This proposal is significant because we aim to develop novel treatments for secondary lymphedema, a common and morbid complication of cancer treatment. This is important because current therapies for this disease are palliative and inadequate. In our previous studies, we have shown that the pathology of lymphedema is secondary to progressive fibrosis and is mediated by chronic T-helper (CD4+) cell inflammation and T-helper 2 (Th2) differentiation. We have used this information to develop novel therapies for the treatment of secondary lymphedema and have recently translated our work from the bench to the bedside in an investigator-initiated trial using Th2 cytokine neutralizing antibodies. The objective of this application is to identify the cellular mechanisms that initiate CD4+ cell inflammatory responses following lymphatic injury. This objective is a logical extension of our previous work and should identify additional targets that can be targeted pharmacologically to treat/prevent lymphedema. Our long-term objective is to use the information we gain from this basic understanding of lymphedema to develop therapies that disrupt the cycle of events that promote progressive fibrosis and lymphatic dysfunction. Our approach is innovative since we use a combination of mouse models and clinical specimens to dissect the cellular mechanisms of lymphedema pathology. Our group is uniquely positioned to accomplish our goals on the basis of our multidisciplinary team, our access to clinical tissues, and our novel mouse models. We plan to achieve our objectives using 2 specific aims:
Aim 1. Determine how lymphatic injury activates CD4+ cells.
This aim will use clinical samples and mouse models to test the hypothesis that keratinocytes play a key role in the activation and migration of CD4+ cells to lymphedematous tissues. In addition, we will test the hypothesis that single nucleotide polymorphisms in immune response genes will increase the risk of lymphedema.
Aim 3. Determine how inflammation impairs lymphatic function.
This aim will test the hypothesis that inflammatory responses in lymphedema impair lymphatic function by multiple effects, including tissue and lymphatic fibrosis, perilymphatic inflammation, and impaired formation of collateral lymphatic vessels.

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 #
5R01HL111130-09
Application #
10063531
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kindzelski, Andrei L
Project Start
2012-09-01
Project End
2021-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
9
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
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:
Huang, Jung-Ju; Gardenier, Jason C; Hespe, Geoffrey E et al. (2016) Lymph Node Transplantation Decreases Swelling and Restores Immune Responses in a Transgenic Model of Lymphedema. PLoS One 11:e0168259
Gardenier, Jason C; Hespe, Geoffrey E; Kataru, Raghu P et al. (2016) Diphtheria toxin-mediated ablation of lymphatic endothelial cells results in progressive lymphedema. JCI Insight 1:e84095
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

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