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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Jul 27

PMID 35886961

Authors

Ryohei Ogino

Tomoharu Yokooji

Maiko Hayashida

Shota Suda

Sho Yamakawa

Kenji Hayashida

Affiliations

Soon will be listed here.

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.

Citing Articles

Dynamics of Immune Cell Infiltration and Fibroblast-Derived IL-33/ST2 Axis Induction in a Mouse Model of Post-Surgical Lymphedema.

Uemura K, Katayama K, Nishioka T, Watanabe H, Yamada G, Inoue N Int J Mol Sci. 2025; 26(3).

PMID: 39941140 PMC: 11818732. DOI: 10.3390/ijms26031371.

Closing the Gaps: An Integrative Review of Yoga's Benefits for Lymphedema in Breast Cancer Survivors.

Freguia S, Platano D, Donati D, Giorgi F, Tedeschi R Life (Basel). 2024; 14(8).

PMID: 39202741 PMC: 11355715. DOI: 10.3390/life14080999.

Vascular Endothelial Growth Factor C (VEGF-C) Sensitizes Lymphatic Endothelial Cells to Oxidative-Stress-Induced Apoptosis through DNA Damage and Mitochondrial Dysfunction: Implications for Lymphedema.

Hossain L, Gomes K, Yang X, Liu E, Du Toit J, von der Weid P Int J Mol Sci. 2024; 25(14).

PMID: 39063073 PMC: 11277328. DOI: 10.3390/ijms25147828.

[Research advances on stem cell-based treatments in animal studies and clinical trials of lymphedema].

Chen J, Deng C Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2024; 38(1):99-106.

PMID: 38225848 PMC: 10796233. DOI: 10.7507/1002-1892.202309045.

Lymphatic vessel: origin, heterogeneity, biological functions, and therapeutic targets.

Hu Z, Zhao X, Wu Z, Qu B, Yuan M, Xing Y Signal Transduct Target Ther. 2024; 9(1):9.

PMID: 38172098 PMC: 10764842. DOI: 10.1038/s41392-023-01723-x.

References

Bruns F, Micke O, Bremer M . Current status of selenium and other treatments for secondary lymphedema. J Support Oncol. 2004; 1(2):121-30. View

Ogata F, Fujiu K, Matsumoto S, Nakayama Y, Shibata M, Oike Y . Excess Lymphangiogenesis Cooperatively Induced by Macrophages and CD4(+) T Cells Drives the Pathogenesis of Lymphedema. J Invest Dermatol. 2016; 136(3):706-714. DOI: 10.1016/j.jid.2015.12.001. View

Raju A, Chang D . Vascularized lymph node transfer for treatment of lymphedema: a comprehensive literature review. Ann Surg. 2014; 261(5):1013-23. DOI: 10.1097/SLA.0000000000000763. View

Teijeira A, Rouzaut A, Melero I . Initial afferent lymphatic vessels controlling outbound leukocyte traffic from skin to lymph nodes. Front Immunol. 2013; 4:433. PMC: 3856852. DOI: 10.3389/fimmu.2013.00433. View

Maldonado G, Perez C, Covarrubias E, Cabriales S, Leyva L, Perez J . Autologous stem cells for the treatment of post-mastectomy lymphedema: a pilot study. Cytotherapy. 2011; 13(10):1249-55. DOI: 10.3109/14653249.2011.594791. View

Rokunohe A, Matsuzaki Y, Rokunohe D, Sakuraba Y, Fukui T, Nakano H . Immunosuppressive effect of adipose-derived stromal cells on imiquimod-induced psoriasis in mice. J Dermatol Sci. 2016; 82(1):50-3. DOI: 10.1016/j.jdermsci.2015.12.007. View

Hou C, Wu X, Jin X . Autologous bone marrow stromal cells transplantation for the treatment of secondary arm lymphedema: a prospective controlled study in patients with breast cancer related lymphedema. Jpn J Clin Oncol. 2008; 38(10):670-4. DOI: 10.1093/jjco/hyn090. View

