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T-cell deficiency is associated with accelerated lymphatic regeneration
Jamie C. Zampell, MD, Alan Yan, MD, Tomer Avraham, MD, Nicole Yoder, MD, Nicolas Fort, MD, Babak J. Mehrara, MD.
Sloan Kettering Institute, New York, NY, USA.

BACKGROUND: Recent studies suggest that chronic T-helper cell (CD4+) inflammation may contribute to fibrosis and lymphatic dysfunction in chronic lymphedema. The purpose of this study was therefore to determine the effect of loss of T-cell function on lymphatic repair during wound healing.
METHODS: The rate of lymphatic regeneration in wild-type or nude mice (T-cell deficient) was compared using a mouse tail model in which superficial and deep lymphatics are excised microsurgically. Lymphatic function and expression of pro- and anti-lymphangiogenic cytokines were evaluated at 2, 4 or 6 weeks post-operatively.
RESULTS: Nude animals demonstrate significantly reduced tail edema by measurement of tail volume (2.9-fold peak reduction; p<0.01). Decreased edema correlated with reduced inflammation, dermal thickness, and fibrosis (2-fold reduction, p<0.05) as compared to controls. Nude animals additionally demonstrate markedly improved lymphatic transport of fluorescent labeled colloid by microlymphangiography and increased nodal uptake of technetium labeled sulfur colloid on lymphoscintigraphy (>5-fold, p<0.05). Lymphatic vessel immunohistochemical staining for podoplanin demonstrated microlymphatic regeneration spanning wounds of nude but not wild-type animals beginning at week 4. Interestingly, while western blotting showed no difference between groups in the expression of pro-lymphangiogenic cytokines (VEGF-A, VEGF-C, HGF), a marked reduction in the expression of anti-lymphangiogenic cytokines (IFN-y, TGF-B1, and endostatin) was present in nude animals at both 2 and 4 weeks post-operatively.
CONCLUSIONS: These results demonstrate that the absence of T-cell mediated inflammation markedly decreases tail edema and accelerates lymphatic regeneration during wound healing. In addition, we show that this effect is not associated with increased expression of pro-lymphangiogenic cytokines but rather due to down-regulation of anti-lymphangiogenic molecules in nude animals. These findings suggest for the first time that similar to angiogenesis, the balance of pro- and anti-lymphangiogenic cytokines is a critical regulator of lymphatic regeneration. These strategies may have important implications in the treatment of lymphedema and prevention of lymphatic metastasis.


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