Advertisement

TNF Blockade: An Inflammatory Issue

  • B. B. Aggarwal
  • S. Shishodia
  • Y. Takada
  • D. Jackson-Bernitsas
  • K. S. Ahn
  • G. Sethi
  • H. Ichikawa
Part of the Ernst Schering Research Foundation Workshop book series (SCHERING FOUND, volume 56)

Abstract

Tumor necrosis factor (TNF), initially discovered as a result of its antitumor activity, has now been shown to mediate tumor initiation, promotion, and metastasis. In addition, dysregulation of TNF has been implicated in a wide variety of inflammatory diseases including rheumatoid arthritis, Crohn’s disease, multiple sclerosis, psoriasis, scleroderma, atopic dermatitis, systemic lupus erythematosus, type II diabetes, atherosclerosis, myocardial infarction, osteoporosis, and autoimmune deficiency disease. TNF, however, is a critical component of effective immune surveillance and is required for proper proliferation and function of NK cells, T cells, B cells, macrophages, and dendritic cells. TNF activity can be blocked, either by using antibodies (Remicade and Humira) or soluble TNF receptor (Enbrel), for the symptoms of arthritis and Crohn’s disease to be alleviated, but at the same time, such treatment increases the risk of infections, certain type of cancers, and cardiotoxicity. Thus blockers of TNF that are safe and yet efficacious are urgently needed. Some evidence suggests that while the transmembrane form of TNF has beneficial effects, soluble TNF mediates toxicity. In most cells, TNF mediates its effects through activation of caspases, NF- k B, AP-1, c-jun N-terminal kinase, p38 MAPK, and p44/p42 MAPK. Agents that can differentially regulate TNF expression or TNF signaling can be pharmacologically safe and effective therapeutics. Our laboratory has identified numerous such agents from natural sources. These are discussed further in detail.

Keywords

Tumor Necrosis Factor Receptor Ursolic Acid Standardize Incidence Ratio Betulinic Acid Tumor Necrosis Factor Production 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745–756PubMedCrossRefGoogle Scholar
  2. Aggarwal BB, Moffat B, Harkins RN (1984) Human lymphotoxin. Production by a lymphoblastoid cell line, purification, and initial characterization. Biol J Chem 259:686–691Google Scholar
  3. Aggarwal BB, Schwarz L, Hogan ME, Rando RF (1996) Triple helix-forming oligodeoxyribonucleotides targeted to the human tumor necrosis factor (TNF) gene inhibit TNF production and block the TNF-dependent growth of human glioblastoma tumor cells. Cancer Res 56:5156–5164PubMedGoogle Scholar
  4. Aggarwal BB, Shishodia S, Ashikawa K, Bharti AC (2002) The role of TNF and its family members in inflammation and cancer: lessons from gene deletion. Curr Drug Targets Inflamm Allergy 1:327–341PubMedCrossRefGoogle Scholar
  5. Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y (2004) Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res 24:2783–2840PubMedGoogle Scholar
  6. Ameloot P, Declercq W, Fiers W, Vandenabeele P, Brouckaert P (2001) Heterotrimers formed by tumor necrosis factors of different species or muteins. Biol J Chem 276:27098–27103CrossRefGoogle Scholar
  7. Arnott CH, Scott KA, Moore RJ, Robinson SC, Thompson RG, Balkwill FR (2004) Expression of both TNF-alpha receptor subtypes is essential for optimal skin tumour development. Oncogene 23:1902–1910PubMedCrossRefGoogle Scholar
  8. Baraliakos X, Braun J (2004) Current concepts in the therapy of the spondyloarthritides. BioDrugs 18:307–314PubMedCrossRefGoogle Scholar
  9. Bennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, Bhagwat SS, Manning AM, Anderson DW (2001) SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A 98:13681–13686PubMedCrossRefGoogle Scholar
  10. Berman B, Wietzerbin J (1992) Tumor necrosis factor-alpha (TNF-alpha), interferon-alpha (IFN-alpha) and interferon-gamma (IFN-gamma) receptors on human normal and scleroderma dermal fibroblasts in vitro. Dermatol J Sci 3:82–90CrossRefGoogle Scholar
