Evolution of Interleukin 7, Fat Mass and Metabolic Profile Before and After Transplantation
Condition: Immunodeficiency Secondary to Organ Transplantation
MeSH terms: Immunologic Deficiency Syndromes
Study type: Observational

Summary: 
      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: 
      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.
    

Intervention name(s): transplantation
Intervention type(s): Procedure
Intervention description(s): transplantation of islet, kidney or liver
Observational model: Case-Only
Time perspective: Other
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.
      
Biospecimen description: 
      wholeblood and tissue bank
    
Keywords: interleukin 7; transplantation; liver; kidney; islet; diabetes