Evolution of Interleukin 7, Fat Mass and Metabolic Profile Before and After Transplantation (IL-7tran)

Adipocytes, Insulin Resistance and Immunity: Evolution of Interleukin 7, Fat Mass and Metabolic Profile Before and After Transplantation

Three different white adipose tissue-related disorders, whether due to its excess (obesity), absence (lipoatrophies) or aberrant distribution (lipodystrophies), are paradoxically able to induce metabolic insulin resistance syndrome. The respective roles played by quantitative and qualitative anomalies of adipose tissue, gluco- and lipo-toxicity, liver and muscle insulin resistance, low-grade fat inflammation and immune alterations are not yet perfectly understood. In contrast to most organ transplantations that are often complicated by post-transplantation diabetes, diabetes cell therapy is associated with body weight loss, which is possibly related to the antiadipogenic effects of mTOR inhibitors (rapamycin or sirolimus). The aim of this study is thus to determine and monitor blood interleukin-7 and other cytokine levels; metabolic parameters; and fat mass distribution with DEXA and RMN, before and after a immunosuppressive regimen in patients receiving different kinds of transplantation (liver, kidney or islets) with normal weight and no type 2 diabetes before transplantation. In these patients, blood samples will be taken before and after transplantation, as will adipose tissue during the transplantation surgery, in order to constitute a plasma serum, gene and tissue bank for improving our knowledge of disorders linking fat mass, insulin resistance and immunity, especially post-transplantation diabetes.

Study Overview

• Status: Completed
• Conditions: Immunodeficiency Secondary to Organ Transplantation
• Intervention / Treatment: Procedure: transplantation

Detailed Description

Rationale: Due to their ability to store fatty acids and to secrete numerous pro-inflammatory cytokines, adipocytes appear to be key cells in the regulation of energy metabolism and immune response. Moreover, it has been recently shown that adipocytes play a role in the recruitment of cells involved in innate and adaptive immunity in adipose tissue.

White adipose tissue-related diseases are numerous, whether from its excess (obesity), or its complete (lipoatrophies) or partial absence (lipodystrophies); these 3 different disorders are paradoxically able to induce metabolic insulin resistance syndrome.

Among the involved cytokines, interleukin-7 (IL-7), mostly known for its immune functions, also participates in the quantitative and qualitative balance of fat mass. Thus, IL-7 over-expression in animal models induces a lipodystrophic syndrome with insulin resistance, whereas in humans a preliminary study shows that LMNA-linked lipodystrophies are associated with an increase of blood IL-7 levels. IL-7 also participates in reactivation of autoimmunity in patients with autoimmune type 1 after islet transplantation.

Otherwise, mammalian target of rapamycin (mTOR) inhibitors have immunosuppressive, metabolic and anti-tumoral properties through different signaling pathways. Rapamycin (or sirolimus) (Rapamune®), an mTOR inhibitor used in islet transplantation, has much greater ability to inhibit adipocyte differentiation and to modulate ß cell function according to the energetic status. In contrast to most organ transplantation, diabetes cell therapy is associated with body weight loss, which is possibly related to the antiadipogenic effects of mTOR inhibitors; the specific role that this plays on the prognostic factors of islet transplantation remains to be determined. Conversely, organ transplantation is usually associated with weight gain, which is involved in the genesis of post-transplantation diabetes, AKA new-onset diabetes after transplantation (NODAT), and long-term vascular complications of transplantation. Adipose tissue redistribution has not yet been studied in patients after transplantation.

The aim of this study is thus to determine blood IL-7 and other cytokine levels; metabolic parameters; and fat mass distribution before and after a immunosuppressive regimen in patients receiving different kinds of transplantation (liver, kidney or islets) with normal weight and no type 2 diabetes before transplantation. In these patients, blood samples will be taken before and after transplantation, as will adipose tissue during the transplantation surgery, in order to constitute a plasma, serum, gene and tissue bank for determining the mechanisms linking fat mass, insulin resistance and immunity, both ex vivo and in vitro.

Patients: The included patients are normal-weight subjects enlisted for liver, kidney or islet transplantation, with no type 2 diabetes (for liver and kidney transplantation).

Methods: Blood IL-7 levels, other immune and/or pro-inflammatory cytokines, lymphocyte immunophenotype, metabolic parameters, and fat mass with non-invasive methods (DEXA and RMN) will be assessed before and one-year after transplantation. Blood, before and after transplantation, as well as adipose tissue during transplantation surgery, will be sampled in order to constitute a blood, gene and tissue bank for defining the inflammatory status of this tissue using histological and molecular analysis.

