Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls

Flon, Pierre de; Söderström, Lars; Laurell, Katarina; Dring, Ann; Sundström, Peter; Gunnarsson, Martin; Svenningsson, Anders

doi:10.1371/journal.pone.0192516

Cited by 16 publications

(15 citation statements)

References 24 publications

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“…25,26 Switching to RTX from using other drugs also showed improvements of disease progression. 27 However, no study to our knowledge described the effect of RTX as a preventive agent. Prevention is highly important, and it may save the patients lots of aggravated pain before the disease progresses.…”

Section: Discussionmentioning

confidence: 99%

Rituximab Prevents the Development of Experimental Autoimmune Encephalomyelitis (EAE): Comparison with Prophylactic, Therapeutic or Combinational Regimens

Al‐Ani¹,

Raju²,

Hachim³

et al. 2020

JIR

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Objective: To investigate, in detail, the effects of rituximab (RTX), an off-label drug for treating multiple sclerosis (MS) disease on preventing and/or ameliorating experimental autoimmune encephalomyelitis (EAE). Methods: Using bioinformatics analysis of publicly available transcriptomics data, we determined the accumulation of B cells, plasma cells and T cells in different compartments of multiple sclerosis patients (MS) and healthy individual brains. Based on these observations and on the literature search, we dosed RTX in EAE mice either orally, or injected intraperitoneally (IP). The latter route was used either prophylactically (asymptomatic stage; upon the induction of the disease), or therapeutically (acute stage; upon the appearance of the first sign of the disease). Further, we used RTX as a preventive drug either as a single agent or in combination with other routes of administration. Results: Because no complete recovery was observed when RTX was used prophylactically or therapeutically, we devised another protocol of injecting this drug before the onset of the disease and designated this regiment as prevention. We demonstrated that the 20 μg/mouse prevention completely reduced the EAE clinical score, impaired infiltration of T and B cells into the perivascular space of mice brains, along with inhibiting the inflammation and demyelination. However, the 5 and 10 μg/mouse doses although reduced all aspects of inflammation in these mice, their effects were not as potent as the 20 μg/mouse RTX dose. Finally, we combined the 5 μg/mouse prevention treatment with either the prophylactic or therapeutic regimen and observed a robust effect. Conclusion: We observed that combinatorial regimens resulted in further reduction of inflammation, T and B cell extravasation into the brains of EAE mice and improved the remyelination.

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Section: Discussionmentioning

confidence: 99%

Rituximab Prevents the Development of Experimental Autoimmune Encephalomyelitis (EAE): Comparison with Prophylactic, Therapeutic or Combinational Regimens

Al‐Ani¹,

Raju²,

Hachim³

et al. 2020

JIR

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“…128,129 Further, the levels of CXCL8 and CXCL10 chemokines decreased significantly after treatment with rituximab. 130…”

Section: Rituximab Effects On the Chemokines And Chemokine Receptorsmentioning

confidence: 99%

Targeting Chemokines and Chemokine Receptors in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Dhaiban

Al‐Ani

Elemam

et al. 2020

JIR

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Multiple sclerosis (MS) is an immune-mediated and neurodegenerative disorder that results in inflammation and demyelination of the central nervous system (CNS). MS symptoms include walking difficulties, visual weakening, as well as learning and memory impairment, thus affecting the quality of the patient's life. Chemokines and chemokine receptors are expressed on the immune cells as well as the CNS resident cells. Several sets of chemokine receptors and their ligands tend to be pathogenic players in MS, including CCL2,

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“…This is in accordance with previous reporting that the highest risk of shunt failure is acute, which decreases over time and over number of revised shunts 43 , and the fact that hydrocephalus is more common in infants 6,9 . Data for healthy controls was retrieved from previous publications where similar multiplex ELISAs were performed using agematched patient CSF whenever possible [20][21][22]47 and added to the gures as a dotted line. All pediatric subjects underwent routine MRIs and/or CT to assist in the diagnosis of a shunt malfunction.…”

Section: Study Populationmentioning

confidence: 99%

Cerebrospinal Fluid Biomarkers of Neuroinflammation in Children with Hydrocephalus and Shunt Malfunction

