The TNF & TNF receptor superfamillies

Transcription

1 TNF Luca Tordella

2 The TNF & TNF receptor superfamillies R.M.Locksley et al.,the TNF and TNF receptor superfamilies: integrating mammalian biology, Cell, 104:487,2001

3 Late 1800s: Dr William Coley at the NY Memorial Hospital : a long patient search & finding of the Streptococcus pyogenes 1893 : Coley s Toxin! (mix of 2 killed bacteria) Coley WB. The treatment of malignant inoperable tumors with the mixed toxins of erysipelas and bacillus prodigiosus with a brief report of 80 case successfully treated with the toxins from Brussels: M Weissenbruch, : according to the American Medical Ass. the Coley s toxin is the only known systemic therapy for cancer 1936 : Coley s death.radiotherapy, chemotherapy and others immunosoppresive approaches

4 The 1900s : research and characterization of the active component of the Coley s vaccine Murray Shear : the LPS or endotoxin Carswell EA, Old LJ, et al An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A The enodotoxin acts indirectly by causing the host to release a substance, which we named tumor necrosis factor (TNF)

5 Great expectations TNF causes HEMORRHAGIC NECROSIS and complete regression of certain trasplantated tumors in mice by : destroying the tumor s vascolature Enhancing phagocytosis & cytotoxicity neutrophilic granulocytes In vitro effects TNF shares cytotoxic or cytostatic effects on trasformed human cell lines TNF has no effects on normal human cells

6 Cloning of TNF Onset of side effects Production and use of recombinant TNF in cancer treatment 1) Same cytotoxic & cytostatic activity on mouse and human cancer cells 2) HEMORRHAGIC NECROSIS of mouse tumors Lethality caused by But even SIDE EFFECTS Cachessia Septic shock Neo-angiogenesis

7 A little bit of light on TNF biological activities CACHECTIN = TNF! A pivotal role of TNF on CHRONIC INFLAMMATIONS High levels of TNF are associated with develoment of autoimmune diseases

8 Anti-TNF therapies in clinical testing approved by FDA but.. incidence of lymphoma & onset of TUBERCOLOSIS and other infections

9 TNF is a PRO-INFIAMMATORY cytokine important in the immune-response to infections Mice deficient in TNF fail to recruit inflammatory cells on site of infection and fail to form functional granulomas New therapies using molecules that regulate TNF activity

10 New therapeutic strategies in cancer treatment dose : TNF is pro-angiogenic dose : SEPTIC SHOCK Development of a new way of administer TNF REGIONAL PERFUSION

11 Biological activities of TNF It is produced following bacterial infection (Gram-) by fagocyties & T- cells activated Abul K. Abbas, MD, MBBS, Andrew H. Lichtman, Cellular and Molecular Immunology, 4th Edition TNF is the main mediator of the acute inflammatory response

12 TNF acts as an homotrimer R.M.Locksley et al.,the TNF and TNF receptor superfamilies: integrating mammalian biology, Cell, 104:487,2001

13 Two different forms of ligand & two different receptors 2 1 M.A.Palladino et al.,anti-tnf-α therapies: the next generation, Nature Rev.,2:736,2003 The soluble TNF is able to bind both the two receptors The membrane-associated form binds primarily the type-2 receptor

14 TNFR-1 Costitutive expression on most cell types Irreversible binding

15 TNFR-2 Its expression can be induced Reversible binding

16 References L.J.Old, Tumor Necrosis Factor, Science, 230:630,1985 E.A.Carswell et al., An endotoxin-induced serum factor that causes necrosis of tumors, PNAS, 76:3666,1975 S.Green et al., Partial purification of a serum factor that causes necrosis of tumors, PNAS, 73:381,1976 M.F.Schroder et al., Tumor necrosis factos type α, a potent inhibitor of endothelial cell growth, is angiogenic in vivo, PNAS, 84:5277,1987 R.J.North et al., The antitumor function of tumor necrosis factor (TNF), J.Exp.Med.,167:1086,1988 S.A.H.Cann et al., Dr William Coley and tumor regression: a place in history or in the future, Postgrad.Med.J., 79:672,2003 K.Chatzantoni et al., Anti-tnf-alfa antibody therapies in autoimmune diseases, Current Topics in Medicinal Chemistry, 6:1707,2006 A.T.Paul et al., Modulating TNF-alfa signaling with natural products, Drug Discovery Today, 11:725, 2006 B.Beutler et al., Purification of Cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced raw cells, J.Exp.Med., 161:984,1985

17 F.J.Lejeune et al., Efficiency of recombinant human TNF in human cancer therapy, Cancer Immunity, 6:1,2006 K.L.Winthrop, Risk and prevention of tuberculosis and other serious opportunistic infections associated with inhibition of TNF, Nature Clinical Practice, 2:602,2006 M.A.Palladino et al., Anti-TNF-alfa therapies: the next generation, Nature Reviews, 2:736,2003 R.M.Locksley et al., The TNF receptor superfamilies: integrating mammalian biology, Cell, 104:487,2001 Abul K. Abbas, MD, MBBS, Andrew H. Lichtman, Cellular and Molecular Immunology, 4th Edition