Clavin N, Avraham T, Fernandez J, Daluvoy S, Soares M, Chaudhry A . TGF-beta1 is a negative regulator of lymphatic regeneration during wound repair. Am J Physiol Heart Circ Physiol. 2008; 295(5):H2113-27. DOI: 10.1152/ajpheart.00879.2008. View

Lee Y, Sah S, Lee J, Seo K, Kang K, Kim T . Human umbilical cord blood-derived mesenchymal stem cells ameliorate psoriasis-like skin inflammation in mice. Biochem Biophys Rep. 2017; 9:281-288. PMC: 5614481. DOI: 10.1016/j.bbrep.2016.10.002. View

10.

Nores G, Ly C, Cuzzone D, Kataru R, Hespe G, Torrisi J . CD4 T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema. Nat Commun. 2018; 9(1):1970. PMC: 5958132. DOI: 10.1038/s41467-018-04418-y. View

11.

Ismail A, Abdou S, Abdelnaby A, Hamdy M, El Saka A, Gawaly A . Stem Cell Therapy Using Bone Marrow-Derived Mononuclear Cells in Treatment of Lower Limb Lymphedema: A Randomized Controlled Clinical Trial. Lymphat Res Biol. 2018; 16(3):270-277. DOI: 10.1089/lrb.2017.0027. View

12.

Keith L, Rowsemitt C, Richards L . Lifestyle Modification Group for Lymphedema and Obesity Results in Significant Health Outcomes. Am J Lifestyle Med. 2020; 14(4):420-428. PMC: 7692018. DOI: 10.1177/1559827617742108. View

13.

Jurado M, De La Mata C, Ruiz-Garcia A, Lopez-Fernandez E, Espinosa O, Remigia M . Adipose tissue-derived mesenchymal stromal cells as part of therapy for chronic graft-versus-host disease: A phase I/II study. Cytotherapy. 2017; 19(8):927-936. DOI: 10.1016/j.jcyt.2017.05.002. View

14.

Salek Farrokhi A, Zarnani A, Kahmini F, Moazzeni S . Mesenchymal stem cells induce expansion of regulatory T cells in abortion-prone mice. Reproduction. 2021; 161(4):477-487. DOI: 10.1530/REP-20-0320. View

15.

Mand S, Debrah A, Klarmann U, Batsa L, Marfo-Debrekyei Y, Kwarteng A . Doxycycline improves filarial lymphedema independent of active filarial infection: a randomized controlled trial. Clin Infect Dis. 2012; 55(5):621-30. PMC: 3412691. DOI: 10.1093/cid/cis486. View

16.

de Castro L, Lopes-Pacheco M, Weiss D, Cruz F, Rocco P . Current understanding of the immunosuppressive properties of mesenchymal stromal cells. J Mol Med (Berl). 2019; 97(5):605-618. DOI: 10.1007/s00109-019-01776-y. View

17.

Ghanta S, Cuzzone D, Torrisi J, Albano N, Joseph W, Savetsky I . Regulation of inflammation and fibrosis by macrophages in lymphedema. Am J Physiol Heart Circ Physiol. 2015; 308(9):H1065-77. PMC: 4551121. DOI: 10.1152/ajpheart.00598.2014. View

18.

Avraham T, Zampell J, Yan A, Elhadad S, Weitman E, Rockson S . Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema. FASEB J. 2012; 27(3):1114-26. PMC: 3574290. DOI: 10.1096/fj.12-222695. View

19.

Tal O, Lim H, Gurevich I, Milo I, Shipony Z, Ng L . DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling. J Exp Med. 2011; 208(10):2141-53. PMC: 3182054. DOI: 10.1084/jem.20102392. View

20.

Avraham T, Yan A, Zampell J, Daluvoy S, Haimovitz-Friedman A, Cordeiro A . Radiation therapy causes loss of dermal lymphatic vessels and interferes with lymphatic function by TGF-beta1-mediated tissue fibrosis. Am J Physiol Cell Physiol. 2010; 299(3):C589-605. PMC: 2944320. DOI: 10.1152/ajpcell.00535.2009. View