Accession Number : ADA567843


Title :   Adaptive Immune Responses Regulate the Pathophysiology of Lymphedema


Descriptive Note : Annual summary rept. 1 September 2011 - 31 August 2012


Corporate Author : SLOAN-KETTERING INST FOR CANCER RESEARCH NEW YORK


Personal Author(s) : Zampell, Jamie ; Mehrara, Babak ; Weitman, Evan ; Elhadad, Sonia ; Yan, Alan


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a567843.pdf


Report Date : Sep 2012


Pagination or Media Count : 102


Abstract : Lymphedema is a debilitating disorder affecting as many as 1 in 8 cancer survivors. Despite wide prevalence, limited understanding of disease pathogenesis has prevented development of effective treatment strategies. While inflammation, fibrosis, and lymphatic dysfunction are known clinical hallmarks, the mechanisms promoting these pathologic changes are unknown. The aim of this study therefore was to determine the cellular mechanisms regulating chronic lymphedema pathogenesis. Using a mouse models of lymphatic fluid stasis and chronic lymphedema, we show that sustained lymphatic fluid stasis leads to CD4+ T cell inflammation with a mixed T-helper cell type 1 (Th1)/T-helper cell type 2 (Th2) phenotype. Matched clinical specimens similarly demonstrate increased CD4+ T cell infiltrate and elevations in Th2-type cytokines. Furthermore, loss of CD4 prevents lymphedema development mouse models; more specifically, inhibition of Th2 differentiation through IL-4 and IL-13 blockade prevents both initiation of lymphedema development and progression of established lymphedema. Following Th2 abrogation, fibrosis is reduced, lymphatic function is improved, and lymphangiogenesis is augmented without a concomitant alteration in lymphangiogenic cytokines. The findings of this study demonstrate that lymphedema pathogenesis results from progressive lymphatic dysfunction resulting from chronic CD4+ inflammation, Th2 differentiation, and fibrosis. Blockade of Th2 responses prevents both initiation and progression of lymphedema without altering lymphangiogenic cytokines locally. Attenuation of Th2 inflammation therefore may be an effective strategy for blocking this pathologic sequence of events without altering metastatic risk in cancer survivors.


Descriptors :   *LYMPHATIC SYSTEM , CYTOKINES , FIBROSIS , IMMUNITY , INFLAMMATION , PATHOGENESIS , PATHOPHYSIOLOGY , RESPONSE(BIOLOGY) , T LYMPHOCYTES


Subject Categories : Anatomy and Physiology
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE