Changes in nutritional status impact immune cell metabolism and function

Frontiers in Immunology

Volumn 9, Issue MAY, 2018, Pages

  Alwarawrah, Yazan ^a   Kiernan, Kaitlin ^a   MacIver, Nancie J ^a  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

Cellular metabolism; Inflammation; Leptin; Malnutrition; Obesity; T cells

Indexed keywords

3 (3 PYRIDINYL) 1 (4 PYRIDINYL) 2 PROPEN 1 ONE; BENZODIAZEPINE DERIVATIVE; BRANCHED CHAIN AMINO ACID AMINOTRANSFERASE; BRANCHED CHAIN AMINO ACID AMINOTRANSFERASE 1; CYTOKINE; FRUCTOSE 2,6 BISPHOSPHATE; GLUCOSE TRANSPORTER 1; INTERLEUKIN 17; INTERLEUKIN 6; LEPTIN; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; T LYMPHOCYTE RECEPTOR; TUMOR NECROSIS FACTOR; UNCLASSIFIED DRUG;

APOPTOSIS; AUTOIMMUNE DISEASE; AUTOIMMUNITY; CARDIOVASCULAR DISEASE; CD4+ T LYMPHOCYTE; CELL METABOLISM; CHRONIC INFLAMMATION; DELAYED HYPERSENSITIVITY; GLUCOSE METABOLISM; HUMAN; IMMUNITY; IMMUNOCOMPETENT CELL; IMMUNOSUPPRESSIVE TREATMENT; INFECTION SENSITIVITY; MALNUTRITION; MEMORY T LYMPHOCYTE; NONHUMAN; NUTRITIONAL DISORDER; NUTRITIONAL STATUS; REGULATORY T LYMPHOCYTE; REVIEW; TH1 CELL; TH17 CELL;

EID: 85047003105     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2018.01055     Document Type: Review

References (182)

1. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science (1993) 259(5091):87-91. doi:10.1126/science.7678183
2. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest (1995) 95(5):2409-15. doi:10.1172/JCI117936
3. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest (1995) 95(5):2111-9. doi:10.1172/JCI117899
4. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature (1997) 389(6651):610-4. doi:10.1038/39335
5. Sewter CP, Digby JE, Blows F, Prins J, O'Rahilly S. Regulation of tumour necrosis factor-alpha release from human adipose tissue in vitro. J Endocrinol (1999) 163(1):33-8. doi:10.1677/joe.0.1630033
6. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest (2005) 115(5):1111-9. doi:10.1172/JCI200525102
7. Kopp A, Buechler C, Neumeier M, Weigert J, Aslanidis C, Scholmerich J, et al. Innate immunity and adipocyte function: ligand-specific activation of multiple toll-like receptors modulates cytokine, adipokine, and chemokine secretion in adipocytes. Obesity (Silver Spring) (2009) 17(4):648-56. doi:10.1038/oby.2008.607
8. Yasukawa K, Hirano T, Watanabe Y, Muratani K, Matsuda T, Nakai S, et al. Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6) gene. EMBO J (1987) 6(10):2939-45
9. Woloski BM, Fuller GM. Identification and partial characterization of hepatocyte-stimulating factor from leukemia cell lines: comparison with interleukin 1. Proc Natl Acad Sci U S A (1985) 82(5):1443-7. doi:10.1073/pnas.82.5.1443
10. Rose-John S. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci (2012) 8(9):1237-47. doi:10.7150/ijbs.4989
11. Atreya R, Mudter J, Finotto S, Mullberg J, Jostock T, Wirtz S, et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. Nat Med (2000) 6(5):583-8. doi:10.1038/75068
12. Korn T, Mitsdoerffer M, Croxford AL, Awasthi A, Dardalhon VA, Galileos G, et al. IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A (2008) 105(47):18460-5. doi:10.1073/pnas.0809850105
13. Romani L, Mencacci A, Cenci E, Spaccapelo R, Toniatti C, Puccetti P, et al. Impaired neutrophil response and CD4+ T helper cell 1 development in interleukin 6-deficient mice infected with Candida albicans. J Exp Med (1996) 183(4):1345-55. doi:10.1084/jem.183.4.1345
14. Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia (1997) 40(11):1286-92. doi:10.1007/s001250050822
15. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab (2001) 280(5):E745-51. doi:10.1152/ajpendo.2001.280.5.E745
16. Yamaguchi K, Nishimura T, Ishiba H, Seko Y, Okajima A, Fujii H, et al. Blockade of interleukin 6 signalling ameliorates systemic insulin resistance through upregulation of glucose uptake in skeletal muscle and improves hepatic steatosis in high-fat diet fed mice. Liver Int (2015) 35(2):550-61. doi:10.1111/liv.12645
17. Kraakman MJ, Kammoun HL, Allen TL, Deswaerte V, Henstridge DC, Estevez E, et al. Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell Metab (2015) 21(3):403-16. doi:10.1016/j.cmet.2015.02.006
18. Xu E, Pereira MMA, Karakasilioti I, Theurich S, Al-Maarri M, Rappl G, et al. Temporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance. Nat Commun (2017) 8:14803. doi:10.1038/ncomms14803
19. Friedman JM. The function of leptin in nutrition, weight, and physiology. Nutr Rev (2002) 60(10 Pt 2):S1-14; discussion S68-84, 5-7. doi:10.1301/002966402320634878