Harris

Morales

Arshad

et al. 2020

Preprint

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Background: Cerebrospinal fluid (CSF) shunt systems fail approximately 30% of the time within the first year of shunt implantation, while 98% of all patients with hydrocephalus (HCP) will suffer shunt failure in their lifetime. Perhaps due to the heterogeneity in etiology or the unique environment housing CSF shunt systems, the underlying reasons for shunt failure continue to elude researchers and clinicians. Still, obstruction remains the most common reason for shunt failure and it is vital to understand what factors may be contributing or driving shunt failure for improving patient outcomes and ultimately quality of life.Methods: Using multiplex ELISA, this study first examined the protein concentration profiles of select pro-inflammatory and anti-inflammatory cytokines, as well as select matrix metalloproteinases (MMPs) in 38 pediatric patients and their CSF obtained at shunt revision operation; all patients pediatric (<18). Shunt failure was further examined for interdependencies between the past number of previous revisions, length of time implanted, patient age, and the surgeon-described reason for revision noted as obstruction or non-obstruction. The pro-inflammatory cytokines were IL-1β, IL-2, IL-5, IL-6, IL-8, IL-12, IL-17, TNF-α, GM-CSF, IFN-γ. The anti-inflammatory cytokines were IL-4 and IL-10, and the MMPs are MMP-2, MMP-3, MMP-7, MMP-9. protein concentration is reported as pg/mL for each analyte. Results: IL-10, IL-6, IL-8 and MMP-7 demonstrated significantly increased concentrations in patient CSF for the non-obstructed subgroup compared to the obstructed subgroup (p=<0.05). Under generalized etiology, these analytes present within communicating HCP cases (15 of which were diagnosed with PHH) compared to non-communicating HCP or traumatic brain injury (TBI) cases. Further examination revealed that CSF IL-6 was significantly increased in both obstructed and non-obstructed cases, predominately for PHH and congenital HCP patients while IL-8 was significantly higher only in PHH patients. In terms of number of past revisions, IL-10, IL-6, IL-8, MMP-7 and MMP-9 significantly and progressively increased from zero to two past revisions and then significantly declined and remained low for subsequent revisions (p=<0.05). In terms of implantation time, CSF from shunts implanted for three months or less show significantly increased concentration for IL-6, IL-8, and MMP-7 (p=<0.05). Lastly, Six months or less was the age identified to coincide with significantly increased concentration of IL-6, IL-8, and MMP-7 (p=<0.05). Conclusion: Of all the cytokines and MMPs tested, IL-10, IL-6, IL-8, MMP-7 and MMP-9 were significantly elevated compared to other cytokines and MMPs in the various dependencies evaluated. IL-6 and IL-8 stand out in our study with significantly increased concentration in select etiologies, age, length of time implanted. The aforementioned cytokines and MMPs all showed an interesting relation with number of past revisions which warrants further examination. Non-obstruction cases were determined to be accompany significantly higher CSF cytokine MMP presence compared to obstructive cases. This suggests closer examination to the extent of the role neuroinflammation plays for causing obstruction in HCP patients. Additionally, IL-10 was associated with the length of time implanted as well as number of past revisions, and higher in non-obstructed cases compared to obstructed cases. A severity-dependent interplay between IL-10, IL-6 and IL-8 is an area for expansion and may provide foundation for therapeutic control of neuroinflammation.Trial registration: Not applicable.

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Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls

Cited by 16 publications

References 24 publications

<p>Rituximab Prevents the Development of Experimental Autoimmune Encephalomyelitis (EAE): Comparison with Prophylactic, Therapeutic or Combinational Regimens</p>

<p>Rituximab Prevents the Development of Experimental Autoimmune Encephalomyelitis (EAE): Comparison with Prophylactic, Therapeutic or Combinational Regimens</p>

<p>Targeting Chemokines and Chemokine Receptors in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis</p>

Cerebrospinal Fluid Biomarkers of Neuroinflammation in Children with Hydrocephalus and Shunt Malfunction

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