  11. Beutler B, Milsark IW, Cerami AC (1985) Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 229:869–871PubMedCrossRefGoogle Scholar
  12. Borset M, Waage A, Brekke OL, Helseth E (1994) TNF and IL-6 are potent growth factors for OH-2, a novel human myeloma cell line. Eur Haematol J 53:31–37CrossRefGoogle Scholar
  13. Burke JR, Pattoli MA, Gregor KR, Brassil PJ, MacMaster JF, McIntyre KW, Yang X, Iotzova VS, Clarke W, Strnad J, Qiu Y, Zusi FC (2003) BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappaB-dependent transcription in mice. J Biol Chem 278:1450–1456PubMedCrossRefGoogle Scholar
  14. Campbell J, Ciesielski CJ, Hunt AE, Horwood NJ, Beech JT, Hayes LA, Denys A, Feldmann M, Brennan FM, Foxwell BM (2004) A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappaB with implications for therapy in rheumatoid arthritis. Immunol J 173:6928–6937Google Scholar
  15. Carlsen H, Alexander G, Austenaa LM, Ebihara K, Blomhoff R (2004) Molecular imaging of the transcription factor NF-kappaB, a primary regulator of stress response. Mutat Res 551:199–211PubMedGoogle Scholar
  16. Chapekar MS, Huggett AC, Thorgeirsson SS (1989) Growth modulatory effects of a liver-derived growth inhibitor, transforming growth factor beta 1, and recombinant tumor necrosis factor alpha, in normal and neoplastic cells. Exp Cell Res 185:247–257PubMedCrossRefGoogle Scholar
  17. Chen G, Goeddel DV (2002) TNF-R1 signaling: a beautiful pathway. Science 296:1634–1635PubMedCrossRefGoogle Scholar
  18. De Alvaro C, Teruel T, Hernandez R, Lorenzo M (2004) Tumor necrosis factor alpha produces insulin resistance inskeletalmuscle by activation of inhibitor kappaB kinase in a p38 MAPK-dependentmanner. Biol J Chem 279:17070–17078CrossRefGoogle Scholar
  19. Devos SA, Van Den Bossche N, De Vos M, Naeyaert JM (2003) Adverse skin reactions to anti-TNF-alpha monoclonal antibody therapy. Dermatology 206:388–390PubMedCrossRefGoogle Scholar
  20. Dorai T, Aggarwal BB (2004) Role of chemopreventive agents in cancer therapy. Cancer Lett 215:129–140PubMedCrossRefGoogle Scholar
  21. Estrov Z, Kurzrock R, Pocsik E, Pathak S, Kantarjian HM, Zipf TF, Harris D, Talpaz M, Aggarwal BB (1993) Lymphotoxin is an autocrine growth factor for Epstein-Barr virus-infected B cell lines. Exp J Med 177:763–774CrossRefGoogle Scholar
  22. Giri DK, Aggarwal BB (1998) Constitutive activation of NF-kappaB causes resistance to apoptosis in human cutaneous T cell lymphoma HuT-78 cells. Autocrine role of tumor necrosis factor and reactive oxygen i ntermediates. Biol J Chem 273:14008–14014CrossRefGoogle Scholar
  23. Goetze S, Xi XP, Kawano Y, Kawano H, Fleck E, Hsueh WA, Law RE (1999) TNF-alpha-induced migration of vascular smooth muscle cells is MAPK dependent. Hypertension 33:183–189PubMedGoogle Scholar
  24. Grell M, Douni E, Wajant H, Lohden M, Clauss M, Maxeiner B, Georgopoulos S, Lesslauer W, Kollias G, Pfizenmaier K et al. (1995) The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 83:793–802PubMedCrossRefGoogle Scholar
  25. Han SS, Keum YS, Seo HJ, Chun KS, Lee SS, Surh YJ (2001) Capsaicin suppresses phorbol ester-induced activation of NF-kappaB/Rel and AP-1 transcription factors in mouse epidermis. Cancer Lett 164:119–126PubMedCrossRefGoogle Scholar
  26. Hanauer SB (2004) Efficacy and safety of tumor necrosis factor antagonists in Crohn’s disease: overviewof randomized clinical studies. Rev Gastroenterol Disord 4[Suppl 3]:S18–S24PubMedGoogle Scholar
  27. Haridas V, Darnay BG, Natarajan K, Heller R, Aggarwal BB (1998) Over-expression of the p80 TNF receptor leads to TNF-dependent apoptosis, nuclear factor-kappa B activation, and c-Jun kinase activation. Immunol J 160:3152–3162Google Scholar