20. Naylor C, Petri WA Jr. Leptin regulation of immune responses. Trends Mol Med (2016) 22(2):88-98. doi:10.1016/j.molmed.2015.12.001
21. Gainsford T, Willson TA, Metcalf D, Handman E, McFarlane C, Ng A, et al. Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc Natl Acad Sci U S A (1996) 93(25):14564-8. doi:10.1073/pnas.93.25.14564
22. Mandel MA, Mahmoud AA. Impairment of cell-mediated immunity in mutation diabetic mice (db/db). J Immunol (1978) 120(4):1375-7
23. Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, et al. Leptin regulates proinflammatory immune responses. FASEB J (1998) 12(1):57-65. doi:10.1096/fasebj.12.1.57
24. CioffiJA, Shafer AW, Zupancic TJ, Smith-Gbur J, Mikhail A, Platika D, et al. Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction. Nat Med (1996) 2(5):585-9. doi:10.1038/nm0596-585
25. Procaccini C, Jirillo E, Matarese G. Leptin as an immunomodulator. Mol Aspects Med (2012) 33(1):35-45. doi:10.1016/j.mam.2011.10.012
26. Saucillo DC, Gerriets VA, Sheng J, Rathmell JC, Maciver NJ. Leptin metabolically licenses T cells for activation to link nutrition and immunity. J Immunol (2014) 192(1):136-44. doi:10.4049/jimmunol.1301158
27. Gerriets VA, Danzaki K, Kishton RJ, Eisner W, Nichols AG, Saucillo DC, et al. Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity. Eur J Immunol (2016) 46(8):1970-83. doi:10.1002/eji.201545861
28. van Stijn CM, Kim J, Lusis AJ, Barish GD, Tangirala RK. Macrophage polarization phenotype regulates adiponectin receptor expression and adiponectin anti-inflammatory response. FASEB J (2015) 29(2):636-49. doi:10.1096/fj.14-253831
29. Luo Y, Liu M. Adiponectin: a versatile player of innate immunity. J Mol Cell Biol (2016) 8(2):120-8. doi:10.1093/jmcb/mjw012
30. Al-Suhaimi EA, Shehzad A. Leptin, resistin and visfatin: the missing link between endocrine metabolic disorders and immunity. Eur J Med Res (2013) 18(1):12. doi:10.1186/2047-783X-18-12
31. Dostálová I, Sedlácková D, Papezova H, Nedvídková J, Haluzik M. Serum visfatin levels in patients with anorexia nervosa and bulimia nervosa. Physiol Res (2009) 58:903-7
32. Azevedo ZMA, Luz RA, Victal SH, Kurdian B, Fonseca VM, Fitting C, et al. Increased production of tumor necrosis factor-a in whole blood cultures from children with primary malnutrition. Braz J Med Biol Res (2005) 38:171-83. doi:10.1590/S0100-879X2005000200005
33. Fock RA, Vinolo MAR, de Moura Sá Rocha V, de Sá Rocha LC, Borelli P. Protein-energy malnutrition decreases the expression of TLR-4/MD-2 and CD14 receptors in peritoneal macrophages and reduces the synthesis of TNF-a in response to lipopolysaccharide (LPS) in mice. Cytokine (2007) 40(2):105-14. doi:10.1016/j.cyto.2007.08.007
34. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol (2016) 12(1):49-62. doi:10.1038/nrrheum.2015.169
35. Bing C. Is interleukin-1β a culprit in macrophage-adipocyte crosstalk in obesity? Adipocyte (2015) 4(2):149-52. doi:10.4161/21623945.2014.979661
36. Muñoz C, Arévalo M, López M, Schlesinger L. Impaired interleukin-1 and tumor necrosis factor production in protein-calorie malnutrition. Nutr Res (1994) 14(3):347-52. doi:10.1016/S0271-5317(05)80173-3
37. Eder K, Baffy N, Falus A, Fulop AK. The major inflammatory mediator interleukin-6 and obesity. Inflamm Res (2009) 58(11):727. doi:10.1007/s00011-009-0060-4
38. Straczkowski M, Dzienis-Straczkowska S, Stêpieñ A, Kowalska I, Szelachowska M, Kinalska I. Plasma interleukin-8 concentrations are increased in obese subjects and related to fat mass and tumor necrosis factor-a system. J Clin Endocrinol Metab (2002) 87(10):4602-6. doi:10.1210/jc.2002-020135
39. Kim CS, Park HS, Kawada T, Kim JH, Lim D, Hubbard NE, et al. Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. Int J Obes (2006) 30:1347. doi:10.1038/sj.ijo.0803259
40. Makki K, Froguel P, Wolowczuk I. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm (2013) 2013:139239. doi:10.1155/2013/139239
41. Calcaterra V, De Amici M, Klersy C, Torre C, Brizzi V, Scaglia F, et al. Adiponectin, IL-10 and metabolic syndrome in obese children and adolescents. Acta Biomed (2009) 80:117-23
42. Esposito K, Pontillo A, Giugliano F, Giugliano G, Marfella R, Nicoletti G, et al. Association of low interleukin-10 levels with the metabolic syndrome in obese women. J Clin Endocrinol Metab (2003) 88(3):1055-8. doi:10.1210/jc.2002-021437
43. Mello AS, de Oliveira DC, Bizzarro B, Sá-Nunes A, Hastreiter AA, de Oliveira Beltran JS, et al. Protein malnutrition alters spleen cell proliferation and IL-2 and IL-10 production by affecting the STAT-1 and STAT-3 balance. Inflammation (2014) 37(6):2125-38. doi:10.1007/s10753-014-9947-5
