Immunodeficiency Secondary to Organ Transplantation Clinical Trial
Official title:
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.
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.
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