Multiple SclerosisNCT03735823
IL-11 in the Development of Multiple Sclerosis
An observational study of Multiple Sclerosis, run by Thomas Jefferson University at 1 site in United States.
Trial summary
Since the last submission, the investigator have further characterized the potential of IL--11 to induce encephalitogenic CD4+IL--17A+, IL--21+ and GM--CSF+ cells, which upon passive transfer induced severe RREAE with IL--17A+CCR6+ CD4+ cell, neutrophil, CD8+ and B--cell accumulation within the CNS (manuscript… Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Multiple Sclerosis
- How many people
- 96 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jun 2018to 31 May 2023
- How long will I take part?
- 1 Year
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: 56 untreated patients with CIS according to the Revised McDonald Diagnostic Criteria and 40 control subjects with no evidence of the inflammatory diseases will be enrolled. Female and male subjects will be enrolled.
Who may be able to join
- First clinical presentation and at least two central nervous system MRI lesions consistent with demyelinating disease;
- Age 18-65 inclusive;
- Extended disability status score (EDSS) 1.5-5.5;
- No immunomodulatory or immunosuppresive therapy prior to the enrollment in the study.
Who cannot join
- Concomitant infection;
- Significant medical and psychiatric condition at the disgression of principal investigator;
- Pregnant women;
- Children and patients participating in research trials will not be enrolled in this study.
Trial locations and contacts
1 site in 1 country.
United States1 site, 1 recruiting
- Recruiting
Thomas Jefferson University
Philadelphia, Pennsylvania, 19446
Silva Markovic-Plese, MD PhD, 215-955-6871, silva.Markovic-Plese@jefferson.edu
About this study
Official title: The Role of IL-II in the Development of Autoimmune Response in Multiple Sclerosis
Since the last submission, the investigator have further characterized the potential of IL--11 to induce encephalitogenic CD4+IL--17A+, IL--21+ and GM--CSF+ cells, which upon passive transfer induced severe RREAE with IL--17A+CCR6+ CD4+ cell, neutrophil, CD8+ and B--cell accumulation within the CNS (manuscript submitted for publication). These findings confirmed our hypothesis and further characterization of the IL--11--induced encephalitogenic CD4+ cells will be performed as planned in the grant proposal
Read the detailed description
Immunomodulatory therapies are most effective when administered early in the course of relapsing remitting multiple sclerosis (RRMS). Therefore, investigators are seeking biomarkers of the autoimmune response to accurately identify patients with clinically isolated syndrome (CIS), the earliest phase of the disease. Investigators' preliminary studies have identified IL--11 as the most significantly increased cytokine in the serum and cerebrospinal fluid (CSF) of CIS patients. Serum IL--11 and IL--17A levels correlate with brain MRI T2 and T1 lesion load and were significantly increased during clinical exacerbations in comparison to disease remissions in untreated RRMS patients. Investigators also found that IL--11 induces Th17 cell differentiation and expansion in CIS patients. Investigators' human studies have identified that CD4+ cells represent the predominant source of IL--11 within the peripheral circulation. In comparison to healthy controls (HCs), IL--11+CD4+ cells from CIS patients were significantly increased in the peripheral circulation and exhibited the highest CCR6 expression (86 %) among CD4+ T cell subsets. This implied their potential for early migration to the CNS. Indeed, IL-11+CD4+ cells were significantly enriched in the CSF of RRMS patients in comparison to their matched blood samples (40.9 vs. 2.3%), with the most prominent increase in the number of IL--17A+IL--11+CD4+ cells. Immunohistochemistry studies of active brain MS lesion biopsy samples revealed an enrichment of IL--11+ cells within CD4+ infiltrating cells, suggesting their important role in the development of inflammatory CNS lesions. Animal studies have confirmed the causal role of IL--11 in the exacerbation of RR experimental autoimmune encephalomyelitis (EAE), where IL--11 increased the number of central nervous system (CNS)--infiltrating IL-17A+CD4+ cells in comparison to control mice with EAE, reflecting IL--11 induction of CCR6 expression in CD4+ cells. IL--11Ra KO mice had an attenuated EAE clinical course and lower serum IL--17A levels, as well as lower numbers of Il--17A+CD4+ cells in the brain and spinal cord inflammatory infiltrates, similar to the IL23p19 KO mice. Administration of mouse anti IL--11R mAb in the preclinical phase of EAE induced a delayed onset and decreased disease severity, with decreased IL--17A serum levels. The objectives of this study are to (1) identify the molecular mechanisms involved in the IL--11--induced migration of CD4+ cell subsets to the CNS, (2) Functionally characterize CSF--enriched IL--11+CD4+ cells in CIS patients, (3) examine the potential of IL--11 to induce encephalitogenic CD4+ cells, and determine the therapeutic effect of anti IL--11R mAb in RREAE.
