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Targeting obesity, insulin resistance and Type 2 diabetes with immunotherapy: the challenges ahead “Obesity and insulin resistance are closely associated with chronic low-grade tissue inflammation, therefore, immunotherapy can potentially be used to combat these diseases.” KEYWORDS: apoptosis inhibitor of macrophage n CTLA‑4 Ig n macrophage polarization n obesity n Type 2 diabetes
Obesity is associated with chronic low-grade tissue inflammation The prevalence of obesity and insulin resistance is rapidly increasing worldwide. These growing lifestyle-related diseases are problematic and strongly correlated with several associated disorders, such as dyslipidemia, hypertension and glucose intolerance [1,2]. Obesity is considered an independent risk factor for stroke, myocardial infarction, peripheral artery disease and Type 2 diabetes [3,4]. A recent meta-analysis reported that obesity is significantly associated with higher rates of mortality overall [5], therefore, measures against obesity must be taken. A number of studies have reported that levels of adipose tissue macrophages (ATMs) are elevated in obese epididymal and subcutaneous fat tissue [1,6–8]. Infiltration by ATMs into fat tissues is an essential step in the pathogenesis of metabolic diseases [9,10]. ATMs are a basic source of inflammatory regulators and mediators, including TNF‑a, IL‑1, IL‑6, MCP‑1 and matrix metalloproteinases, that contribute to insulin resistance in adipocytes [11,12]. It has been reported that CD4+Foxp3+ T cells can induce the anti-inflammatory M2 macrophage, which secretes IL‑10 and protects against insulin resistance [13]. Obesity and insulin resistance are closely associated with chronic low-grade tissue inflammation, therefore, immunotherapy can potentially be used to combat these diseases. A number of in vitro, in vivo and clinical research studies have revealed the relationship between obesity, insulin resistance and immune system abnormalities, and also demonstrated the efficacy of immunotherapy [14–21]. Immune system abnormalities & insulin resistance Feuerer et al. demonstrated the anti-inflammatory roles of Tregs in fat tissue. They reported that
CD4+Foxp3+ Tregs, which are considered a potent immunosuppressive population of cells during inflammatory disorders, were highly enriched in the abdominal fat of normal mice. However, their numbers were significantly reduced in the abdominal fat of Lepob/ob, Ay/a and high fat diet (HFD) obese mice. The depletion of Tregs affected insulin signaling because of decreases in insulin receptor tyrosine phosphorylation in epididymal fat. Therefore, insulin concentrations were significantly increased in Treg-depleted mice compared with control mice. This group also found higher levels of Foxp3 transcripts in human adipose tissue, and revealed a correlation between BMI and the reduction in number of Tregs [14]. Eller et al. intravenously injected CD4+FoxP3+ T cells into db/db mice, a leptin receptor-deficient Type 2 diabetes model. Treated mice showed significant improvements in both insulin sensitivity and diabetic nephropathy. Furthermore, they had increased mRNA expression levels for Foxp3, and less proinflammatory T cells in visceral adipose tissue (VAT) and the kidneys. By contrast, Treg depletion using a monoclonal anti-CD25 antibody, induced insulin resistance and increased fasting blood glucose levels [18]. Mice lacking in lymphocytes and subjected to a HFD were treated with CD4+ T cells, which resulted in a small weight gain in subcutaneous adipose tissue, but a slightly greater gain in VAT. The extent of the adipocyte decrease paralleled that of the adipocytokines. Wild-type mice that were fed a HFD and administered a CD3-specific antibody had high levels of CD4+Foxp3+ T cells in VAT. Both of these treatments improved insulin sensitivity. Winer et al. investigated the presence of antiinflammatory M2 macrophages containing the macrophage mannose receptor (MMR) in VAT. These MMR cells were characterized as ‘high’ (IL‑10-expressing), ‘low’ (MCP‑1-expressing),
10.2217/IMT.13.142 © 2014 Future Medicine Ltd
Immunotherapy (2014) 6(1), 5–7
Masakazu Fujii Author for correspondence: Department of Internal Medicine & Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Noriyuki Sonoda Department of Internal Medicine & Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan and Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Ryoichi Takayanagi Department of Internal Medicine & Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Tosyoshi Inoguchi Department of Internal Medicine & Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan and Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Fujii, Sonoda, Takayanagi & Inoguchi
and ‘negative’ (expressed MCP‑1 and TNF‑a). Therapy using the nonmitogenic F(ab´)2 fragment of the CD3-specific antibody increased the number of MMR hi cells but reduced the number of MMR- cells; these observations clearly showed the advantages of increasing the numbers of anti-inflammatory T cells and macrophages in VAT [15]. Another group showed that oral treatment with an anti-CD3 antibody and b-glucosylceramide in leptin-deficient ob/ob mice decreased fat accumulation in the liver, and infiltration of CD11b+F4/80+ inflammatory M1 macrophages in adipose tissue. At the same time, there were increases in the number of CD4+Foxp3+ Tregs in fat, and improvements in serum glucose levels [19]. Certain cytokine levels have been considered crucial factors for glucose metabolism, and have been targeted in clinical trials for Type 2 diabetes patients. The findings from this research showed amelioration in the metabolic control of Type 2 diabetes via blocking of IL‑1 with either antibodies or IL‑1 receptor antagonists [20]. These efforts are complicated by the role of inflammatory cytokines in the normal immune response against viruses, bacteria and tumors. Other studies have shown that expansion of Th17 cells are accelerated in obese individuals, and this corresponds to an increase in IL‑17 levels. This affects inflammation and autoimmunity by inducing proinflammatory cytokines and chemokines to recruit neutrophils, enhance antibody production and activate T-cell production. Expression of IL‑17 in Type 2 diabetes patients was higher than that in healthy controls, and stem cell educator therapy markedly reduced IL‑17 levels in these patients [21]. We recently reported a novel treatment for obesity and Type 2 diabetes that involved an immunoglobulin (Ig) fused to CTLA‑4, CTLA-4 Ig.
