Lymph Node Transplantation Decreases Swelling and Restores Immune Responses in a Transgenic Model of Lymphedema

Abstract

IntroductionSecondary lymphedema is a common complication of cancer treatment and recent studies have demonstrated that lymph node transplantation (LNT) can decrease swelling, as well as the incidence of infections. However, although these results are exciting, the mechanisms by which LNT improves these pathologic findings of lymphedema remain unknown. Using a transgenic mouse model of lymphedema, this study sought to analyze the effect of LNT on lymphatic regeneration and T cell-mediated immune responses.MethodsWe used a mouse model in which the expression of the human diphtheria toxin receptor is driven by the FLT4 promoter to enable the local ablation of the lymphatic system through subdermal hindlimb diphtheria toxin injections. Popliteal lymph node dissection was subsequently performed after a two-week recovery period, followed by either orthotopic LNT or sham surgery after an additional two weeks. Hindlimb swelling, lymphatic vessel regeneration, immune cell trafficking, and T cell-mediated immune responses were analyzed 10 weeks later.ResultsLNT resulted in a marked decrease in hindlimb swelling, fibroadipose tissue deposition, and decreased accumulation of perilymphatic inflammatory cells, as compared to controls. In addition, LNT induced a marked lymphangiogenic response in both capillary and collecting lymphatic vessels. Interestingly, the resultant regenerated lymphatics were abnormal in appearance on lymphangiography, but LNT also led to a notable increase in dendritic cell trafficking from the periphery to the inguinal lymph nodes and improved adaptive immune responses.ConclusionsLNT decreases pathological changes of lymphedema and was shown to potently induce lymphangiogenesis. Lymphatic vessels induced by LNT were abnormal in appearance, but were functional and able to transport antigen-presenting cells. Animals treated with LNT have an increased ability to mount T cell-mediated immune responses when sensitized to antigens in the affected hindlimb.

Histopathologic Features of Lymphedema: A Molecular Review

“…K14-VEGFR-3-Ig mice were also found to have decreased antibody titers in response to dermal immunization, a phenomenon attributed to impaired antigen transport and DC trafficking that was seen in these animals, since B cells isolated from transgenic mice demonstrated similar functionality compared to those of WT mice [72]. Similarly, in an inducible mouse mode of local lymphatic ablation, lymph node transplant improved lymphedema as well as DC trafficking and the adaptive immune response [73]. Taken together, these results suggest an interconnected role of the lymphatics system and infection in which microorganisms contain innate mechanisms to damage host lymphatics; at the same time, lymphatic dysfunction can impair the host immune response.…”

T helper 2 differentiation is necessary for development of lymphedema

“…Near-infrared lymphangiography using indocyanine green (ICG) was utilized for assessment of ipsilateral hindlimb collecting lymphatic vessel function after PLND per a previously validated protocol [30][31][32][33]. Briefly, 15 μL of 0.15 mg/mL (Sigma-Aldrich) was injected intradermally into the first webspace of the hindpaws of anesthetized mice.…”

Developing Computational Geometry and Network Graph Models of Human Lymphatic System

“…As the lymphatic system plays a key role in tumor dissemination, tissue fluid balance and systemic infections' development (e.g., HIV), the mechanistically-oriented modeling based on anatomically-consistent representation of the system structure should provide the research community with novel analytical tools for 3D simulation-assisted resection of lymph nodes, transplantation of lymph nodes [29], understanding the pathogenesis of sepsis, the cure of HIV infection and drug pharmacokinetics.…”