44. Hasan A, Al-Ghimlas F, Warsame S, Al-Hubail A, Ahmad R, Bennakhi A, et al. IL-33 is negatively associated with the BMI and confers a protective lipid/metabolic profile in non-diabetic but not diabetic subjects. BMC Immunol (2014) 15(1):19. doi:10.1186/1471-2172-15-19
45. Ragusa R, Cabiati M, Guzzardi MA, D'Amico A, Giannessi D, Del Ry S, et al. Effects of obesity on IL-33/ST2 system in heart, adipose tissue and liver: study in the experimental model of Zucker rats. Exp Mol Pathol (2017) 102(2):354-9. doi:10.1016/j.yexmp.2017.03.002
46. Jung C, Gerdes N, Fritzenwanger M, Figulla HR. Circulating levels of interleukin-1 family cytokines in overweight adolescents. Mediators Inflamm (2010) 2010:6. doi:10.1155/2010/958403
47. Meier CA, Bobbioni E, Gabay C, Assimacopoulos-Jeannet F, Golay A, Dayer J-M. IL-1 receptor antagonist serum levels are increased in human obesity: a possible link to the resistance to leptin? J Clin Endocrinol Metab (2002) 87(3):1184-8. doi:10.1210/jcem.87.3.8351
48. Wolf AM, Wolf D, Rumpold H, Enrich B, Tilg H. Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem Biophys Res Commun (2004) 323(2):630-5. doi:10.1016/j.bbrc.2004.08.145
49. Bartz S, Mody A, Hornik C, Bain J, Muehlbauer M, Kiyimba T, et al. Severe acute malnutrition in childhood: hormonal and metabolic status at presentation, response to treatment, and predictors of mortality. J Clin Endocrinol Metab (2014) 99(6):2128-37. doi:10.1210/jc.2013-4018
50. Hambor JE, Fleck L, Stevenson JR. Impairment of macrophage migration inhibitory factor synthesis and macrophage migration in protein-malnourished mice. Cell Immunol (1983) 81(2):306-12. doi:10.1016/0008-8749(83)90238-1
51. Surmi BK, Hasty AH. Macrophage infiltration into adipose tissue: initiation, propagation and remodeling. Future Lipidol (2008) 3(5):545-56. doi:10.2217/17460875.3.5.545
52. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest (2003) 112(12):1796-808. doi:10.1172/JCI200319246
53. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest (2006) 116(6):1494-505. doi:10.1172/JCI26498
54. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med (2009) 15(8):914-20. doi:10.1038/nm.1964
55. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest (2007) 117(1):175-84. doi:10.1172/JCI29881
56. Huh JY, Park YJ, Ham M, Kim JB. Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. Mol Cells (2014) 37(5):365-71. doi:10.14348/molcells.2014.0074
57. Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science (2011) 332(6026):243-7. doi:10.1126/science.1201475
58. Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, et al. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature (2012) 486(7404):549-53. doi:10.1038/nature11132
59. Lund FE. Cytokine-producing B lymphocytes-key regulators of immunity. Curr Opin Immunol (2008) 20(3):332-8. doi:10.1016/j.coi.2008.03.003
60. Lynch L, O'Shea D, Winter DC, Geoghegan J, Doherty DG, O'Farrelly C. Invariant NKT cells and CD1d(+) cells amass in human omentum and are depleted in patients with cancer and obesity. Eur J Immunol (2009) 39(7):1893-901. doi:10.1002/eji.200939349
61. Huh JY, Kim JI, Park YJ, Hwang IJ, Lee YS, Sohn JH, et al. A novel function of adipocytes in lipid antigen presentation to iNKT cells. Mol Cell Biol (2013) 33(2):328-39. doi:10.1128/MCB.00552-12
62. Lynch L, Nowak M, Varghese B, Clark J, Hogan AE, Toxavidis V, et al. Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity (2012) 37(3):574-87. doi:10.1016/j.immuni.2012.06.016
63. Gerriets VA, MacIver NJ. Role of T cells in malnutrition and obesity. Front Immunol (2014) 5:379. doi:10.3389/fimmu.2014.00379
64. Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med (2009) 15(8):921-9. doi:10.1038/nm.2001
65. Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med (2009) 15(8):930-9. doi:10.1038/nm.2002
66. Kolodin D, van Panhuys N, Li C, Magnuson AM, Cipolletta D, Miller CM, et al. Antigen-and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab (2015) 21(4):543-57. doi:10.1016/j.cmet.2015.03.005
67. Panduro M, Benoist C, Mathis D. Tissue Tregs. Annu Rev Immunol (2016) 34:609-33. doi:10.1146/annurev-immunol-032712-095948
68. Cipolletta D, Cohen P, Spiegelman BM, Benoist C, Mathis D. Appearance and disappearance of the mRNA signature characteristic of Treg cells in visceral adipose tissue: age, diet, and PPARgamma effects. Proc Natl Acad Sci U S A (2015) 112(2):482-7. doi:10.1073/pnas.1423486112