CTLA‑4 Ig treatment for obesity & insulin resistance The T-cell receptors CD28 and CTLA‑4 bind to the same ligands on macrophages as the B7 family members CD80 (B7–1) and CD86 (B7–2). The binding of CD28 and CTLA‑4 with B7 molecules provides a key costimulatory signal. Although T-cell activity is greatly enhanced by the binding of CD28 to a monoclonal antibody or B7 ligands, binding of CTLA‑4 with a specific monoclonal antibody suppresses T-cell proliferation. Based on these findings, CTLA‑4 Ig was developed as a therapeutic intervention for rheumatoid arthritis and transplant rejection, which are both associated with T-cell activation. 6
Immunotherapy (2014) 6(1)
To date, focus has been on the relationship between CTLA‑4 Ig and T-cell suppression. We hypothesized that CTLA‑4 Ig transmits an inhibitory signal to T cells and also effects a change in macrophage polarization to the M2 state, thereby leading to amelioration of microinflammation and insulin metabolism. CTLA‑4 Ig (10 mg/kg) administered for 6 weeks into C57BL/6 diet-induced obesity mice resulted in decreased levels of inducible nitric oxide synthase mRNA transcripts, an M1 marker, and significant increases in arginase 1, CD206 and CD163 levels, an M2 marker, in adipose tissue. Flow cytometry analysis confirmed the shift from M1 to M2 macrophages. With respect to glucose metabolism, CTLA‑4 Ig completely abrogated HFD-induced insulin resistance. Inflammatory cytokine levels were increased in the obese state, while IL‑6, TNF‑a, chemokines and MCP1/3 were significantly decreased in adipose tissues. CTLA‑4 Ig-treated HFD mice exhibited a reduction in epididymal and subcutaneous fat tissue weight, with increasing mRNA levels of the apoptosis inhibitor of macrophage (AIM) in adipose tissue [22]. Previous reports have shown that recombinant AIM significantly decreased the number of 3T3-L1 cells containing lipid droplets. Adipocyte hypertrophy was less advanced in AIM+/+ compared with AIM-/- mice, and the overall mass of visceral fat and body weight was markedly reduced [23]. AIM is transported to the adipocyte by CD36 and exerts inhibitory effects on fatty acid synthase in adipocytes. This leads to lipolysis and a subsequent decrease in the size and number of lipid droplets, which finally results in a decrease in adipocyte size. Although there was AIM-induced lipolysis in the adipose tissues of CTLA‑4 Ig treated HFD mice, the secretion of inflammatory chemokines due to increased levels of free fat acid were inhibited by alteration of macrophage polarization from M1 to M2 by CTLA‑4 Ig. The dual effect of AIM-induced lipolysis and anti-inflammation by CTLA‑4 Ig suggests that it might be a promising and attractive agent in treating obesity-induced insulin resistance or Type 2 diabetes. Treatment with CTLA‑4 Ig opens up the possibility of manipulating macrophage polarization, leading to amelioration of glucose metabolism. Many researchers are trying to reveal the mechanisms of, and treat dysfunction of, glucose metabolism in obese individuals using immunotherapy. We hope to develop effective treatments against obesity, insulin resistance and Type 2 diabetes in the future, as well as against other lifestyle-related diseases. future science group
Targeting obesity, insulin resistance & Type 2 diabetes with immunotherapy
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes
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