Primary endpoint: The primary endpoint will be IL-7 blood levels in the different groups according to fat mass, metabolic parameters and immunosuppressive regimen. The hypothesis is that an increase of IL-7 levels, possibly induced by immunosuppressive regimen, is associated with quantitative and/or qualitative disturbances of adipose tissue and the development of insulin resistance.

Expected results and possible implications: This study will enable the consequences of immunosuppression on IL-7 levels, adipose tissue disturbances and glucose metabolism to be determined. Our approach combining clinical investigation and ex vivo and in vitro analysis is original and should result in better understanding of the cellular mechanisms responsible for the inflammatory process initiated in white adipose tissue and accompanying the disorders of this tissue (especially post-transplantation diabetes), thus opening new therapeutic perspectives in a major complication of transplantation.

• Study Type: Observational
• Enrollment (Actual): 49

Contacts and Locations

Study Locations

• France
  • Amiens, France
    • Amiens University Hospital
  • Caen, France
    • CAEN University Hospital
  • Lille, France
    • Lille University Hospital
  • Reims, France
    • Reims university Hospital
  • Rouen, France
    • ROUEN university hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients undergoing a transplantation in Endocrinology Metabolism department, Nephrology department and Liver Transplantation department in Lille University Hospital, Amiens University Hospital, Caen University Hospital, Rouen University Hospital and Reims University Hospital.

Description

Inclusion Criteria:

• Male and Female
• More than 18 years old
• BMI inferior to 30 kg/m2
• non diabetic patients who need a kidney or a liver transplantation(Glucose blood level <1,26 g/L without any antidiabetic drug)
• OR included in the islet transplantation protocol because of a C peptide negative brittle or difficult to treat diabetes.
• cover under the social security

Exclusion Criteria:

• Unable to receive enlightened information
• Refusal to sign the consent
• Auto immune disease (kidney, liver or chronic inflammatory disease)
• need for a kidney-pancreas transplantation
• Creatinin > 15 mg / L for patients non concerned by kidney transplantation
• Sepsis
• Oestrogens, raloxifene
• Active alcohol Intoxication
• Cancers or autoimmune diseases;
• Psychiatric Pathology
• Active infection including hepatitis C or HIV;
• Age under 18 years or above 65 years
• Participation in another study excluded the possibility of participating in another protocol
• No cover under the social security
• Pregnant or lactating women
• patients under guardianship, persons deprived of liberty

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
islet; type 1 diabetic patients undergoing islet transplantation	Procedure: transplantation; transplantation of islet, kidney or liver
liver; non diabetic patients undergoing a liver transplantation	Procedure: transplantation; transplantation of islet, kidney or liver
kidney; non diabetic patients undergoing a kidney transplantation	Procedure: transplantation; transplantation of islet, kidney or liver

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
interleukin 7	1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Interleukin 2	1 year
Interleukin 4	1 year
Interleukin 9	1 year
Interleukin 15	1year
Interleukin 21	1year
TNFa	1 year
Interleukin 1b	1 year
Interleukin 6	1year
Interleukin 8	1 year
Interleukin 10	1 year
Interleukin 18	1 year
leptin	1 year
adiponectin	1 year
Blood cells of innate and adaptative immunity analysis	1 year
fat mass	1 year
metabolic parameters	1 years

Collaborators and Investigators

• Sponsor: University Hospital, Lille
• Investigators: Principal Investigator: Marie-Christine VANTYGHEM, MD, PhD, Lille University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 9, 2010
• Primary Completion (Actual): February 1, 2018
• Study Completion (Actual): February 1, 2018

Study Registration Dates

• First Submitted: August 10, 2011
• First Submitted That Met QC Criteria: August 10, 2011
• First Posted (Estimate): August 11, 2011

Study Record Updates

• Last Update Posted (Actual): June 7, 2018
• Last Update Submitted That Met QC Criteria: June 5, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: diabetes; transplantation; kidney; liver; islet; interleukin 7
• Additional Relevant MeSH Terms: Immune System Diseases; Immunologic Deficiency Syndromes
• Other Study ID Numbers: 2009_09/0940; 2009-A01169-48 (Other Identifier: ID-RCB number, ANSM); B91413-80 (Other Identifier: AFSSAPS); PHRC 2009/API (Other Identifier: DHOS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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