69. Bapat SP, Myoung Suh J, Fang S, Liu S, Zhang Y, Cheng A, et al. Depletion of fat-resident Treg cells prevents age-associated insulin resistance. Nature (2015) 528(7580):137-41. doi:10.1038/nature16151
70. Howard JK, Lord GM, Matarese G, Vendetti S, Ghatei MA, Ritter MA, et al. Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J Clin Invest (1999) 104(8):1051-9. doi:10.1172/JCI6762
71. Procaccini C, De Rosa V, Galgani M, Carbone F, Cassano S, Greco D, et al. Leptin-induced mTOR activation defines a specific molecular and transcriptional signature controlling CD4+ effector T cell responses. J Immunol (2012) 189(6):2941-53. doi:10.4049/jimmunol.1200935
72. Pena-Cruz V, Reiss CS, McIntosh K. Sendai virus infection of mice with protein malnutrition. J Virol (1989) 63(8):3541-4
73. Taylor AK, Cao W, Vora KP, De La Cruz J, Shieh WJ, Zaki SR, et al. Protein energy malnutrition decreases immunity and increases susceptibility to influenza infection in mice. J Infect Dis (2013) 207(3):501-10. doi:10.1093/infdis/jis527
74. Najera O, Gonzalez C, Toledo G, Lopez L, Ortiz R. Flow cytometry study of lymphocyte subsets in malnourished and well-nourished children with bacterial infections. Clin Diagn Lab Immunol (2004) 11(3):577-80. doi:10.1128/CDLI.11.3.577-580.2004
75. Savino W, Dardenne M, Velloso LA, Dayse Silva-Barbosa S. The thymus is a common target in malnutrition and infection. Br J Nutr (2007) 98(Suppl 1):S11-6. doi:10.1017/S0007114507832880
76. Saha S, Shalova IN, Biswas SK. Metabolic regulation of macrophage phenotype and function. Immunol Rev (2017) 280(1):102-11. doi:10.1111/imr.12603
77. Boothby M, Rickert RC. Metabolic regulation of the immune humoral response. Immunity (2017) 46(5):743-55. doi:10.1016/j.immuni.2017.04.009
78. MacIver NJ, Michalek RD, Rathmell JC. Metabolic regulation of T lymphocytes. Annu Rev Immunol (2013) 31:259-83. doi:10.1146/annurev-immunol-032712-095956
79. Yusuf I, Fruman DA. Regulation of quiescence in lymphocytes. Trends Immunol (2003) 24(7):380-6. doi:10.1016/S1471-4906(03)00141-8
80. Rathmell JC, Vander Heiden MG, Harris MH, Frauwirth KA, Thompson CB. In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. Mol Cell (2000) 6(3):683-92. doi:10.1016/S1097-2765(00)00066-6
81. Jameson SC. Maintaining the norm: T-cell homeostasis. Nat Rev Immunol (2002) 2(8):547-56. doi:10.1038/nri853
82. Warburg O. On the origin of cancer cells. Science (1956) 123(3191):309-14. doi:10.1126/science.123.3191.309
83. Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci (2016) 41(3):211-8. doi:10.1016/j.tibs.2015.12.001
84. Bental M, Deutsch C. Metabolic changes in activated T cells: an NMR study of human peripheral blood lymphocytes. Magn Reson Med (1993) 29(3):317-26. doi:10.1002/mrm.1910290307
85. Greiner EF, Guppy M, Brand K. Glucose is essential for proliferation and the glycolytic enzyme-induction that provokes a transition to glycolytic energy-production. J Biol Chem (1994) 269(50):31484-90
86. Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, et al. The CD28 signaling pathway regulates glucose metabolism. Immunity (2002) 16(6):769-77. doi:10.1016/S1074-7613(02)00323-0
87. Keating R, McGargill MA. mTOR regulation of lymphoid cells in immunity to pathogens. Front Immunol (2016) 7:180. doi:10.3389/fimmu.2016.00180
88. Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol (2012) 12(5):325-38. doi:10.1038/nri3198
89. Powell JD, Delgoffe GM. The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity (2010) 33(3):301-11. doi:10.1016/j.immuni.2010.09.002
90. Kopf H, de la Rosa GM, Howard OM, Chen X. Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int Immunopharmacol (2007) 7(13):1819-24. doi:10.1016/j.intimp.2007.08.027
91. Zheng Y, Collins SL, Lutz MA, Allen AN, Kole TP, Zarek PE, et al. A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J Immunol (2007) 178(4):2163-70. doi:10.4049/jimmunol.178.4.2163
92. MacIver NJ, Blagih J, Saucillo DC, Tonelli L, Griss T, Rathmell JC, et al. The liver kinase B1 is a central regulator of T cell development, activation, and metabolism. J Immunol (2011) 187(8):4187-98. doi:10.4049/jimmunol.1100367
93. Dang CV, Le A, Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res (2009) 15(21):6479-83. doi:10.1158/1078-0432.CCR-09-0889
94. Widnell CC. Control of glucose transport by GLUT1: regulated secretion in an unexpected environment. Biosci Rep (1995) 15(6):427-43. doi:10.1007/BF01204347
95. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity (2011) 35(6):871-82. doi:10.1016/j.immuni.2011.09.021
