Evolution of Interleukin 7, Fat Mass and Metabolic Profile Before and After Transplantation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Immunodeficiency Secondary to Organ Transplantation

Intervention / Treatment
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* Procedure: transplantation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| islet<br>type 1 diabetic patients undergoing islet transplantation | Procedure: transplantation<br>* transplantation of islet, kidney or liver<br>|
| liver<br>non diabetic patients undergoing a liver transplantation | Procedure: transplantation<br>* transplantation of islet, kidney or liver<br>|
| kidney<br>non diabetic patients undergoing a kidney transplantation | Procedure: transplantation<br>* transplantation of islet, kidney or liver<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| interleukin 7 |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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interleukin 7, transplantation, liver, kidney, islet, diabetes