Initial lymphatic vessels collect interstitial fluid to create lymph. The collected lymph is transported through collecting lymphatic vessels towards lymph nodes, and eventually returned to blood circulation to maintain tissue fluid balance. Antigen and dendritic cells (DC) use this route to enter the draining lymph node (LN) and initiate an immune response. Metastatic tumor cells frequently spread through lymphatic vessels and colonize in LNs. Smooth muscle driven lymphatic contraction is the major force of collecting lymphatic vessel transport. Following the treatment with radiation and surgery, cancer patients frequently develop lymphedema. While in the US about 3 million patients develop lymphedema as a result of cancer therapy, the major cause of lymphedema world-wide is lymphatic filariasis caused by mosquito-borne parasitic infections of the lymphatic system. Globally, it is estimated that there are 120 million filiarial infections, with over 1.3 billion people at risk. Although malfunctions/disruptions of collecting lymphatic vessels are responsible for most cases of acquired lymphedema, the function and biology of these vessels are poorly understood due to the lack of a mouse model. Chronic infections are frequently associated with lymphedema. It is completely unknown whether these difficult to resolve infections are hindered by an impairment of lymphatic contraction, reduced transport to the lymph node and thereby impair immune response and antigen clearance. I have developed a novel intravital microscopy to visualize mouse lymphatic contraction. With this system, I have determined that CD11b+Gr1+ cells infiltrate into inflamed areas attenuated collecting lymphatic vessel contraction via expression of inducible nitric oxide synthase (iNOS). In the Mentored Phase of this career development proposal, I will further address the functional role of lymphatic contraction in immune regulation during cancer progression. First, I will determine if the infiltrated CD11b+Gr1+ cells regulate lymphatic contraction in cancer progression. I will address this aim by measuring the lymphatic contraction using multiple cancer models with NOS blockade and myeloid cell depletion. In the Independent Phase, I will determine if antigen specific immune response is impaired during the period of lymphatic malfunction by measuring the immune response to ovalbumin (OVA) and a self-antigen (myelin oligodendrocyte glycoprotein peptide 35-55). I will characterize which step was interrupted to cause the impaired immune response by measuring i) antigen/DC travel through the afferent lymphatic vessel;ii) antigen/DC distribution in the LN;iii) the interaction between DC and T cells and iv) T cell response. In the end, I will determine if myeloid cells suppress T cell response indirectly via regulating lymphatic vessel function by monitoring immune cell entry, distribution and egress of the draining LN during pathological conditions. These studies will provide novel insights into the mechanisms of lymphatic malfunction and identify targets for improving immune protection during edema, autoimmune diseases, infectious diseases and cancer metastasis.

Public Health Relevance

Chronic disruption of lymphatic function leads to lymphedema, which frequently associated with chronic infection. I have established the first mouse model that allows intravital imaging of lymphatic contraction to study the disease processes during inflammation and cancer. The proposed studies will uncover mechanisms of the impaired immune response associated with lymphatic malfunction in order to improve immune protection in lymphedema, autoimmune diseases, infectious diseases and cancer.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Career Transition Award (K99)
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Special Emphasis Panel (ZHL1-CSR-P (M3))
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Sarkar, Rita
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Massachusetts General Hospital
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Liao, Shan; Jones, Dennis; Cheng, Gang et al. (2014) Method for the quantitative measurement of collecting lymphatic vessel contraction in mice. J Biol Methods 1:
Samuel, Rekha; Daheron, Laurence; Liao, Shan et al. (2013) Generation of functionally competent and durable engineered blood vessels from human induced pluripotent stem cells. Proc Natl Acad Sci U S A 110:12774-9
Liao, Shan; Padera, Timothy P (2013) Lymphatic function and immune regulation in health and disease. Lymphat Res Biol 11:136-43