96. Lindsten T, June CH, Thompson CB. Multiple mechanisms regulate c-Myc gene expression during normal T cell activation. EMBO J (1988) 7(9):2787-94
97. Kelly K, Cochran BH, Stiles CD, Leder P. Cell-specific regulation of the c-Myc gene by lymphocyte mitogens and platelet-derived growth factor. Cell (1983) 35(3 Pt 2):603-10. doi:10.1016/0092-8674(83)90092-2
98. Park BV, Pan F. Metabolic regulation of T cell differentiation and function. Mol Immunol (2015) 68(2 Pt C):497-506. doi:10.1016/j.molimm.2015.07.027
99. Palmer CS, Ostrowski M, Balderson B, Christian N, Crowe SM. Glucose metabolism regulates T cell activation, differentiation, and functions. Front Immunol (2015) 6:1. doi:10.3389/fimmu.2015.00001
100. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol (2011) 186(6):3299-303. doi:10.4049/jimmunol.1003613
101. Michalek RD, Rathmell JC. The metabolic life and times of a T-cell. Immunol Rev (2010) 236(1):190-202. doi:10.1111/j.1600-065X.2010.00911.x
102. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature (2009) 460(7251):103-7. doi:10.1038/nature08097
103. Kishore M, Cheung KCP, Fu H, Bonacina F, Wang G, Coe D, et al. Regulatory T cell migration is dependent on glucokinase-mediated glycolysis. Immunity (2017) 47(5):875-89.e10. doi:10.1016/j.immuni.2017.10.017
104. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity (2009) 30(6):832-44. doi:10.1016/j.immuni.2009.04.014
105. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol (2011) 12(4):295-303. doi:10.1038/ni.2005
106. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med (1995) 1(11):1155-61. doi:10.1038/nm1195-1155
107. De Rosa V, Procaccini C, La Cava A, ChieffiP, Nicoletti GF, Fontana S, et al. Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis. J Clin Invest (2006) 116(2):447-55. doi:10.1172/JCI26523
108. Wang S, Baidoo SE, Liu Y, Zhu C, Tian J, Ma J, et al. T cell-derived leptin contributes to increased frequency of T helper type 17 cells in female patients with Hashimoto's thyroiditis. Clin Exp Immunol (2013) 171(1):63-8. doi:10.1111/j.1365-2249.2012.04670.x
109. Deng J, Liu Y, Yang M, Wang S, Zhang M, Wang X, et al. Leptin exacerbates collagen-induced arthritis via enhancement of Th17 cell response. Arthritis Rheum (2012) 64(11):3564-73. doi:10.1002/art.34637
110. Yu Y, Liu Y, Shi FD, Zou H, Matarese G, La Cava A. Cutting edge: leptin-induced RORgammat expression in CD4+ T cells promotes Th17 responses in systemic lupus erythematosus. J Immunol (2013) 190(7):3054-8. doi:10.4049/jimmunol.1203275
111. Shepherd PR, Kahn BB. Glucose transporters and insulin action-implications for insulin resistance and diabetes mellitus. N Engl J Med (1999) 341(4):248-57. doi:10.1056/NEJM199907223410406
112. Mandarino LJ, Printz RL, Cusi KA, Kinchington P, O'Doherty RM, Osawa H, et al. Regulation of hexokinase II and glycogen synthase mRNA, protein, and activity in human muscle. Am J Physiol (1995) 269(4 Pt 1):E701-8
113. Dimitriadis G, Parry-Billings M, Bevan S, Leighton B, Krause U, Piva T, et al. The effects of insulin on transport and metabolism of glucose in skeletal muscle from hyperthyroid and hypothyroid rats. Eur J Clin Invest (1997) 27(6):475-83. doi:10.1046/j.1365-2362.1997.1380688.x
114. Dimitriadis G, Parry-Billings M, Bevan S, Dunger D, Piva T, Krause U, et al. Effects of insulin-like growth factor I on the rates of glucose transport and utilization in rat skeletal muscle in vitro. Biochem J (1992) 285(Pt 1):269-74. doi:10.1042/bj2850269
115. Dimitriadis G, Mitrou P, Lambadiari V, Maratou E, Raptis SA. Insulin effects in muscle and adipose tissue. Diabetes Res Clin Pract (2011) 93(Suppl 1):S52-9. doi:10.1016/S0168-8227(11)70014-6
116. Dimitriadis GD, Leighton B, Vlachonikolis IG, Parry-Billings M, Challiss RA, West D, et al. Effects of hyperthyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat. Biochem J (1988) 253(1):87-92. doi:10.1042/bj2530087
117. Helderman JH, Reynolds TC, Strom TB. The insulin receptor as a universal marker of activated lymphocytes. Eur J Immunol (1978) 8(8):589-95. doi:10.1002/eji.1830080810
118. Fischer HJ, Sie C, Schumann E, Witte AK, Dressel R, van den Brandt J, et al. The insulin receptor plays a critical role in T cell function and adaptive immunity. J Immunol (2017) 198(5):1910-20. doi:10.4049/jimmunol.1601011
119. Matarese G, Carrieri PB, La Cava A, Perna F, Sanna V, De Rosa V, et al. Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25+ regulatory T cells. Proc Natl Acad Sci U S A (2005) 102(14):5150-5. doi:10.1073/pnas.0408995102
