Targeted inhibition of T-cell inflammation can prevent and treat lymphedema by reducing fibrosis
Tomer Avraham, MD, Jamie Zampell, MD, Alan Yan, MD, Sanjay V. Daluvoy, MD, Essie Kueberuwa, MBBS, Babak J. Mehrara, MD.
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
BACKGROUND: Lymphedema is a common and highly morbid condition that occurs in up to 50% of patients who undergo lymph node dissection for cancer management. Although the clinical hallmarks of lymphedema are chronic inflammation and lymphatic fibrosis, the molecular mechanisms that regulate these changes remain unknown. The lack of this knowledge has prevented development of targeted methods designed to prevent or treat lymphedema. Instead, patients are treated symptomatically with manual massage and tight fitting garments. We have previously shown that lymphedema induced fibrosis is a key regulator of lymphatic function and that this pathology occurs as a result of chronic T-cell inflammation. The purpose of these studies was therefore to determine the specific type of T-cell inflammatory reaction that is responsible for lymphedema induced fibrosis and design targeted treatments to prevent and treat lymphedema.
METHODS: We used a mouse tail model of lymphedema in wild-type, nude (lack all T-cells), or CD4 knockout (CD4KO; lack T-helper cells) to evaluate the role of T-cells on the development of chronic inflammation and fibrosis. In this model, lymphedema is induced by microsurgically excising the superficial and deep lymphatics resulting in tail swelling that lasts at least 12 weeks. To design a targeted treatment for inhibiting fibrosis associated with lymphedema, we evaluated the effect of neutralizing antibodies against IL4 (IL4mab) since iIL4 is a critical regulator of Th2 type T-helper cell differentiation and has been shown to play a critical role in liver and lung models of fibrosis.
RESULTS: 6 weeks following surgery, wild-type mice had nearly a 10-fold increase in tail volumes. In contrast, nude or CD4KO mice had tail swelling that lasted 2 weeks but decreased significantly thereafter resulting in more than a 3-fold decrease as compared to wild-type animals. Decreased tail lymphedema was associated with markedly (2-fold; p<0.01) decreased fibrosis and significantly improved lymphatic function indicating that lymphedema induced fibrosis and lymphatic dysfunction are dependent on T-helper cells. When we inhibited IL4 beginning immediately after surgery, we prevented the initiation of lymphedema and there was a significant decrease in tail volume (3-fold), improved lymphatic function, and decreased fibrosis (3-fold) as compared to controls. Similarly, when we treated mice with established lymphedema (i.e. Started treatment 6 weeks after lymphatic ligation) with IL4mab, lymphedema was completely reversed and tail volumes and tissue fibrosis returned to normal. In contrast, control animals had little spontaneous improvement in tail lymphedema even 12 weeks after surgery, Most importantly, treatment with IL4mab improved lymphatic function without causing alterations in the expression of lymphangiogenic growth factors. This is critical in the treatment of cancer survivors
CONCLUSIONS: Chronic T-cell inflammation in general and Th2 differentiation in particular are necessary for fibrosis and lymphatic dysfunction in lymphedema. IL4 is necessary for Th2 differentiation and is a critical regulator of fibrosis and lymphatic dysfunction. Antifibrotic therapies can be used to both prevent and treat lymphedema without altering the expression of lymphangiogenic growth factors.
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