Specific Aims:
Aim 1. Characterize the IL--11--induced migration of CD4+ cell subsets in CIS patients.
1.A. Identify signaling pathways involved in the IL--11--induced migration of CD4+ cell subsets to the CNS. Investigators will identify IL--11--stimulated signaling pathways mediating expression of CCR6 and adhesion molecules on CD45RO+ cells.
- B. Determine direct chemotactic effect of IL--11 in CD4+ cell subsets. In vitro migration assays will determine a direct chemotactic effect of IL--11 on the migration of CD4+ cell subsets through the endothelial cell (EC) barrier. Aim 2. Identify the transcriptional profile and TCRVb repertoire of CSF--enriched IL--11+CD4+ cells from CIS patients.
- A. Characterize the phenotype and transcriptional profile of CSF--enriched IL--11+CD4+ cells. Flow cytometry phenotyping and RNA sequencing will be performed on IL--11+CD4+ cells from CSF and matched blood samples.
2.B. Determine the TCRVb repertoire of CSF IL--11+CD4+ cells. Identify whether they can be tracked to the peripheral circulation.
Aim 3. Characterize the role of IL--11 in the induction of encephalitogenic CD4+ cells.
3.A. Determine the capacity of IL--11 to induce encephalitogenic CD4+ cells. In vivo experiments will test the effect of IL--11 on the encephalitogenic capacity of CD4+ cells.
3.B. Determine the efficacy of anti IL--11R mAb in preventing and suppressing RREAE. Mice with RREAE will be treated prior to and during the clinical flare--ups and the remission of the disease. The therapeutic effect of anti IL--11R mAb will be characterized via the clinical response, immunohistochemistry, and flow cytometry studies of CNS infiltrating cells.
- Conditions
- Multiple Sclerosis
- Being tested
- No intervention, just collect blood samples and CSF samples
- Keywords
- IL-11 T cell migration
- Medical subject headings
- Multiple Sclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
No intervention, just collect blood samples and CSF samplesOther
Also called No intervention
No intervention
What is being measured
The primary outcome is the main question the study is designed to answer.
