02898nas a2200421   4500000000100000008004100001260001300042653001200055653003100067653003100098653001400129653001900143653001400162653002500176653001200201653002600213653002200239653000900261653001900270653003700289653005200326653003200378100001200410700001600422700001500438700001100453700001200464700001400476700001800490700001300508245013900521856007900660300001200739490000800751050001500759520168800774022001402462       2009                            d  c2009 Apr10aAnimals10aCD4-Positive T-Lymphocytes10aCD8-Positive T-Lymphocytes10aCytokines10aFlow Cytometry10aGranuloma10aImmunohistochemistry10aleprosy10aLymphocyte Activation10aLymphotoxin-alpha10aMice10aMice, Knockout10aReceptors, Tumor Necrosis Factor10aReverse Transcriptase Polymerase Chain Reaction10aTumor Necrosis Factor-alpha1 aHagge D1 aSaunders BM1 aEbenezer G1 aRay NA1 aMarks V1 aBritton W1 aKrahenbuhl JL1 aAdams LW00aLymphotoxin-alpha and TNF have essential but independent roles in the evolution of the granulomatous response in experimental leprosy.  uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671369/pdf/JPATH174001379.pdf  a1379-890 v174  aHAGGE 20093 a<p>Recent studies identified an association between genetic variants in the lymphotoxin-alpha (LTalpha) gene and leprosy. To study the influence of LTalpha on the control of experimental leprosy, both low- and high-dose Mycobacterium leprae foot pad (FP) infections were evaluated in LTalpha-deficient chimeric (cLTalpha(-/-)) and control chimeric (cB6) mice. Cellular responses to low-dose infection in cLTalpha(-/-) mice were dramatically different, with reduced accumulation of CD4(+) and CD8(+) lymphocytes and macrophages and failure to form granulomas. Growth of M. leprae was contained for 6 months, but augmented late in infection. In contrast, tumor necrosis factor knockout and tumor necrosis factor receptor 1 knockout FPs exhibited extensive inflammatory infiltration with an increase in M. leprae growth throughout infection. Following high-dose infection, cB6 FP induration peaked at 4 weeks and was maintained for 12 weeks. Induration was not sustained in cLTalpha(-/-) FPs that contained few lymphocytes and no granulomas. There was a reduction in the expression levels of inflammatory cytokines, chemokines, and chemokine receptors, including nitric oxide synthase 2, vascular cell adhesion molecule, and intercellular cell adhesion molecule. Furthermore, cLTalpha(-/-) popliteal lymph nodes contained a higher proportion of naïve CD44(lo)CD62L(hi) T cells than cB6 mice, suggestive of reduced T cell activation. Therefore, both LTalpha and tumor necrosis factor are essential for the regulation of the granuloma, but they have distinctive roles in the recruitment of lymphocytes and maintenance of the granulomatous response during chronic M. leprae infection.</p>  a1525-2191