Leptin replacement therapy modulates circulating lymphocyte subsets and cytokine responsiveness in severe lipodystrophy.
BACKGROUND
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).


METHODS
We conducted an open-label study with patients serving as their own control at the Clinical Research Center of the National Institutes of Health.


METHODS
Ten patients (age range, 15-63 yr; one male and nine females) with generalized forms of lipodystrophy were studied.


METHODS
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.


CONCLUSIONS
These data support existing evidence that leptin has a modest immunomodulatory effect in hypoleptinemic humans.
Oral
Elif Arioglu
EA
Clinical 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
Javor
Edward D
ED
Ding
Li
L
Uzel
Gulbu
G
Cochran
Elaine K
EK
Young
Janice Ryan
JR
DePaoli
Alex M
AM
Holland
Steven M
SM
Gorden
Phillip
P
D000293:Adolescent; D000328:Adult; D016516:CD4-CD8 Ratio; D005260:Female; D005434:Flow Cytometry; D006442:Glycated Hemoglobin / Q000276:immunology; D020249:Hormone Replacement Therapy; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D020738:Leptin / Q000008:administration & dosage*; D008060:Lipodystrophy / Q000188:drug therapy* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000008:administration & dosage; D018709:Statistics, Nonparametric; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D006442:Glycated Hemoglobin; D007371:Interferon-gamma; D020738:Leptin; D011994:Recombinant Proteins; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha