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Leptin replacement therapy modulates circulating lymphocyte subsets and cytokine responsiveness in severe
Elif Arioglu Oral1, Edward D Javor, Li Ding
1Clinical Endocrinology Branch, National Institute of Diabetes, Digestive and Kidney Diseases/NIH, 10 Center Drive, MSC 1612, Room CRC 65940, Bethesda, MD 20892-1612, USA. eliforal@umich.edu
Insights
Leptin therapy improved metabolic control and modulated immune function in patients with severe lipodystrophy. This study shows leptin’s immunomodulatory role in hypoleptinemic individuals.
Area of Science:
- Immunology
- Endocrinology
- Metabolic Disorders
Background:
- Severe lipodystrophy is associated with low serum leptin levels.
- Leptin's role in immunomodulation requires further investigation.
Purpose of the Study:
- To investigate the immunomodulatory effects of leptin therapy in severe lipodystrophy.
- To assess changes in lymphocyte subpopulations and peripheral blood mononuclear cell (PBMC) activation.
Main Methods:
- Open-label, self-controlled study at the NIH Clinical Research Center.
- Ten patients with generalized lipodystrophy received recombinant human leptin for 4-8 months.
- Flow cytometry and in vitro PBMC activation assays were performed.
Main Results:
- Leptin therapy normalized leptin levels, improved metabolic control (HbA1c, triglycerides), and corrected T lymphocyte subset abnormalities.
- Relative percentages of B lymphocytes and monocytes were elevated at baseline but normalized with therapy.
- In vitro TNF-alpha secretion from PBMCs increased significantly to normal levels after leptin treatment.
Conclusions:
- Leptin therapy demonstrates a modest immunomodulatory effect in hypoleptinemic humans.
- Leptin treatment can restore immune cell balance and function in severe lipodystrophy.
Context:
We conducted this study to understand the role of leptin therapy in immunomodulation.
Objective:
Our objective was to study lymphocyte subpopulations and in vitro peripheral blood mononuclear cell (PBMC) activation during a study evaluating the effects of leptin on metabolic functions in severe lipodystrophy (serum leptin levels < 4 ng/ml).
Design And Setting:
We conducted an open-label study with patients serving as their own control at the Clinical Research Center of the National Institutes of Health.
Patients:
Ten patients (age range, 15-63 yr; one male and nine females) with generalized forms of lipodystrophy were studied.
Intervention:
Patients were treated with recombinant human leptin to achieve high normal concentrations for 4 to 8 months.
Results:
Leptin levels increased from 1.8 +/- 0.4 to 16.5 +/- 3.9 ng/dl (P < 0.001), whereas metabolic control improved [glycosylated hemoglobin (HbA(1c)) fell from 9.3 +/- 0.4 to 7.1 +/- 1.4%, P < 0.001, and triglycerides decreased by 45 +/- 11% from a mean of 1490 +/- 710 mg/dl, P = 0.001]. Lymphocyte subsets were studied by flow cytometry at baseline and at 4 and 8 months of therapy. PBMC responsiveness was evaluated by cytokine release and proliferation after stimulation with phytohemagglutinin, phytohemagglutinin plus IL-12, lipopolysaccharide, and lipopolysaccharide plus interferon-gamma at baseline and 4 months. Various T lymphocyte subsets were significantly lower than age- and sex-matched controls at baseline; however, the CD4/CD8 ratio was normal. The relative percentages of B lymphocytes and monocytes were elevated, although the absolute levels were normal. Leptin therapy induced significant changes in T lymphocyte subsets, which normalized both the absolute number of T lymphocyte subsets and relative percentages of all lineages. Additionally, in vitro TNF-alpha secreted from PBMC of patients was significantly increased to normal after 4 months of leptin therapy compared with baseline.
Conclusion:
These data support existing evidence that leptin has a modest immunomodulatory effect in hypoleptinemic humans.
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