120. Kraszula L, Jasinska A, Eusebio M, Kuna P, Glabinski A, Pietruczuk M. Evaluation of the relationship between leptin, resistin, adiponectin and natural regulatory T cells in relapsing-remitting multiple sclerosis. Neurol Neurochir Pol (2012) 46(1):22-8. doi:10.5114/ninp.2012.27211
121. Carbone F, De Rosa V, Carrieri PB, Montella S, Bruzzese D, Porcellini A, et al. Regulatory T cell proliferative potential is impaired in human autoimmune disease. Nat Med (2014) 20(1):69-74. doi:10.1038/nm.3411
122. Hedstrom AK, Lima Bomfim I, Barcellos L, Gianfrancesco M, Schaefer C, Kockum I, et al. Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis. Neurology (2014) 82(10):865-72. doi:10.1212/WNL.0000000000000203
123. Kavak KS, Teter BE, Hagemeier J, Zakalik K, Weinstock-Guttman B; New York State Multiple Sclerosis Consortium. Higher weight in adolescence and young adulthood is associated with an earlier age at multiple sclerosis onset. Mult Scler (2015) 21(7):858-65. doi:10.1177/1352458514555787
124. Gianfrancesco MA, Acuna B, Shen L, Briggs FB, Quach H, Bellesis KH, et al. Obesity during childhood and adolescence increases susceptibility to multiple sclerosis after accounting for established genetic and environmental risk factors. Obes Res Clin Pract (2014) 8(5):e435-47. doi:10.1016/j.orcp.2014.01.002
125. Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology (2013) 80(6):548-52. doi:10.1212/WNL.0b013e31828154f3
126. Emamgholipour S, Eshaghi SM, Hossein-nezhad A, Mirzaei K, Maghbooli Z, Sahraian MA. Adipocytokine profile, cytokine levels and foxp3 expression in multiple sclerosis: a possible link to susceptibility and clinical course of disease. PLoS One (2013) 8(10):e76555. doi:10.1371/journal.pone.0076555
127. Frisullo G, Mirabella M, Angelucci F, Caggiula M, Morosetti R, Sancricca C, et al. The effect of disease activity on leptin, leptin receptor and suppressor of cytokine signalling-3 expression in relapsing-remitting multiple sclerosis. J Neuroimmunol (2007) 192(1-2):174-83. doi:10.1016/j.jneuroim.2007.08.008
128. Matarese G, Di Giacomo A, Sanna V, Lord GM, Howard JK, Di Tuoro A, et al. Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J Immunol (2001) 166(10):5909-16. doi:10.4049/jimmunol.166.10.5909
129. Sanna V, Di Giacomo A, La Cava A, Lechler RI, Fontana S, Zappacosta S, et al. Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses. J Clin Invest (2003) 111(2):241-50. doi:10.1172/JCI200316721
130. Matarese G, Sanna V, Di Giacomo A, Lord GM, Howard JK, Bloom SR, et al. Leptin potentiates experimental autoimmune encephalomyelitis in SJL female mice and confers susceptibility to males. Eur J Immunol (2001) 31(5):1324-32. doi:10.1002/1521-4141(200105)31:5<1324::AID-IMMU1324>3.0.CO;2-Y
131. Galgani M, Procaccini C, De Rosa V, Carbone F, ChieffiP, La Cava A, et al. Leptin modulates the survival of autoreactive CD4+ T cells through the nutrient/energy-sensing mammalian target of rapamycin signaling pathway. J Immunol (2010) 185(12):7474-9. doi:10.4049/jimmunol.1001674
132. Piccio L, Stark JL, Cross AH. Chronic calorie restriction attenuates experimental autoimmune encephalomyelitis. J Leukoc Biol (2008) 84(4):940-8. doi:10.1189/jlb.0208133
133. Kafami L, Raza M, Razavi A, Mirshafiey A, Movahedian M, Khorramizadeh MR. Intermittent feeding attenuates clinical course of experimental autoimmune encephalomyelitis in C57BL/6 mice. Avicenna J Med Biotechnol (2010) 2(1):47-52
134. Lourenco EV, Liu A, Matarese G, La Cava A. Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation. Proc Natl Acad Sci U S A (2016) 113(38):10637-42. doi:10.1073/pnas.1607101113
135. Wang X, Qiao Y, Yang L, Song S, Han Y, Tian Y, et al. Leptin levels in patients with systemic lupus erythematosus inversely correlate with regulatory T cell frequency. Lupus (2017) 26(13):1401-6. doi:10.1177/0961203317703497
136. Moraes-Vieira PM, Bassi EJ, Larocca RA, Castoldi A, Burghos M, Lepique AP, et al. Leptin deficiency modulates allograft survival by favoring a Th2 and a regulatory immune profile. [corrected]. Am J Transplant (2013) 13(1):36-44. doi:10.1111/j.1600-6143.2012.04283.x
137. Prentice AM. The thymus: a barometer of malnutrition. Br J Nutr (1999) 81(5):345-7
138. Rytter MJ, Kolte L, Briend A, Friis H, Christensen VB. The immune system in children with malnutrition-a systematic review. PLoS One (2014) 9(8):e105017. doi:10.1371/journal.pone.0105017
139. Ortiz R, Cortes L, Cortes E, Medina H. Malnutrition alters the rates of apoptosis in splenocytes and thymocyte subpopulations of rats. Clin Exp Immunol (2009) 155(1):96-106. doi:10.1111/j.1365-2249.2008.03796.x
