Lymphedema is the accumulation of protein rich fluid in tissues, and in the US, occurs most commonly as a surgical complication of cancer treatment. Despite the fact that 3-5 million Americans suffer from lymphedema, its etiology is unknown and treatment remains palliative. Based on our laboratory data as well as the clinical presentation of lymphedema we hypothesize that the pathology of lymphedema is secondary to progressive fibrosis and is mediated by chronic T-helper (CD4+) cell inflammation. The objective of this proposal is to determine how lymphatic fluid stasis causes tissue fibrosis and lymphatic dysfunction. Our long-term objective is to develop therapies to treat or prevent lymphedema by disrupting the cycle of stasis, fibrosis, and lymphatic dysfunction. This approach is innovative since previous efforts have attempted to treat lymphedema by augmenting lymphatic repair and regeneration using cytokines. These cytokines, however, can also cause tumor metastasis or recurrence thereby limiting the applicability of this approach in cancer patients. This proposal is relevant since lymphedema is a common and morbid complication of cancer treatment for which there is no proven preventative methods and treatment is palliative. We plan to achieve our objectives using 3 specific aims.
Aim 1 : Determine the cellular sources of profibrotic cytokines.
This aim will test the working hypothesis that CD4+ T-cells are the primary source of profibrotic cytokines using transgenic mice, antibody depletion, and adoptive transfer experiments in a mouse-tail and axillary dissection model.
Aim 2 : Determine how the expression of profibrotic cytokines is regulated.
This aim will test the working hypothesis is that lymphatic stasis causes Th2 cell inflammation and IL4 and IL13 expression and that these cytokines interact to cause fibrosis and lymphatic dysfunction. We will use clinical specimens from patients with lymphedema before and after medical or surgical treatment as well as our mouse tail model.
Aim 3 : Determine how profibrotic cytokines regulate lymphatic function and fibrosis.
This aim will test the working hypothesis that impaired lymphatic function secondary to fibrosis is a consequence of indirect effects of T-cells and Th2 cytokines on the lymphatic system rather than down-regulation of lymphangiogenic cytokine expression.

Public Health Relevance

This application is relevant and in-line with the mission of the NIH since we aim to identify the basic pathophysiology of a common and disabling complication of cancer treatment. This information can be used to design targeted, rational treatments and preventative strategies that are oncologically safe. In addition, our research has broader relevance as it will increase our understanding of the lymphatic system which plays a critical role in fat metabolism, immunity, inflammation, and tumor metastasis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111130-03
Application #
8695460
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kindzelski, Andrei L
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
City
New York
State
NY
Country
United States
Zip Code
10065
García Nores, Gabriela D; Ly, Catherine L; Savetsky, Ira L et al. (2018) Regulatory T Cells Mediate Local Immunosuppression in Lymphedema. J Invest Dermatol 138:325-335
Ly, Catherine L; Cuzzone, Daniel A; Kataru, Raghu P et al. (2018) Small numbers of CD4+ T cells can induce development of lymphedema. Plast Reconstr Surg :
Coriddi, Michelle; Kenworthy, Elizabeth; Weinstein, Andrew et al. (2018) The importance of indocyanine green near-infrared fluorescence angiography in perfusion assessment in vascularized omentum lymphatic transplant. J Surg Oncol 118:109-112
García Nores, Gabriela D; Ly, Catherine L; Cuzzone, Daniel A et al. (2018) CD4+ T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema. Nat Commun 9:1970
Gardenier, Jason C; Kataru, Raghu P; Hespe, Geoffrey E et al. (2017) Topical tacrolimus for the treatment of secondary lymphedema. Nat Commun 8:14345
Ly, Catherine L; Kataru, Raghu P; Mehrara, Babak J (2017) Inflammatory Manifestations of Lymphedema. Int J Mol Sci 18:
García Nores, G D; Cuzzone, D A; Albano, N J et al. (2016) Obesity but not high-fat diet impairs lymphatic function. Int J Obes (Lond) 40:1582-1590
Nitti, Matthew D; Hespe, Geoffrey E; Kataru, Raghu P et al. (2016) Obesity-induced lymphatic dysfunction is reversible with weight loss. J Physiol 594:7073-7087
Torrisi, Jeremy S; Hespe, Geoffrey E; Cuzzone, Daniel A et al. (2016) Inhibition of Inflammation and iNOS Improves Lymphatic Function in Obesity. Sci Rep 6:19817
Hespe, Geoffrey E; Kataru, Raghu P; Savetsky, Ira L et al. (2016) Exercise training improves obesity-related lymphatic dysfunction. J Physiol 594:4267-82

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