P398 Leptin controls immune cell composition and activity in acquired generalised lipodystrophy with combined Crohn's disease. (25th January 2019) - Ziegler, J F
Abstract: Background: Leptin, a fat-derived adipokine, has been suggested to modulate intestinal inflammation in mice. However, clinical evidence regarding its immune-stimulatory potential in Crohn's disease remains sparse. We here describe a 21-year-old patient with the solitaire combination of acquired generalised lipodystrophy and combined Crohn's disease (AGLCD) featuring a complete lack of visceral and subcutaneous adipose tissue, absent leptin production and severe intestinal inflammation, who received daily injections with 2.5 mg recombinant n -Methionylleptin (rLeptin). Methods: Using mass and flow cytometry, immunohistochemistry (IHC), ELISA and Seahorse analyses, we characterised the effects of rLeptin substitution on the patient's immune cell composition and function in vivo and in vitro and compared our results to a cohort of healthy donors and Crohn's disease patients. Furthermore, the immune-stimulatory effects of leptin substitution were assessed in a mouse model of acute DSS colitis. Results: In the absence of mesenteric fat, we observed a unique immune cell composition in the peripheral blood of the AGLCD patient, characterised by reduced frequencies of NK cells and CD14 + monocytes, an accumulation of lipid droplets in monocytes, NK and CD8 + T cells, decreased expression of CCR7 on T cells and an increased expression of CD38 on T and NK cells compared with healthy donors and Crohn's disease patients. Treatment of the AGLCD patient with rLeptin reduced the lipid droplet contents of immune cells and in vitro application of leptin decreased fatty acid oxidation in macrophages. Furthermore, rLeptin treatment led to increased expression of pro-inflammatory markers in monocytic cells as well as increased TNFα production in monocytes and T cells, ultimately resulting in a high inflammatory disease activity and subsequently ileocolic resection. Accordingly, IHC of the resected specimen of the AGLCD patient showed a higher infiltration of TNFα-producing cells and reduced numbers of CD206 + anti-inflammatory cells compared with CD patients. Likewise, injection of leptin aggravated intestinal inflammation in colitic mice by inducing TNFα-producing CD4 + T cells. Importantly, these pro-inflammatory effects of rLeptin in the AGLCD patient could be overcome by treatment with the TNF-blocking antibody adalimumab, which resulted in complete clinical and endoscopic remission 6 month after initiation of therapy despite ongoing rLeptin treatment. Conclusions: Our results suggest that leptin might play a crucial role in human immune cell homeostasis and that in the setting of a pre-existing inflammatory condition leptin therapy might fuel inflammation and increase disease activity via the induction of TNFα-producing cells, which can be reversed by TNFα-blockade.