140. Cegielski JP, McMurray DN. The relationship between malnutrition and tuberculosis: evidence from studies in humans and experimental animals. Int J Tuberc Lung Dis (2004) 8(3):286-98
141. Verhagen LM, Gomez-Castellano K, Snelders E, Rivera-Olivero I, Pocaterra L, Melchers WJ, et al. Respiratory infections in Enepa Amerindians are related to malnutrition and Streptococcus pneumoniae carriage. J Infect (2013) 67(4):273-81. doi:10.1016/j.jinf.2013.06.010
142. Ritz BW, Aktan I, Nogusa S, Gardner EM. Energy restriction impairs natural killer cell function and increases the severity of influenza infection in young adult male C57BL/6 mice. J Nutr (2008) 138(11):2269-75. doi:10.3945/jn.108.093633
143. Petri WA Jr, Mondal D, Peterson KM, Duggal P, Haque R. Association of malnutrition with amebiasis. Nutr Rev (2009) 67(Suppl 2):S207-15. doi:10.1111/j.1753-4887.2009.00242.x
144. Huttunen R, Syrjanen J. Obesity and the risk and outcome of infection. Int J Obes (Lond) (2013) 37(3):333-40. doi:10.1038/ijo.2012.62
145. Van Kerkhove MD, Vandemaele KA, Shinde V, Jaramillo-Gutierrez G, Koukounari A, Donnelly CA, et al. Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: a global pooled analysis. PLoS Med (2011) 8(7):e1001053. doi:10.1371/journal.pmed.1001053
146. Louie JK, Acosta M, Samuel MC, Schechter R, Vugia DJ, Harriman K, et al. A novel risk factor for a novel virus: obesity and 2009 pandemic influenza A (H1N1). Clin Infect Dis (2011) 52(3):301-12. doi:10.1093/cid/ciq152
147. Diaz E, Rodriguez A, Martin-Loeches I, Lorente L, Del Mar Martin M, Pozo JC, et al. Impact of obesity in patients infected with 2009 influenza A(H1N1). Chest (2011) 139(2):382-6. doi:10.1378/chest.10-1160
148. Riquelme R, Jimenez P, Videla AJ, Lopez H, Chalmers J, Singanayagam A, et al. Predicting mortality in hospitalized patients with 2009 H1N1 influenza pneumonia. Int J Tuberc Lung Dis (2011) 15(4):542-6. doi:10.5588/ijtld.10.0539
149. Choban PS, Flancbaum L. The impact of obesity on surgical outcomes: a review. J Am Coll Surg (1997) 185(6):593-603. doi:10.1016/S1072-7515(97)00109-9
150. Arslan E, Atilgan H, Yavasoglu I. The prevalence of Helicobacter pylori in obese subjects. Eur J Intern Med (2009) 20(7):695-7. doi:10.1016/j.ejim.2009.07.013
151. Uberos J, Molina-Carballo A, Fernandez-Puentes V, Rodriguez-Belmonte R, Munoz-Hoyos A. Overweight and obesity as risk factors for the asymptomatic carrier state of Neisseria meningitidis among a paediatric population. Eur J Clin Microbiol Infect Dis (2010) 29(3):333-4. doi:10.1007/s10096-009-0849-7
152. Hemalatha Rajkumar PB. The impact of obesity on immune response to infection and vaccine: an insight into plausible mechanisms. Endocrinol Metab Synd (2013) 2(2):113. doi:10.4172/2161-1017.1000113
153. Karlsson EA, Sheridan PA, Beck MA. Diet-induced obesity impairs the T cell memory response to influenza virus infection. J Immunol (2010) 184(6):3127-33. doi:10.4049/jimmunol.0903220
154. Freemerman AJ, Johnson AR, Sacks GN, Milner JJ, Kirk EL, Troester MA, et al. Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem (2014) 289(11):7884-96. doi:10.1074/jbc. M113.522037
155. Blair D, Dufort FJ, Chiles TC. Protein kinase Cbeta is critical for the metabolic switch to glycolysis following B-cell antigen receptor engagement. Biochem J (2012) 448(1):165-9. doi:10.1042/BJ20121225
156. Cao Y, Rathmell JC, Macintyre AN. Metabolic reprogramming towards aerobic glycolysis correlates with greater proliferative ability and resistance to metabolic inhibition in CD8 versus CD4 T cells. PLoS One (2014) 9(8):e104104. doi:10.1371/journal.pone.0104104
157. Zhao Q, Chu Z, Zhu L, Yang T, Wang P, Liu F, et al. 2-Deoxy-d-glucose treatment decreases anti-inflammatory M2 macrophage polarization in mice with tumor and allergic airway inflammation. Front Immunol (2017) 8:637. doi:10.3389/fimmu.2017.00637
158. Raez LE, Papadopoulos K, Ricart AD, Chiorean EG, Dipaola RS, Stein MN, et al. A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol (2013) 71(2):523-30. doi:10.1007/s00280-012-2045-1
159. Stein M, Lin H, Jeyamohan C, Dvorzhinski D, Gounder M, Bray K, et al. Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies. Prostate (2010) 70(13):1388-94. doi:10.1002/pros.21172
160. Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC, Deoliveira D, et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab (2014) 20(1):61-72. doi:10.1016/j.cmet.2014.05.004
161. Caro-Maldonado A, Wang R, Nichols AG, Kuraoka M, Milasta S, Sun LD, et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J Immunol (2014) 192(8):3626-36. doi:10.4049/jimmunol.1302062
