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BACKGROUND:
Lymph node transplantation (LNT) has gained increasing favor for the treatment of lymphedema. However, although LNT has been shown to be beneficial in some patients, others that are identically treated do not show significant improvements in clinical parameters. The cause(s) of this inconsistency remains unknown, however, it is likely that inadequate lymphangiogenesis plays an important role. Recently, our lab developed a mouse model of LNT in which interventions designed to improve lymphangiogenesis and function could easily and rapidly be screened. The purpose of this study was therefore to use this model to test the hypothesis that inflammation could increase lymphangiogenesis. This hypothesis was based on the well described role of inflammation in expanding lymphatic networks.
METHODS:
Adult male lymphatic reporter mice developed in our lab underwent axillary dissection (ALND) followed by LNT from age-matched littermates. Mice were divided into 4 groups. Groups 1 and 2 served as controls and consisted of sham operated group mice (axillary incision without lymph node dissection) and ALND followed by immediate LNT without inflammation. Animals in group 3 underwent ALND and were transplanted with nodes harvested from donor animals in which inflammation was induced using Freund’s complete adjuvant (CFA; a vaccine booster) prior to transfer. Group 4 animals had ALND, LNT, and inflammation induced with CFA 2 weeks after transfer. All animals were sacrificed and analyzed one month after surgery.
RESULTS:
Consistent with our previous report, we found that LNT signficantly increased lymphatic function as assessed by lymphoscintigraphy when compared with animals that had ALND alone. Induction of inflammation in donor animals (i.e. prior to LNT) increased lymphatic function and lymphangiogenesis marginally when compared to animals that did not have inflammation; however, these differences were not statistically significant. In contrast, induction of inflammation after LNT markedly increased lymphangiogenesis around the transplanted lymph node, increased Tc99 uptake by lymphoscintigraphy, and increased the number of functional vessels in the lymph node (all p<0.01). Furthermore, the induction of inflammation after LN transfer resulted in preservation of a more normal LN architecture including a more expansive B cell zone and decreased T cell zone compared to the other groups.
CONCLUSIONS:
Our findings suggest that induction of sterile inflammation, with commonly used immune adjuvants, in the recipient limb markedly increases lymphangiogenesis and function of transplanted lymph nodes in mice. This finding is important as it suggests that simple interventions can be used to increase vascular endothelial growth factor C expression and lymphangiogenesis physiologically (rather than conventional approaches using gene therapy or large concentrations of recombinant protein). This approach will not only be more cost effective but may also decrease the risk of tumor recurrence or metastasis by avoiding supraphysiological doses of lymphangiogenic cytokines.