Adhesion marker expression of IL-11 producing CD4 T cells in the CNS and peripheral
surface adhesion marker Vla-4,Vla-2 and ICAM-1 expression pattern
Measured: baseline
Cytokine receptor expression of IL-11 producing CD4 T cells in the CNS and peripheral
cytokine receptor IL1R,IL6R,IL23R,IL11RA,IL21R and IL17RA expression pattern
Measured: baseline
Chemokine receptor expression of IL-11 producing CD4 T cells in the CNS and peripheral
chemokine receptor CXCR3,CCR7,CCR6,CCR10 and CCR4 expression
Measured: baseline
transcription factor expression of IL-11 producing CD4 T cells in the CNS and peripheral
transcription factor pstat3, Gata3, Tbet,RORrt and Foxp3 expression pattern
Measured: baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Nov 2018
- Study start1 Jun 2018
- Primary completion31 May 2023 (estimated)
- Study completion31 May 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Multiple SclerosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 96 participants (estimated)
- Target duration
- 1 Year
Sponsor and investigators
- Lead sponsor
- Thomas Jefferson University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Silva Markovic-Plese, MD PhD, Principal investigator, Thomas Jefferson University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03735823
- Sponsor's protocol ID
- 080-19000-S31301
- Status last verified
- Jun 2022
- First submitted
- 7 Nov 2018
- Last updated
- 6 Jun 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: Investigators probably share data with other potential collaborators for further research
Study at a glance
From the registry record, last updated by the sponsor on 6 Jun 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Role of IL-II in the Development of Autoimmune Response in Multiple Sclerosis
- ClinicalTrials.gov ID
- NCT03735823
- Acronym / sponsor ID
- 080-19000-S31301
- Conditions
- Multiple Sclerosis
- Keywords
- IL-11 T cell migration
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 96 participants (estimated)
- Lead sponsor
- Thomas Jefferson UniversityUniversity, hospital or other
- Study start
- 1 Jun 2018 (actual)
- Primary completion
- 31 May 2023 (estimated)
- Study completion
- 31 May 2023 (estimated)
- First posted
- 8 Nov 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Since the last submission, the investigator have further characterized the potential of IL--11 to induce encephalitogenic CD4+IL--17A+, IL--21+ and GM--CSF+ cells, which upon passive transfer induced severe RREAE with IL--17A+CCR6+ CD4+ cell, neutrophil, CD8+ and B--cell accumulation within the CNS (manuscript submitted for publication). These findings confirmed our hypothesis and further characterization of the IL--11--induced encephalitogenic CD4+ cells will be performed as planned in the grant proposal
Detailed description
Immunomodulatory therapies are most effective when administered early in the course of relapsing remitting multiple sclerosis (RRMS). Therefore, investigators are seeking biomarkers of the autoimmune response to accurately identify patients with clinically isolated syndrome (CIS), the earliest phase of the disease. Investigators' preliminary studies have identified IL--11 as the most significantly increased cytokine in the serum and cerebrospinal fluid (CSF) of CIS patients. Serum IL--11 and IL--17A levels correlate with brain MRI T2 and T1 lesion load and were significantly increased during clinical exacerbations in comparison to disease remissions in untreated RRMS patients. Investigators also found that IL--11 induces Th17 cell differentiation and expansion in CIS patients. Investigators' human studies have identified that CD4+ cells represent the predominant source of IL--11 within the peripheral circulation. In comparison to healthy controls (HCs), IL--11+CD4+ cells from CIS patients were significantly increased in the peripheral circulation and exhibited the highest CCR6 expression (86 %) among CD4+ T cell subsets. This implied their potential for early migration to the CNS. Indeed, IL-11+CD4+ cells were significantly enriched in the CSF of RRMS patients in comparison to their matched blood samples (40.9 vs. 2.3%), with the most prominent increase in the number of IL--17A+IL--11+CD4+ cells. Immunohistochemistry studies of active brain MS lesion biopsy samples revealed an enrichment of IL--11+ cells within CD4+ infiltrating cells, suggesting their important role in the development of inflammatory CNS lesions. Animal studies have confirmed the causal role of IL--11 in the exacerbation of RR experimental autoimmune encephalomyelitis (EAE), where IL--11 increased the number of central nervous system (CNS)--infiltrating IL-17A+CD4+ cells in comparison to control mice with EAE, reflecting IL--11 induction of CCR6 expression in CD4+ cells. IL--11Ra KO mice had an attenuated EAE clinical course and lower serum IL--17A levels, as well as lower numbers of Il--17A+CD4+ cells in the brain and spinal cord inflammatory infiltrates, similar to the IL23p19 KO mice. Administration of mouse anti IL--11R mAb in the preclinical phase of EAE induced a delayed onset and decreased disease severity, with decreased IL--17A serum levels. The objectives of this study are to (1) identify the molecular mechanisms involved in the IL--11--induced migration of CD4+ cell subsets to the CNS, (2) Functionally characterize CSF--enriched IL--11+CD4+ cells in CIS patients, (3) examine the potential of IL--11 to induce encephalitogenic CD4+ cells, and determine the therapeutic effect of anti IL--11R mAb in RREAE.