162. Dror E, Dalmas E, Meier DT, Wueest S, Thevenet J, Thienel C, et al. Postprandial macrophage-derived IL-1beta stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nat Immunol (2017) 18(3):283-92. doi:10.1038/ni.3659
163. Ung PM, Song W, Cheng L, Zhao X, Hu H, Chen L, et al. Inhibitor discovery for the human GLUT1 from homology modeling and virtual screening. ACS Chem Biol (2016) 11(7):1908-16. doi:10.1021/acschembio.6b00304
164. Siebeneicher H, Cleve A, Rehwinkel H, Neuhaus R, Heisler I, Muller T, et al. Identification and optimization of the first highly selective GLUT1 inhibitor BAY-876. ChemMedChem (2016) 11(20):2261-71. doi:10.1002/cmdc.201600276
165. Liu Y, Cao Y, Zhang W, Bergmeier S, Qian Y, Akbar H, et al. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther (2012) 11(8):1672-82. doi:10.1158/1535-7163.MCT-12-0131
166. De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med (1991) 325(10):703-9. doi:10.1056/NEJM199109053251006
167. Brockmann K, Wang D, Korenke CG, von Moers A, Ho YY, Pascual JM, et al. Autosomal dominant glut-1 deficiency syndrome and familial epilepsy. Ann Neurol (2001) 50(4):476-85. doi:10.1002/ana.1222
168. Van Schaftingen E, Jett MF, Hue L, Hers HG. Control of liver 6-phosphofructokinase by fructose 2, 6-bisphosphate and other effectors. Proc Natl Acad Sci U S A (1981) 78(6):3483-6. doi:10.1073/pnas.78.6.3483
169. Yalcin A, Telang S, Clem B, Chesney J. Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatases in cancer. Exp Mol Pathol (2009) 86(3):174-9. doi:10.1016/j.yexmp.2009.01.003
170. Rodriguez-Prados JC, Traves PG, Cuenca J, Rico D, Aragones J, Martin-Sanz P, et al. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol (2010) 185(1):605-14. doi:10.4049/jimmunol.0901698
171. Telang S, Clem BF, Klarer AC, Clem AL, Trent JO, Bucala R, et al. Small molecule inhibition of 6-phosphofructo-2-kinase suppresses t cell activation. J Transl Med (2012) 10:95. doi:10.1186/1479-5876-10-95
172. Clem BF, O'Neal J, Tapolsky G, Clem AL, Imbert-Fernandez Y, Kerr DA II, et al. Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol Cancer Ther (2013) 12(8):1461-70. doi:10.1158/1535-7163.MCT-13-0097
173. Tom A, Nair KS. Assessment of branched-chain amino acid status and potential for biomarkers. J Nutr (2006) 136(1 Suppl):324S-30S. doi:10.1093/jn/136.1.324S
174. Sweatt AJ, Wood M, Suryawan A, Wallin R, Willingham MC, Hutson SM. Branched-chain amino acid catabolism: unique segregation of pathway enzymes in organ systems and peripheral nerves. Am J Physiol Endocrinol Metab (2004) 286(1):E64-76. doi:10.1152/ajpendo.00276.2003
175. Papathanassiu AE, Ko JH, Imprialou M, Bagnati M, Srivastava PK, Vu HA, et al. BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases. Nat Commun (2017) 8:16040. doi:10.1038/ncomms16040
176. Benke PJ, Drisko J, Ahmad P. Increased oxidative metabolism in phytohemagglutinin-stimulated lymphocytes from patients with systemic lupus erythematosus is associated with serum SSA antibody. Biochem Med Metab Biol (1991) 45(1):28-40. doi:10.1016/0885-4505(91)90005-6
177. Kuhnke A, Burmester GR, Krauss S, Buttgereit F. Bioenergetics of immune cells to assess rheumatic disease activity and efficacy of glucocorticoid treatment. Ann Rheum Dis (2003) 62(2):133-9. doi:10.1136/ard.62.2.133
178. Wahl DR, Petersen B, Warner R, Richardson BC, Glick GD, Opipari AW. Characterization of the metabolic phenotype of chronically activated lymphocytes. Lupus (2010) 19(13):1492-501. doi:10.1177/0961203310373109
179. Johnson KM, Chen X, Boitano A, Swenson L, Opipari AW Jr, Glick GD. Identification and validation of the mitochondrial F1F0-ATPase as the molecular target of the immunomodulatory benzodiazepine Bz-423. Chem Biol (2005) 12(4):485-96. doi:10.1016/j.chembiol.2005.02.012
180. Bednarski JJ, Warner RE, Rao T, Leonetti F, Yung R, Richardson BC, et al. Attenuation of autoimmune disease in Fas-deficient mice by treatment with a cytotoxic benzodiazepine. Arthritis Rheum (2003) 48(3):757-66. doi:10.1002/art.10968
181. Blatt NB, Bednarski JJ, Warner RE, Leonetti F, Johnson KM, Boitano A, et al. Benzodiazepine-induced superoxide signals B cell apoptosis: mechanistic insight and potential therapeutic utility. J Clin Invest (2002) 110(8):1123-32. doi:10.1172/JCI0216029
182. Gatza E, Wahl DR, Opipari AW, Sundberg TB, Reddy P, Liu C, et al. Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease. Sci Transl Med (2011) 3(67):67ra8. doi:10.1126/scitranslmed.3001975