Kringle Pharma (Japan)

Intestinal fatty acid binding protein (I‐FABP) was proposed as a plasma marker of enterocyte turnover that could be applied to estimate the level of gut damage in HIV‐1 infected patients. We investigated the kinetics of I‐FABP in patients starting antiretroviral therapy (ART) in a clinical cohort (CC) (n=32), and in a clinical trial (RCT), where patients were randomized to lopinavir/r (LPV/r) or efavirenz (EFV)‐based therapy (n=71). I‐FABP was analyzed at baseline (BL) and after 48 and 72 weeks of ART, respectively. Additionally we estimated levels of LPS and sCD14 in both cohorts. At baseline, we found elevated plasma levels of I‐FABP, LPS, and sCD14 in patients with HIV‐1 infection as compared to controls. During ART I‐FABP levels increased from BL to week 48 (1.66 ng/ml [IQR 1.29–2.88] vs. 2.56 ng/ml [IQR 1.29–5.26]; p=0.02) in CC group. Similar pattern was seen in the RCT group at week 72 as compared to BL (2.26 ng/ml [IQR 1.4–3.6] vs 3.13 ng/ml [IQR 1.8–4.9]; p<0.0001). Levels of sCD14 decreased at the end of study period in both groups. The levels of LPS decreased in RCT cohort but not in CC cohort. Interestingly, we found that the I‐FABP levels increased in both cohorts despite 48–72 weeks of efficient ART. A subgroup analysis of the RCT cohort revealed that the I‐FABP increase occurred in the patients treated with EFV (2.32 ng/ml [IQR 1.5–3.8] vs. 4.29 ng/ml [IQR 2.4–5.9]; p<0.0001), but not in those with LPV/r. This finding was not confirmed in the CC group. The possibility of immune reconstitution in the gut as a cause of the increasing I‐FABP levels seems to be less likely, as CD4 T‐cell recovery tended to be lower in efavirenz‐treated patients. In RCT cohort, the established MT markers lipopolysaccharide (LPS) and sCD14 were both reduced after 72 weeks (data not shown), supporting a reduced MT. Most likely the systemic I‐FABP levels in patients on ART do not reflect only MT itself. Further studies should address this issue.

Immune-mediated diseases of the CNS, such as multiple sclerosis and its animal model, experimental autoimmune encephalitis (EAE), are characterized by the activation of antigen-presenting cells and the infiltration of autoreactive lymphocytes within the CNS, leading to demyelination, axonal damage, and neurological deficits. Hepatocyte growth factor (HGF) is a pleiotropic factor known for both neuronal and oligodendrocytic protective properties. Here, we assess the effect of a selective overexpression of HGF by neurons in the CNS of C57BL/6 mice carrying an HGF transgene (HGF-Tg mice). EAE induced either by immunization with myelin oligodendrocyte glycoprotein peptide or by adoptive transfer of T cells was inhibited in HGF-Tg mice. Notably, the level of inflammatory cells infiltrating the CNS decreased, except for CD25(+)Foxp3(+) regulatory T (T(reg)) cells, which increased. A strong T-helper cell type 2 cytokine bias was observed: IFN-gamma and IL-12p70 decreased in the spinal cord of HGF-Tg mice, whereas IL-4 and IL-10 increased. Antigen-specific response assays showed that HGF is a potent immunomodulatory factor that inhibits dendritic cell (DC) function along with differentiation of IL-10-producing T(reg) cells, a decrease in IL-17-producing T cells, and down-regulation of surface markers of T-cell activation. These effects were reversed fully when DC were pretreated with anti-cMet (HGF receptor) antibodies. Our results suggest that, by combining both potentially neuroprotective and immunomodulatory effects, HGF is a promising candidate for the development of new treatments for immune-mediated demyelinating diseases associated with neurodegeneration such as multiple sclerosis.