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Cd4+ Cells Home To And Initiate Pathological Changes Of Lymphedema After Lymphatic Injury.
Gabriela D. Garcia Nores, M.D.1, Daniel A. Cuzzone, M.D.2, Jason C. Gardenier, M.D.1, Ira L. Savetsky, M.D.1, Jeremy S. Torrisi, B.A.1, Matthew D. Nitti, B.A.1, Geoffrey E. Hespe, B.S.1, Raghu P. Kataru, Ph.D.1, Babak J. Mehrara, M.D.1.
1Memorial Sloan Kettering Cancer Center, New York, NY, USA, 2Nw York University Hospital Center, New York, NY, USA.
Lymphedema is a common complication of cancer treatment and our group has previously shown that CD4+ cells play a key role in the pathophysiology of this disease by regulating fibrosis and lymphatic function. However although it is clear that CD4+ cells, in general, are critically necessary for the pathology of LE, it remains unknown if thymus derived CD4+ cells home to lymphedematous tissues and if these cells can modulate the function of lymphatic collectors. Therefore, the purpose of this study was to use compare lymphatic changes in mouse models of lymphedema after bone marrow transplantation or adoptive transfer of CD4+ cells.
To test the hypothesis that bone marrow derived cells regulate development of lymphedema, CD4 knockout (CD4KO) and wild-type (WT) mice underwent lethal irradiation and were reconstituted with bone marrow cells from donor CD4KO or WT mice, respectively. After engraftment, animals underwent excision lymphatic vessels in the tail or bilateral popliteal lymph node dissection. In other experiments, to test the hypothesis that CD4+ cells home to lymphedematous tissues, CD4KO mice that had undergone lymphatic ablation were adoptively transferred with WT CD4+ cells injected via the retro-orbital veins. Adipose deposition, lymphatic function, and lymphangiogenesis were analyzed. In addition, we analyzed lymphatic pumping function using near infra-red imaging (NIR) using indocyanine green injection (ICG).
As expected, CD4KO mice were protected from developing lymphedema after lymphatic injury as compared with WT mice. Interestingly, WT mice transplanted with bone marrow derived from CD4KO mice developed lymphedema and had impaired lymphatic function suggesting that a non-bone marrow source (e.g. thymus) plays an important role in the pathology of lymphedema. Similarly, we found that adoptive transfer of CD4+ cells to CD4KO mice resulted in development of lymphedema with fibrosis, adipose deposition, and impaired lymphatic function (Tc99 transport) as compared with controls (p<0.001). CD4KO mice that had adoptive transfer of CD4+ cells had markedly impaired lymphatic collector function in the hindlimb on ICG imaging demonstrating decreased lymphatic pumping function as compared with controls (p<0.003). Moreover, using flow cytometry and immunohistochemistry we found that CD4KO mice adoptively transferred with CD4+ cells had significant accumulation of CD4+ cells in the dermis/subcutaneous fat (p<0.001) and in the peri-lymphatic regions of lymphedematous tissues.
Our study demonstrates that peripheral tissue derived CD4+ cells play an important role in the pathology of lymphedema. In addition, we have shown that CD4+ cells actively home to lymphedematous tissues and regulate tissue fibrosis, adipose deposition, and lymphatic function. CD4+ cells localize to the perilymphatic regions and are associated with impaired lymphatic collector function. These findings will enable us to determine the mechanisms that regulate CD4+ cell homing and develop targeted treatments for lymphedema.
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