tenzin Tender ◽  
Rakesh Ravishankar Rahangdale ◽  
Sridevi Balireddy ◽  
Madhavan Nampoothiri ◽  
K. Krishna Sharma ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Motor Nerve ◽  
Symptomatic Relief ◽  
Neurological Complication ◽  
Treatment Protocol ◽  
Chemotherapeutic Agents ◽  
Lens Protein ◽  
Active Constituent ◽  
Honeybee Venom ◽  
Eye Lens Protein

Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of cancer treatment which involves sensory and motor nerve dysfunction. Severe CIPN has been reported in around 5% of patients treated with single and up to 38% of patients treated with multiple chemotherapeutic agents. Present medications available for CIPN are the use of opioids, nonsteroidal anti-inflammatory agents, and tricyclic antidepressants, which are only marginally effective in treating neuropathic symptoms. In reality, symptom reappears after these drugs are discontinued. The pathogenesis of CIPN has not been sufficiently recognized and methods for the prevention and treatment of CIPN remain vulnerable to therapeutic problems. It has witnessed that the present medicines available for the disease offer only symptomatic relief for the short term and have severe adverse side effects. There is no standard treatment protocol for preventing, reducing, and treating CIPN. Therefore, there is a need to develop curative therapy that can be used to treat this complication. Melittin is the main pharmacological active constituent of honeybee venom and has therapeutic values including in chemotherapeutic-induced peripheral neuropathy. It has been shown that melittin and whole honey bee venom are effective in treating paclitaxel and oxaliplatin-induced peripheral neuropathy. The use of melittin against peripheral neuropathy caused by chemotherapy has been limited despite having strong therapeutic efficacy against the disease. Melittin mediated haemolysis is the key reason to restrict its use. In our study, it is found that α-Crystallin (an eye lens protein) is capable of inhibiting melittin-induced haemolysis which gives hope of using an appropriate combination of melittin and α-Crystallin in the treatment of CIPN. The review summarizes the efforts made by different research groups to address the concern with melittin in the treatment of chemotherapeutic-induced neuropathy. It also focuses on the possible approaches to overcome melittin-induced haemolysis. Graphic Abstract

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