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Leptin Replacement Therapy Modulates Circulating Lymphocyte Subsets and Cytokine Responsiveness in Severe Lipodystrophy

Clinical Endocrinology Branch (E.A.O., E.D.J., E.K.C., J.R.Y., P.G.), National Institute of Diabetes, Digestive, and Kidney Diseases, and Laboratory of Clinical Infectious Diseases (L.D., G.U., S.M.H.), National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892; and Amgen, Inc. (A.M.D.), Thousand Oaks, California 91320

Address all correspondence and requests for reprints to: Phillip Gorden, M.D., 10 Center Drive, MSC 1612, Room CRC 65940, Bethesda, Maryland 20892-1612. E-mail: PhillipG{at}intra.niddk.nih.gov.

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- 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 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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				J. Y. Park, A. Y. Chong, E. K. Cochran, D. E. Kleiner, M. J. Haller, D. A. Schatz, and P. Gorden Type 1 Diabetes Associated with Acquired Generalized Lipodystrophy and Insulin Resistance: The Effect of Long-Term Leptin Therapy J. Clin. Endocrinol. Metab., January 1, 2008; 93(1): 26 - 31. [Abstract] [Full Text] [PDF]