Context: To understand the role of leptin therapy in immunomodulation.

Objective: To study lymphocyte subpopulations and in vitro peripheral blood cell (PBMC) activation during a study evaluating leptin's effects on metabolic functions in severe lipodystrophy (serum leptin levels <4ng/mL).

Design: Open label study with patients serving as their own control.

Setting: Clinical Research Center of the National Institutes of Health

Patients: Ten patients (age range: 15-63 yr, 1M/9F) 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) while metabolic control improved (HgA1c 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 following stimulation with phytohemagglutin (PHA), PHA + interleukin 12, lipopolysaccharide (LPS), and LPS + interferon 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- secreted from PBMCs 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.