In Vitro Immunomodulation in Membranous Nephropathy Relapses (BIOGEM)

In Vitro Study of the Efficacy of Different Immunomodulators on the Th17/Treg Balance in a Cohort of Relapsed Membranous Nephropathy

In order to propose the best therapeutic option to relapsed MN patients with strong activation of the Th17 pathway, the investigators propose to study in vitro the effect of different immunomodulators on the Th17/Treg balance, assessed by cytokine profile and lymphocyte phenotyping using flow cytometry.

Study Overview

• Status: Recruiting
• Conditions: Extramembranous Glomerulopathy
• Intervention / Treatment: Other: Blood sample

Detailed Description

Membranous Nephropathy (MN) is a rare autoimmune renal disease and the first cause of nephrotic syndrome in adults. In one third of cases, it progresses to end-stage renal failure. Rituximab has shown very good efficacy (60-80%) and excellent safety in this indication. However, one third of MN patients relapse after a course of rituximab, raising the question of maintenance treatment or repeated courses of rituximab whose long-term impact is unknown.

The investigators studied the cytokine profile of MN patients and demonstrated, after non-specific stimulation of innate immunity cells and T cells, a Th17 profile (increased levels of interleukin-6 (Il-6) and interleukin-17A (Il-17A) compared to healthy subjects), and inhibition of the Th1 (decreased IL-12p70 and Interferon-γ (IFN-γ)) and T regulatory T reg pathways (decreased IL-10) (doi: 10. 3389/fimmu.2020.574997).

Th17 cells and Treg cells with interconnected development have opposite roles. Th17 cells induce inflammation to initiate a reaction against a pathogen, while Treg cells control an inflammatory reaction.

The investigators showed that high Il-17A levels were associated with a risk of thrombotic events (p = 0.03) and relapse (p = 0.0006). A patient with an IL-17A level > 73 pg/ml had a 10.5-fold increased risk of relapse.

Rituximab-induced remission leads to an increase in Treg and Th1 pathway cytokines but has no impact on IL-17A production, which remains important even in remission.

Thus, in this group of patients with high IL-17A levels, targeted action on B lymphocytes is probably not sufficient to avoid relapse and the addition of a treatment aimed at inhibiting the Th17 pathway and promoting Treg induction seems legitimate.

Various potential treatment exist: anti-Il-6 antibodies (tocilizumab), anti-Il-17 antibodies (secukinumab), low-dose Il-2 (a few studies have demonstrated its ability to induce Treg in various autoimmune diseases), hydroxychloroquine in low doses (used in lupus to limit relapses and having an anti-inflammatory effect), the plant extract Alphanosos (anti-Th1) or Levamizole (validated in nephrotic syndrome in children).

In order to propose the best therapeutic option to relapsed MN patients with a strong activation of the Th17 pathway, the investigators propose to study in vitro the effect of these different immunomodulators on the Th17/Treg balance evaluated by cytokine profile and lymphocyte phenotyping in flow cytometry.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Barbara SEITZ-POLSKI, MD, PhD; Phone Number: +33492035990; Email: seitz-polski.b@chu-nice.fr
• Study Contact Backup: Name: Céline FERNANDEZ; Phone Number: +33492038828; Email: fernandez.c3@chu-nice.fr

Study Locations

• France
  • Nice, France, 06200
    • Recruiting
    • Centre Hospitalier Universitaire de Nice
    • Contact: FERNANDEZ Céline; Phone Number: +33492038828; Email: fernandez.c3@chu-nice.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years
2. Patient with MN proven on renal biopsy or by the presence of anti-PLA2R1 or anti-THDS71 antibodies
3. Relapsed MN, defined as proteinuria > 3.5g/g after achieving remission (partial or complete, definitions according to KDIGO 2012 guidelines)
4. At a distance from any immunosuppressive treatment (at least 6 months)
5. Freely given informed consent signed by the patient after clear, fair and appropriate information
6. Affiliated to a social security system

Exclusion Criteria:

1. Pregnant or breastfeeding woman
2. Patient under 18 years of age
3. Persons of legal age

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GEM patients	Other: Blood sample; 10 mL on lithium heparinate tubes, 10 mL on EDTA tubes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cytokine ELISA profiles of the Th17 pathway (IL-17 level), the Treg pathway (IL-10 level), the Th1 pathway (IL-12p70, IFN-γ) and the Th2 pathway (IL-4 and IL-5)	All cytokines (IL-17, IL-10, IL-12p70, IFN-γ, IL-4 and IL-5) measured by ELISA will be expressed in pg/ml.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lymphocyte phenotyping (Treg and Th17) determined by flow cytometry	Percentage of cells expressing the fluorescent marker of interest	18 months

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nice

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2022
• Primary Completion (Estimated): November 23, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: June 10, 2022
• First Submitted That Met QC Criteria: June 20, 2022
• First Posted (Actual): June 23, 2022

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: relapse; immunomodulation; membranous nephropathy; Th17/Treg pathways
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Urologic Diseases; Nephritis; Glomerulonephritis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Glomerulonephritis, Membranous
• Other Study ID Numbers: 20-AOIP-06

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD is not planned to be shared with other researchers than the investigators

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No