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Th2 Deficiency Attenuates The Pathologic Findings Of Lymphedema
Catherine L. Ly, MD, Gabriela D. García Nores, MD, Raghu P. Kataru, PhD, Babak J. Mehrara, MD.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Purpose: Lymphedema is a progressive disease that is regulated by CD4+ cells. However, while it is clear that CD4+ cells are important, the effect of cellular differentiation is less clear. Therefore, this study sought to evaluate the roles of T helper 1 (Th1) and T helper 2 (Th2) cells in lymphedema using differentiation-restricted transgenic mice.
Methods: Microsurgical tail lymphatic ligation and popliteal lymph node dissection were performed in wild-type (WT), CD4KO, T-betKO (Th2-restricted), and STAT6KO (Th1-restricted) mice and the development of pathologic changes was analyzed. In other studies, a topically applied Th2 differentiation/proliferation inhibitor was used to determine if these transgenic findings could be clinically translated. We analyzed fibrosis, adipose deposition, inflammation, lymphangiogenesis, and lymphatic function using a variety of assays.
Results: In contrast to WT mice and T-betKO mice that have impaired Th1 cellular differentiation, CD4KO mice that underwent lymphatic injury did not develop pathologic changes of lymphedema. CD4KO mice had significantly decreased fibroadipose tissue deposition (p<0.0001), decreased inflammation (p<0.0001), and increased lymphangiogenesis (p<0.0001) with improved lymphatic collecting vessel pumping (p<0.01) and lymphatic transport function (p<0.01). Similarly, STAT6KO mice that have known deficits in Th2 cellular differentiation did not develop lymphedema, suggesting that Th2 rather Th1 cells play a key role in the pathology of this disease. Treatment of WT mice with a topically applied Th2 differentiation/proliferation inhibitor was well-tolerated and had no evident toxicity. This treatment markedly hindered the development of lymphedema, with significant decreases in both fibroadipose tissue deposition (p<0.0001) and inflammation (p<0.0001), as well as increases lymphangiogenesis (p<0.0001) and improvement in lymphatic collecting vessel pumping (p=0.0002) and lymphatic transport function (p<0.001), as compared to vehicle-treated WT mice.
Conclusions: Our study provides clear evidence that Th2 cellular differentiation is necessary for the development of lymphedema. This response coordinates pathologic changes, including fibroadipose tissue deposition, inflammation, and impaired lymphangiogenesis, lymphatic vessel pumping, and function. Pharmacologic targeting of Th2 cells with topical formulations is highly effective and has significant potential for clinical translation.


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