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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kindzelski, Andrei L
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Sloan-Kettering Institute for Cancer Research
New York
United States
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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 :
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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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