  28. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V, Adams J, Anderson KC (2002) NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277:16639–16647PubMedCrossRefGoogle Scholar
  29. Henry JR, Rupert KC, Dodd JH, Turchi IJ, Wadsworth SA, Cavender DE, Schafer PH, Siekierka JJ (1998) Potent inhibitors of the MAP kinase p38. Bioorg Med Chem Lett 8:3335–3340PubMedCrossRefGoogle Scholar
  30. Hernandez R, Teruel T, de Alvaro C, Lorenzo M (2004) Rosiglitazone ameliorates insulin resistance in brown adipocytes of Wistar rats by impairing TNF-alpha induction of p38 and p42/p44 mitogen-activated protein kinases. Diabetologia 47:1615–1624PubMedCrossRefGoogle Scholar
  31. Hsu SM, Hsu PL (1990) Lack of effect of colony-stimulating factors, interleukins, interferons, and tumor necrosis factor on the growth and differentiation of cultured Reed-Sternberg cells. Comparison with effects of phorbol ester and retinoic acid. AmPathol J 136:181–189Google Scholar
  32. Ishii M, Suzuki Y, Takeshita K, Miyao N, Kudo H, Hiraoka R, Nishio K, Sato N, Naoki K, Aoki T, Yamaguchi K (2004) Inhibition of c-Jun NH2-terminal kinase activity improves ischemia/reperfusion injury in rat lungs. Immunol J 172:2569–2577Google Scholar
  33. Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298:1911–1912PubMedCrossRefGoogle Scholar
  34. Kane D, FitzGerald O (2004) Tumor necrosis factor-alpha in psoriasis a nd psoriatic arthritis: a clinical, genetic, and histopathologic perspective. Curr Rheumatol Rep 6:292–298PubMedGoogle Scholar
  35. Kishore N, Sommers C, Mathialagan S, Guzova J, Yao M, Hauser S, Huynh K, Bonar S, Mielke C, Albee L, Weier R, Graneto M, Hanau C, Perry T, Tripp CS (2003) Aselective IKK-2 inhibitor blocks NF-kappa B-dependent gene expression in interleukin-1 beta-stimulated synovial fibroblasts. J Biol Chem 278:32861–32871PubMedCrossRefGoogle Scholar
  36. Kumar S, Mc PCDonnell, Gum RJ, Hand AT, Lee JC, Young PR (1997) Novel homologues of CSBP/p38 MAP kinase: activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles. Biochem Biophys Res Commun 235:533–538PubMedCrossRefGoogle Scholar
  37. Kumar A, Dhawan S, Hardegen NJ, Aggarwal BB (1998a) Curcumin (diferuloylmethane) inhibition of tumor necrosis factor (TNF)-mediated adhesion of monocytes to endothelial cells by suppression of cell surface expression of adhesion molecules and of nuclear factor-kappaB activation. Biochem Pharmacol 55:775–783PubMedCrossRefGoogle Scholar
  38. Kumar A, Middleton A, Chambers TC, Mehta KD (1998b) Differential roles of extracellular signal-regulated kinase-1/2 and p38(MAPK) in interleukin-1beta-and tumor necrosis factor-alpha-induced low density lipoprotein receptor expression in HepG2 cells. Biol J Chem 273:15742–15748CrossRefGoogle Scholar
  39. Kumar A, Takada Y, Boriek AM, Aggarwal BB (2004) Nuclear factor-kappaB: its role in health and disease. Mol J Med 82:434–448Google Scholar
  40. Kurzrock R, Rosenblum MG, Sherwin SA, Rios A, Talpaz M, Quesada JR, Gutterman JU (1985) Pharmacokinetics, single-dose tolerance, and biological activity of recombinant gamma-interferon in cancer patients. Cancer Res 45:2866–2872PubMedGoogle Scholar
  41. Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, Mc-Nulty D, Blumenthal MJ, Heys JR, Landvatter SW et al (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372:739–746PubMedCrossRefGoogle Scholar
  42. Lee JH, Slifman NR, Gershon SK, Edwards ET, Schwieterman WD, Siegel JN, Wise RP, Brown SL, Udall JN Jr, Braun MM (2002) Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum 46:2565–2570PubMedCrossRefGoogle Scholar
  43. Lukita-Atmadja W, Ito Y, Baker GL, McCuskey RS (2002) Effect of curcuminoids as anti-inflammatory agents on the hepatic microvascular response to endotoxin. Shock 17:399–403PubMedCrossRefGoogle Scholar
  44. Manna SK, Aggarwal BB (2000) Vesnarinone suppresses TNF-induced activation of NF-kappa B, c-Jun kinase, and apoptosis. Immunol J 164:5815–5825Google Scholar
