Small numbers of CD4+ T cells can induce development of lymphedema

Background: CD4+ T cells have been implicated in the pathology of lymphedema. Interestingly, however, there have been case reports of lymphedema development in patients with low levels of CD4+ T cells due to immunosuppression. In this study, we sought to delineate the effect of relative CD4+ T cell deficiency on the development of lymphedema in a mouse model. Methods: A mouse model of relative CD4+ T cell deficiency was created through lethal total body irradiation of wild-type (WT) mice that then underwent bone marrow transplantation with progenitors harvested from CD4 knockout (CD4KO) mice (WT/CD4KO). Irradiated CD4KO mice reconstituted with WT mouse-derived progenitors (CD4KO/WT), as well as unirradiated CD4KO and WT mice were used as controls. All mice underwent tail skin and lymphatic excision to induce lymphedema and analysis was performed six weeks later. Results: WT/CD4KO chimeras were not protected from developing lymphedema. Despite a global deficit in CD4+ T cells, these mice had swelling, fibrosis, inflammation, and impaired lymphatic transport function indistinguishable from that in WT and CD4KO/WT mice. In contrast, unirradiated CD4KO mice had no features of lymphedema after lymphatic injury. Conclusions: Relatively few numbers of bone marrow and peripheral CD4+ T cells are sufficient to induce the development of lymphedema. These findings suggest that lymphatic injury results in expansion of CD4+ T cell populations in lymphedematous tissues. Financial Disclosure Statement: None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript. This work was supported by the National Institutes of Health (NIH) R01 HL111130-01 and R21 CA194882 grants awarded to B.J.M., the NIH T32 CA9501-29 grant to C.L.L., the NIH T32 CA009685-21A1 grant to D.A.C., and the NIH/NCI P30 CA008748 (Cancer Center Support Grant) to Memorial Sloan Kettering Cancer Center. Presented at: Plastic Surgery Research Council 60th Annual Meeting; Seattle, Washington; May 15, 2015 Acknowledgements: The authors thank the Molecular Cytology and Flow Cytometry Cores at Memorial Sloan Kettering Cancer Center for their assistance (Core Grant P30 CA008748). Author contributions: D.A.C. and B.J.M. conceived of the concept and designed the experiments. C.L.L., D.A.C., R.P.K., and B.J.M. performed the experiments and/or analyzed the data. C.L.L. and B.J.M. prepared and edited the manuscript. Corresponding author: Babak J. Mehrara, MD, Member, Memorial Hospital, Professor of Plastic Surgery, Weill Cornell University Medical Center, 1275 York Avenue, Suite MRI 1006, New York, New York, USA 10065, mehrarab@mskcc.org ©2018American Society of Plastic Surgeons

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