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Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis
Veronica De Rosa, … , Serafino Zappacosta, Giuseppe Matarese
Veronica De Rosa, … , Serafino Zappacosta, Giuseppe Matarese
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):447-455. https://doi.org/10.1172/JCI26523.
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Categories: Research Article Autoimmunity

Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis

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Abstract

Recent evidence has indicated that leptin, an adipocyte-secreted hormone belonging to the helical cytokine family, significantly influences immune and autoimmune responses. We investigate here the mechanisms by which in vivo abrogation of leptin effects protects SJL/J mice from proteolipid protein peptide PLP139–151-induced EAE, an animal model of MS. Blockade of leptin with anti-leptin Abs or with a soluble mouse leptin receptor chimera (ObR:Fc), either before or after onset of EAE, improved clinical score, slowed disease progression, reduced disease relapses, inhibited PLP139–151-specific T cell proliferation, and switched cytokine secretion toward a Th2/regulatory profile. This was also confirmed by induction of forkhead box p3 (Foxp3) expression in CD4+ T cells in leptin-neutralized mice. Importantly, anti-leptin treatment induced a failure to downmodulate the cyclin-dependent kinase inhibitor p27 (p27Kip-1) in autoreactive CD4+ T cells. These effects were associated with increased tyrosine phosphorylation of both ERK1/2 and STAT6. Taken together, our data provide what we believe is a new molecular basis for leptin antagonism in EAE and envision novel strategies of leptin-based molecular targeting in the disease.

Authors

Veronica De Rosa, Claudio Procaccini, Antonio La Cava, Paolo Chieffi, Giovanni Francesco Nicoletti, Silvia Fontana, Serafino Zappacosta, Giuseppe Matarese

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Figure 6

In vivo leptin neutralization with ObR:Fc inhibits IFN-γ production and induces the secretion of IL-4 and IL-10 regulatory cytokines.

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In vivo leptin neutralization with ObR:Fc inhibits IFN-γ production and ...
(A and B) IFN-γ secretion of lymph node–derived T cells was inhibited by ObR:Fc treatment when T cells were stimulated with the myelin antigen PLP139–151 (A) and by anti-CD3ε (B). (C and D) IL-4 secretion of lymph node–derived T cells was enhanced by ObR:Fc treatment when T cells were stimulated with the myelin antigen PLP139–151 (C) and by anti-CD3ε (D). (E and F) IL-10 secretion of lymph node–derived T cells was markedly increased by ObR:Fc treatment when T cells were stimulated with the myelin antigen PLP139–151 (E) and by anti-CD3ε (F). Data are from 1 representative experiment of 3. (A) **P = 0.001, day –1 to day 1 and days 8–11 versus control Ig. (C) **P = 0.001, day –1 to day 1, and †P = 0.04, days 8–11, versus control Ig. (E) **P = 0.001, days 8–11, and #P = 0.02, day –1 to day 1, versus control Ig. (B, D, and F) #P = 0.02, *P = 0.002, †P = 0.04 versus control Ig.
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