Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema

Abstract

Secondary lymphedema is a common complication of lymph node dissection or radiation therapy for cancer treatment. Conventional therapies such as compression sleeve therapy, complete decongestive physiotherapy, and surgical therapies decrease edema; however, they are not curative because they cannot modulate the pathophysiology of lymphedema. Recent advances reveal that the activation and accumulation of CD4+ T cells are key in the development of lymphedema. Based on this pathophysiology, the efficacy of pharmacotherapy (tacrolimus, anti-IL-4/IL-13 antibody, or fingolimod) and cell-based therapy for lymphedema has been demonstrated in animal models and pilot studies. In addition, mesenchymal stem/stromal cells (MSCs) have attracted attention as candidates for cell-based lymphedema therapy because they improve symptoms and decrease edema volume in the long term with no serious adverse effects in pilot studies. Furthermore, MSC transplantation promotes functional lymphatic regeneration and improves the microenvironment in animal models. In this review, we focus on inflammatory cells involved in the pathogenesis of lymphedema and discuss the efficacy and challenges of pharmacotherapy and cell-based therapies for lymphedema.

Keywords: CD4+ T cell; lymphedema; mesenchymal stem/stromal cell; pharmacotherapy for lymphedema; regulatory T cell.

Figure 1

Scheme of lymphedema development after lymph node dissection. (1) In normal conditions, lymph flow is generated due to intrinsic pump force by a lymphatic collecting vessel network and extrinsic pump force by surrounding skeletal muscles. (2) In the early phase of lymphatic injury, damage-associated molecular patterns (DAMPs) are released from injured cells and these molecules promote lymphangiogenesis. M2 macrophages secrete vascular endothelial growth factor C (VEGF-C) and serve as lymphatic endothelial cell (LEC) progenitors. Dendritic cells (DCs) are activated at the injured site, and invade into lymphatic vessels along the concentration gradient of the C–C chemokine ligand (CCL) 21 secreted by LECs. (3) Activated DCs flow into draining lymph nodes and activate helper T (Th) cells. Expressions of cutaneous leukocyte antigen (CLA), C–C chemokine receptor (CCR) 4, CCR9, and CCR10 are increased at the surface of activated Th cells. These cells enter systemic circulation. (4) Activated Th cells, guided by adhesion molecules and CCLs, infiltrate the injured site and secrete inflammatory cytokines. M1 macrophages also accumulate at the injured site and cause inflammatory responses. (5) Low-grade inflammatory responses, fibrosis, adipose deposition, and unfunctional lymphangiogenesis (valve defect and contractile dysfunction) occur in the chronic phase of lymphedema. These responses impair lymphatic function and exacerbate lymphedema.

Figure 2

Pharmacological mechanisms of therapeutic agents for lymphedema.