Plastic Surgery Research Council
Members Only  |  Contact  |  PSRC on Facebook
PSRC 60th Annual Meeting
Program and Abstracts

Back to 2015 Annual Meeting Program


T-regulatory Cell Proliferation after Lymphatic Injury Regulates Immune Function in Lymphedema
Ira L. Savetsky, MD, Swapna Ghanta, MD, Nicholas J. Albano, BS, Jason C. Gardenier, MD, Jeremy S. Torrisi, BA, Gabriela D. Garcia Nores, MD, Matthew D. Nitti, BA, Geoffrey E. Hespe, BS, Raghu P. Kataru, PhD, Babak J. Mehrara, MD FACS.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Purpose: Patients with lymphedema have impaired immunity and as a result are at an increased risk for developing infections and mounting inadequate adaptive immune (i.e. T and B cell) responses. However, although these impairments have been well documented in epidemiologic studies, the cellular mechanisms that regulate these responses remain unknown. We have previously shown that axillary lymph node dissection (ALND) in a mouse model results in significant accumulation of T regulatory (Treg) cells. Since Treg cells are known to play a critical role in the regulation of immune responses, we set out to determine how this response contributes to impaired immunity after lymphatic injury.
Methods: We performed ALNDs or sham axillary incisions on Foxp3-EGFP mice to characterize Treg infiltration, proliferation and subtype. In addition, we analyzed matched control and lymphedematous tissue samples obtained from patients with unilateral breast cancer-related upper extremity lymphedema. To determine how Treg cell accumulation after lymphatic injury regulates immune function, we performed ALND or sham axillary incisions in Foxp3-diptheria toxin receptor (DTR) mice. This model enables us to selectively deplete Treg cells and analyze the effect of this treatment on T and B cell responses using a contact hypersensitivity model.
Results: Biopsy samples from patients with lymphedema had nearly a 3 fold increase in the number of Treg cells as compared with matched controls (p<0.001). Similarly, 6 weeks after ALND, there was significantly more Tregs, proliferating Tregs and natural Tregs in lymphedematous tissues of mice treated with ALND. Depletion of Tregs in the setting of lymphatic injury increased macrophage, B cell and T cell infiltration in lymphedematous tissues suggesting that Treg expansion regulates tissue inflammation in this setting. Mice that were sensitized in their ALND arm produced a significantly less robust immune response to the contact hypersensitivity reagent than their sham sensitized counterparts with decreased inflammatory responses (CD45+ cells) and T cell accumulation (CD3+ cells). More importantly, we found that depletion of Tregs restored T cell inflammatory responses to normal levels as compared with controls.
Conclusions: In this study we have shown that lymphatic injury results in significant expansion of Tregs in lymphedematous tissues in both clinical biopsy specimens and mouse models. Moreover, we have shown that this response regulates overall inflammatory responses in lymphedema and is therefore, likely a homeostatic response. However, increased Treg accumulation in lymphedema also results in impaired adaptive immune responses providing a cellular mechanism for impaired immunity in patients with lymphedema. Future studies will assess the role of Tregs in the regulation of increased risk for infections after lymphatic injury.


Back to 2015 Annual Meeting Program