Specific Aims:
Aim 1. Characterize the IL--11--induced migration of CD4+ cell subsets in CIS patients.
1.A. Identify signaling pathways involved in the IL--11--induced migration of CD4+ cell subsets to the CNS. Investigators will identify IL--11--stimulated signaling pathways mediating expression of CCR6 and adhesion molecules on CD45RO+ cells.
- B. Determine direct chemotactic effect of IL--11 in CD4+ cell subsets. In vitro migration assays will determine a direct chemotactic effect of IL--11 on the migration of CD4+ cell subsets through the endothelial cell (EC) barrier. Aim 2. Identify the transcriptional profile and TCRVb repertoire of CSF--enriched IL--11+CD4+ cells from CIS patients.
- A. Characterize the phenotype and transcriptional profile of CSF--enriched IL--11+CD4+ cells. Flow cytometry phenotyping and RNA sequencing will be performed on IL--11+CD4+ cells from CSF and matched blood samples.
2.B. Determine the TCRVb repertoire of CSF IL--11+CD4+ cells. Identify whether they can be tracked to the peripheral circulation.
Aim 3. Characterize the role of IL--11 in the induction of encephalitogenic CD4+ cells.
3.A. Determine the capacity of IL--11 to induce encephalitogenic CD4+ cells. In vivo experiments will test the effect of IL--11 on the encephalitogenic capacity of CD4+ cells.
3.B. Determine the efficacy of anti IL--11R mAb in preventing and suppressing RREAE. Mice with RREAE will be treated prior to and during the clinical flare--ups and the remission of the disease. The therapeutic effect of anti IL--11R mAb will be characterized via the clinical response, immunohistochemistry, and flow cytometry studies of CNS infiltrating cells.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 1 Year
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- 56 untreated patients with CIS according to the Revised McDonald Diagnostic Criteria and 40 control subjects with no evidence of the inflammatory diseases will be enrolled. Female and male subjects will be enrolled.
Key inclusion criteria (4 listed)
- First clinical presentation and at least two central nervous system MRI lesions consistent with demyelinating disease;
- Age 18-65 inclusive;
- Extended disability status score (EDSS) 1.5-5.5;
- No immunomodulatory or immunosuppresive therapy prior to the enrollment in the study.
Key exclusion criteria (4 listed)
- Concomitant infection;
- Significant medical and psychiatric condition at the disgression of principal investigator;
- Pregnant women;
- Children and patients participating in research trials will not be enrolled in this study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| No intervention, just collect blood samples and CSF samplesAlso: No interventionNo intervention | Other | – |
Primary outcome
Adhesion marker expression of IL-11 producing CD4 T cells in the CNS and peripheral
Time frame: baseline
surface adhesion marker Vla-4,Vla-2 and ICAM-1 expression pattern
Cytokine receptor expression of IL-11 producing CD4 T cells in the CNS and peripheral
Time frame: baseline
cytokine receptor IL1R,IL6R,IL23R,IL11RA,IL21R and IL17RA expression pattern
Chemokine receptor expression of IL-11 producing CD4 T cells in the CNS and peripheral
Time frame: baseline
chemokine receptor CXCR3,CCR7,CCR6,CCR10 and CCR4 expression
transcription factor expression of IL-11 producing CD4 T cells in the CNS and peripheral
Time frame: baseline
transcription factor pstat3, Gata3, Tbet,RORrt and Foxp3 expression pattern
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Jun 2022.
- Individual participant dataSharing planned: Undecided. Investigators probably share data with other potential collaborators for further research
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Silva Markovic-Plese, MD PhD principal investigator
Thomas Jefferson University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Multiple Sclerosis, run by Thomas Jefferson University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 6 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Silva Markovic-Plese, MD PhD (215-955-6871, silva.markovic-plese@jefferson.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Adhesion marker expression of IL-11 producing CD4 T cells in the CNS and peripheral (time frame: baseline). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Jun 2022.