  45. Manna SK, Sah NK, Newman RA, Cisneros A, Aggarwal BB (2000) Oleandrin suppresses activation of nuclear transcription factor-kappaB, activator protein-1, and c-Jun NH2-terminal kinase. Cancer Res 60:3838–3847PubMedGoogle Scholar
  46. Masson C, Simon V, Hoppe E, Insalaco P, Cisse I, Audran M (2004) Tumor necrosis factor receptor-associated periodic syndrome (TRAPS): definition, semiology, prognosis, pathogenesis, treatment, and place relative to other periodic joint diseases. Joint Bone Spine 71:284–290PubMedCrossRefGoogle Scholar
  47. Messadi DV, Doung HS, Zhang Q, Kelly AP, Tuan TL, Reichenber E, Le AD (2004) Activation of NFkappaB signal pathways in keloid fibroblasts. Arch Dermatol Res 296:125–133PubMedCrossRefGoogle Scholar
  48. Mohan N, Edwards ET, Cupps TR, Slifman N, Lee JH, Siegel JN, Braun MM (2004) Leukocytoclastic vasculitis associated with tumor necrosis factoralpha blocking agents. Rheumatol J 31:1955–1958Google Scholar
  49. Mukhopadhyay A, Suttles J, Stout RD, Aggarwal BB (2001) Genetic deletion of the tumor necrosis factor receptor p60 or p80 abrogates ligand-mediated activation of nuclear factor-kappaBand of mitogen-activated protein kinases in macrophages. Biol J Chem 276:31906–31912CrossRefGoogle Scholar
  50. Murakami Y, Shoji M, Hanazawa S, Tanaka S, Fujisawa S (2003) Preventive effect of bis-eugenol, a eugenol ortho dimer, on lipopolysaccharide-stimulated nuclear factor kappa B activation and inflammatory cytokine expression in macrophages. Biochem Pharmacol 66:1061–1066PubMedCrossRefGoogle Scholar
  51. Murakami-Mori K, Mori S, Nakamura S (1999) p38MAP kinase is a negative regulator for ERK1/2-mediated growth of AIDS-associated Kaposi’s sarcoma cells. Biochem Biophys Res Commun 264:676–682PubMedCrossRefGoogle Scholar
  52. Murata T, Shimada M, Sakakibara S, Yoshino T, Masuda T, Shintani T, Sato H, Koriyama Y, Fukushima K, Nunami N, Yamauchi M, Fuchikami K, Komura H, Watanabe A, Ziegelbauer KB, Bacon KB, Lowinger TB (2004) Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 3: orally active anti-inflammatory agents. Bioorg Med ChemLett 14:4019–4022CrossRefGoogle Scholar
  53. Nagata S, Golstein P (1995) The Fas death factor. Science 267:1449–1456PubMedCrossRefGoogle Scholar
  54. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (1999) NF-kappaB activation by tumour necrosis factor requires the Akt serinethreonine kinase. Nature 401:82–85PubMedCrossRefGoogle Scholar
  55. Palanki MS, Erdman PE, Ren M, Suto M, Bennett BL, Manning A, Ransone L, Spooner C, Desai S, Ow A, Totsuka R, Tsao P, Toriumi W (2003) The design and synthesis of novel orally active inhibitors of AP-1 and NFkappaB mediated transcriptional activation. SAR of in vitro and in vivo studies. Bioorg Med Chem Lett 13:4077–4080PubMedCrossRefGoogle Scholar
  56. Pastorino JG, Tafani M, Farber JL (1999) Tumor necrosis factor induces phosphorylation and translocation of BAD through a phosphatidylinositide-3-OH kinase-dependent pathway. Biol J Chem 274:19411–19416CrossRefGoogle Scholar
  57. Reiley W, Zhang M, Sun SC (2004) Negative regulation of JNK signaling pathway by the tumor suppressor CYLD. Biol J Chem 279:55161–55167CrossRefGoogle Scholar
  58. Sandborn WJ, Hanauer S, Loftus EV Jr, Tremaine WJ, Kane S, Cohen R, Hanson K, Johnson T, Schmitt D, Jeche R (2004) An open-label study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn’s disease. Am Gastroente Jrol 99:1984–1989CrossRefGoogle Scholar
  59. Shishodia S, Majumdar S, Banerjee S, Aggarwal BB (2003) Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res 63:4375–4383PubMedGoogle Scholar
  60. Slifman NR, Gershon SK, Lee JH, Edwards ET, Braun MM (2003) Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alpha-neutralizing agents. Arthritis Rheum 48:319–324PubMedCrossRefGoogle Scholar
