Lymph Node Transplantation Decreases Local Immunosuppression In Lymphedema
Catherine L. Ly, MD, Raghu P. Kataru, PhD, Babak J. Mehrara, MD.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
PURPOSE: Lymphedema is a morbid disease that is associated with an increased risk of recurrent infections. Microsurgical lymph node transplantation (LNT) has emerged as a promising treatment option particularly because it may lead to a decrease in the incidence of such complications. Recent research has shown that the local immunosuppression predisposing patients to infections can be at least partly attributed to an increase in T regulatory cells (Tregs). However, the mechanisms underlying the effect of Tregs on immune responses and how such mechanisms may be altered following LNT remain unclear. Using preclinical mouse models, this study therefore sought to further elucidate the means by which Tregs mediate immunosuppression in lymphedema and to determine whether LNT mitigates these changes. METHODS: To determine the role of Tregs in lymphedema, we performed axillary lymph node dissection (ALND) on transgenic Foxp3-diphtheria toxin receptor (DTR) mice, in which Foxp3+ Tregs can be depleted using diphtheria toxin (DT). Six weeks after surgery, these mice were randomized to receive DT or control injection. In other experiments, transgenic FLT4-DTR mice, in which DT can be used to locally ablate the lymphatic vasculature, underwent forelimb lymphatic ablation followed by ALND and were then randomized to undergo either orthotopic LNT or sham surgery. Inflammation, bacterial clearance, and antibody production were analyzed to delineate the effects of Treg depletion and LNT on lymphedema. RESULTS: The depletion of Tregs in ALND-treated mice resulted in increased inflammation, consistent with the known role of these cells in homeostasis. Importantly, Treg depletion also led to a 1.4-fold increase in bacterial clearance (P=0.042) and a 4.5-fold increase in antibody production (P=0.0089) as compared to ALND-treated mice with intact Tregs. In addition, compared to Treg-intact mice, Treg-depleted mice had significantly more activated dendritic cells (DCs) both in the ipsilateral forelimb (P<0.0001) and cervical lymph nodes (the closest drainage lymph node basin after ALND) (P<0.0001) following ALND. LNT resulted in a similar mitigation of local immunosuppression. Furthermore, analysis of the transplanted axillary lymph nodes demonstrated that these lymph nodes actively participated in bacterial clearance and DC trafficking. CONCLUSIONS: The accumulation of Tregs in lymphedema impairs bacterial phagocytosis and DC activation, thus contributing to local immunosuppression. LNT results in restoration of these important immune responses.
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