Plastic Surgery Research Council
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Presenter: Nicholas J Albano, Student
Co-Authors: Ghanta S; Zampell JC; Weitman ES; Cuzzone DA; Aschen SZ; Farias-Eisner GT; Yan A; Mehrara BJ
Memorial Sloan Kettering Cancer Center

Introduction: Although it is well known that lymphedema results in immunosuppression and frequent infections of the involved limb, the mechanisms that regulate this response remain unknown. We have previously shown that lymphedema is associated with a chronic CD4+ T cell inflammatory response. Therefore, the purpose of these experiments was to test the hypothesis that lymphedema results in proliferation of T-regulatory cells (TReg; CD4+/CD25+/Foxp3+) which play a critical role in suppression of immune responses.

Methods: We analyzed the type and number of TReg cells in mouse models of lymphedema (tail) and lymphatic fluid stasis (axillary lymph node dissection; ALND) using flow cytometry on single cell suspensions. We also analyzed pathologic tissue changes after depleting CD25+ cells using neutralizing antibodies. To confirm our mouse findings, we analyzed the number of TReg cells in tissues harvested from the normal and lymphedematous limbs of patients with lymphedema.

Results: Lymphedema in the mouse tail model resulted in a massive increase (7.7- fold) in T-Reg cells as compared with control (p<0.05). This finding was also noted in tissues harvested from the upper extremity of mice that had undergone ALND as compared with axillary incision without lymph node harvest (8-fold increase 6 weeks after surgery; p<0.05). Clinical biopsies similarly demonstrated a marked increase in the number of Foxp3+ cells compared to samples from non-lymphedematous limbs (>4-fold increase; P < 0.05). Interestingly, depletion of TReg cells did not significantly decrease pathologic tissue responses to lymphedema (fibrosis, adipose deposition).

Conclusions: We have shown that lymphedema markedly increases the number of tissue TReg cells both in mouse models and clinically. Interestingly, depletion of TReg cells had little effect on pathologic tissue changes associated with lymphedema suggesting that this cell population may play an important role in other findings of lymphedema including local immunosuppression. However, this conclusion requires further study, which is currently ongoing in our lab.

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