  61. Steffan RJ, Matelan E, Ashwell MA, Moore WJ, Solvibile WR, Trybulski E, Chadwick CC, Chippari S, Kenney T, Eckert A, Borges-Marcucci L, Keith JC, Xu Z, Mosyak L, Harnish DC (2004) Synthesis and activity of substituted 4-(indazol-3-yl)phenols as pathway-selective estrogen receptor ligands useful in the treatment of rheumatoid arthritis. J Med Chem 47:6435–6438PubMedCrossRefGoogle Scholar
  62. Sugarman BJ, Aggarwal BB, Hass PE, Figari IS, Palladino MA Jr, Shepard HM (1985) Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science 230:943–945PubMedCrossRefGoogle Scholar
  63. Sugarman BJ, Lewis GD, Eessalu TE, Aggarwal BB, Shepard HM (1987) Effects of growth factors on the antiproliferative activity of tumor necrosis factors. Cancer Res 47:780–786PubMedGoogle Scholar
  64. Takada Y, Aggarwal BB (2003a) Betulinic acid suppresses carcinogen-induced NF-kappa B activation through inhibition of I kappa B alpha kinase and p65 phosphorylation: abrogation of cyclooxygenase-2 and matrix metalloprotease-9. Immunol J 171:3278–3286Google Scholar
  65. Takada Y, Aggarwal BB (2003b) Genetic deletion of the tumor necrosis factor receptor p60 or p80 sensitizes macrophages to lipopolysaccharide-induced nuclear factor-kappa B, mitogen-activated protein kinases, and apoptosis. Biol J Chem 278:23390–23397CrossRefGoogle Scholar
  66. Takada Y, Aggarwal BB (2004) Evidence that genetic deletion of the TNF receptor p60 or p80 in macrophages modulates RANKL-induced signaling. Blood 104:4113–4121PubMedCrossRefGoogle Scholar
  67. Tartaglia LA, Pennica D, Goeddel DV (1993) Ligand passing: the 75-kDa tumor necrosis factor (TNF) receptor recruitsTNFfor signaling by the 55-kDaTNF receptor. Biol J Chem 268:18542–18548Google Scholar
  68. Torii A, Miyake M, Morishita M, Ito K, Torii S, Sakamoto T (2004)Vitamin A reduces lung granulomatous inflammation with eosinophilic and neutrophilic infiltration in Sephadex-treated rats. Eur Pharmacol J 497:335–342CrossRefGoogle Scholar
  69. Tran SE, Holmstrom TH, Ahonen M, Kahari VM, Eriksson JE (2001) MAPK/ERK overrides the apoptotic signaling from Fas, TNF, TRAIL receptors. Biol J Chem 276:16484–16490CrossRefGoogle Scholar
  70. Tucker SJ, Rae C, Littlejohn AF, Paul A, MacEwan DJ (2004) Switching leukemia cell phenotype between life and death. Proc Natl Acad Sci U S A 101:12940–12945PubMedCrossRefGoogle Scholar
  71. Vanden Berghe W, Plaisance S, Boone E, De Bosscher K, Schmitz ML, Fiers W, Haegeman G (1998) p38 and extracellular signal-regulated kinase mitogen-activated protein kinasepathways are required for nuclear factor-kappaB p65 transactivation mediated by tumor necrosis factor. Biol J Chem 273:3285–3290CrossRefGoogle Scholar
  72. Wallis RS, Vinhas SA, Johnson JL, Ribeiro FC, Palaci M, Peres RL, Sa RT, Dietze R, Chiunda A, Eisenach K, Ellner JJ (2003) Whole blood bactericidal activity during treatment of pulmonary tuberculosis. Infect J Dis 187:270–278CrossRefGoogle Scholar
  73. Wolfe F, Michaud K (2004) Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum 50:1740–1751PubMedCrossRefGoogle Scholar
  74. Yang L, Dan HC, Sun M, Liu Q, Sun XM, Feldman RI, Hamilton AD, Polokoff M, Nicosia SV, Herlyn M, Sebti SM, Cheng JQ (2004) Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res 64:4394–4399PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2005

Authors and Affiliations

  • B. B. Aggarwal
    • 1
  • S. Shishodia
    • 2
  • Y. Takada
    • 2
  • D. Jackson-Bernitsas
    • 1
  • K. S. Ahn
    • 1
  • G. Sethi
    • 2
  • H. Ichikawa
    • 1
  1. 1.Cytokine Research Laboratory, Department of Experimental TherapeuticsUniversity of Texas, M.D. Anderson Cancer HospitalHosutonUSA
  2. 2.Cytokine Research Laboratory, Department of Experimental TherapeuticsThe University of Texas, M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations