Lymph Node Transplantation Results in Spontaneous Lymphatic Reconnection and Restoration of Lymphatic Flow

Abstract

Background Although lymph node transplantation has been shown to improve lymphatic function the mechanisms regulating lymphatic vessel reconnection and functional status of lymph nodes remains poorly understood. Methods We developed and used LacZ lymphatic reporter mice to examine the lineage of lymphatic vessels infiltrating transferred lymph nodes. In addition, we analyzed lymphatic function, expression of vascular endothelial growth factor (VEGF-C), maintenance of T and B cell zone, and anatomic localization of lymphatics and high endothelial venules (HEVs). Results Reporter mice were specific and highly sensitive in identifying lymphatic vessels. Lymph node transfer was associated with rapid return of lymphatic function and clearance of Tc99 secondary to a massive infiltration of recipient mouse lymphatics and putative connections to donor lymphatics. T and B cell populations in the lymph node were maintained. These changes correlated with marked increases in the expression of VEGF-C in the perinodal fat and infiltrating lymphatics. Newly formed lymphatic channels in transferred lymph nodes were in close anatomic proximity to HEVs. Conclusions Transferred lymph nodes have rapid infiltration of functional host lymphatic vessels and maintain T and B cell populations. This process correlates with increased endogenous expression of VEGF-C in the perinodal fat and infiltrating lymphatics. Anatomic proximity of newly formed lymphatics and HEVs supports the hypothesis that lymph node transfer can improve lymphedema by exchanges with the systemic circulation.

Diphtheria toxin–mediated ablation of lymphatic endothelial cells results in progressive lymphedema

“…Cre expression was induced in adult male mice by using tamoxifen (300 mg/kg/d subcutaneously for 5 days) followed by either systemic (100 ng i.p.) or local (5 ng subcutaneously daily ×3 doses) DT delivery (58).…”

Vascularized Lymph Node Transfer

“…Recently, Aschen et al, in an innovative experiment on an acute lymphedema model in transgenic mice, were able to show massive infiltration of recipient lymphatics into the transferred lymph nodes, spontaneous anastomosis between the recipient and donor lymphatics, and close proximity of the lymphatics to the high endothelial venules of the lymph nodes. 16 It will be interesting to see whether these results can be reproduced in a chronic lymphedema model. Table 2 3,25,30-34 summarizes study methodologies of the published clinical series on vascularized lymph node transfer.…”

“…20,21 Other experiments have shown that expression of endogenous VEGF-C is markedly raised at the sites of lymphangiogenesis and that it can be further enhanced by induction of a sterile inflammatory response after lymph node transfer. 16,17,22 In summary, there is good evidence to suggest that avascular lymph node fragments autotransplanted into suitable recipient sites will regenerate into lymphoid tissues. Maintaining vascularization of the transferred lymph nodes ensures their survival and is essential when a lymph node-bearing block of tissue is transferred.…”

Breast Cancer-Related Lymphedema (BCRL)

“…Nonetheless, surgery for LE must be performed in conjunction with CDT and should not be performed alone. Both treatment modalities interact positively with each other [6,48,[53][54][55][56].…”