Back to 2011 Program

BACKGROUND: Lymphedema is a devastating complication of lymph node dissection associated with progressive swelling and soft tissue fibrosis. Mechanisms regulating lymphedema pathogenesis are unknown thus limiting development of effective treatments. We have shown that T cell-mediated inflammation, particularly of the Th2-cell lineage, promotes development of fibrosis and lymphatic dysfunction in chronic lymphedema. The purpose of this study was to determine the effect of Th2 abrogation on established lymphedema and whether parallel pathologic findings occur in human lymphedema.
METHODS: Neutralizing antibody to IL-4 was administered at post-operative week 6 following ligation of mouse tail lymphatics and lymphedema development. Treatment was continued for 3 weeks then withdrawn; mice were sacrificed and tissues analyzed after 3 weeks of treatment withdrawal. Matched punch biopsies (n=10) and serum samples (n=16) from normal and contralateral lymphedematous limbs from patients with secondary lymphedema were analyzed for Th2 differentiation markers (IL-13, IgE, CD30).
RESULTS: IL-4 blockade in mice with established lymphedema led to reduced tail volume (4-fold, p<0.05), fibrosis (2-fold), and improved lymphatic function (p<0.01) after a 3 week treatment course. Following 3 weeks of treatment withdrawal, reduced edema (25% reduction, p<0.05), fibrosis, and improved lymphatic function were sustained as compared to controls. Analysis of matched human punch biopsies obtained from lymphedematous or non-lymphedematous contralateral limbs showed a 3-fold increase in CD4+ cell infiltrate (p<0.05) and 2-fold increase in IL-13+ cells in lymphedematous tissues as compared to contralateral normal limbs (p<0.05), and clinical lymphedema grade correlated with the extent of CD4+ cell infiltrate (Spearman r=0.633, p<0.016). Additional analysis revealed that lymphedema treatment reduced serum markers of Th2 differentiation (13% CD30 reduction, p<0.06; 22% IgE reduction, p<0.01).
CONCLUSIONS: Abrogation of Th2-cell mediated inflammation treats established lymphedema in a mouse model, and these effects are sustained following treatment withdrawal. Furthermore, chronic human lymphedema is associated with increased local Th2 cell infiltration which is modified by lymphedema treatment. These results suggest that immunomodulation of the Th2 response may represent a potential therapeutic target in the treatment of clinical lymphedema.