Cytokine Neutralization at specific cellular Sources A new Therapeutic Model?

被引:1
作者
Kruglov, A. A. [1 ,2 ,3 ]
Nedospasov, S. A. [1 ,2 ,3 ]
机构
[1] DRFZ, Inst Leibniz Gemeinschaft, Charitepl 1, D-10117 Berlin, Germany
[2] Engelhardt Inst Mol Biol & Lomonosov, Moscow, Russia
[3] Moscow MV Lomonosov State Univ, Moscow, Russia
来源
ZEITSCHRIFT FUR RHEUMATOLOGIE | 2017年 / 76卷 / 02期
关键词
TUMOR-NECROSIS-FACTOR; AUTOIMMUNE-DISEASE; FACTOR TNF; CELLS; TUBERCULOSIS; DISTINCT; MICE;
D O I
10.1007/s00393-016-0244-6
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Currently, treatment of autoimmune diseases is based on manipulation of general control mechanisms, including those mediated by immunoregulatory cytokines. This approach is non-curative and may cause unwanted side effects due to numerous beneficial and non-redundant functions of a particular cytokine. Methods: Techniques of reverse genetics, such as conditional gene targeting, were employed to uncover the contributions of two proinflammatory and immunomodulatory cytokines, tumour necrosis factor (TNF) and interleukin 6 (IL-6), in various disease states. Results: Several non-redundant functions of TNF from distinct cellular sources were identified. TNF from myeloid cells is pathogenic in several autoimmune diseases, whereas TNF produced by T cells showed non-redundant protective functions in experimental arthritis and in a Mycobacterium tuberculosis infection model. To test the idea of selective pharmacological inhibition of “bad” TNF produced by myeloid cells while sparing “good” TNF produced by T lymphocytes, a myeloid-specific TNF inhibitor (MYSTI) was designed – a recombinant mini-antibody with dual specificity that can bind to the surface molecule F4/80 on myeloid cells and to TNF. In vitro experiments confirmed retention of TNF on the surface of TNF-producing cells and in vivo experiments indicated that MYSTI can protect mice from lethal TNF-mediated hepatotoxicity. MYSTI is also effective in experimental arthritis. Conclusion: The proposed therapeutic strategy may be more effective than systemic anti-cytokine therapy in several human autoimmune diseases, as it would preserve the potentially beneficial effects of the same cytokine produced by other cell types. Such bispecific biological agents may become interesting tools for experimental studies and, eventually, drug development. © 2017, Springer-Verlag Berlin Heidelberg.
引用
收藏
页码:163 / 165
页数:3
相关论文
共 17 条
[1]   Prominent role for T cell-derived Tumour Necrosis Factor for sustained control of Mycobacterium tuberculosis infection [J].
Allie, Nasiema ;
Grivennikov, Sergei I. ;
Keeton, Roanne ;
Hsu, Nai-Jen ;
Bourigault, Marie-Laure ;
Court, Nathalie ;
Fremond, Cecile ;
Yeremeev, Vladimir ;
Shebzukhov, Yuriy ;
Ryffel, Bernhard ;
Nedospasov, Sergei A. ;
Quesniaux, Valerie F. J. ;
Jacobs, Muazzam .
SCIENTIFIC REPORTS, 2013, 3
[2]   B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells [J].
Barr, Tom A. ;
Shen, Ping ;
Brown, Sheila ;
Lampropoulou, Vicky ;
Roch, Toralf ;
Lawrie, Sarah ;
Fan, Boli ;
O'Connor, Richard A. ;
Anderton, Stephen M. ;
Bar-Or, Amit ;
Fillatreau, Simon ;
Gray, David .
JOURNAL OF EXPERIMENTAL MEDICINE, 2012, 209 (05) :1001-1010
[3]   Camel single-domain antibodies as modular building units in bispecific and bivalent antibody constructs [J].
Conrath, KE ;
Lauwereys, M ;
Wyns, L ;
Muyldermans, S .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (10) :7346-7350
[4]   Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases [J].
Dinarello, Charles A. ;
Simon, Anna ;
van der Meer, Jos W. M. .
NATURE REVIEWS DRUG DISCOVERY, 2012, 11 (08) :633-652
[5]   Cell-type-restricted anti-cytokine therapy: TNF inhibition from one pathogenic source [J].
Efimov, Grigory A. ;
Kruglov, Andrei A. ;
Khlopchatnikova, Zoya V. ;
Rozov, Fedor N. ;
Mokhonov, Vladislav V. ;
Rose-John, Stefan ;
Scheller, Juergen ;
Gordon, Siamon ;
Stacey, Martin ;
Drutskaya, Marina S. ;
Tillib, Sergei V. ;
Nedospasov, Sergei A. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2016, 113 (11) :3006-3011
[6]   Role of tumour necrosis factor (TNF) in host defence against tuberculosis: implications for immunotherapies targeting TNF [J].
Ehlers, S .
ANNALS OF THE RHEUMATIC DISEASES, 2003, 62 :37-42
[7]   What have we learnt from targeted anti-TNF therapy? [J].
Feldmann, M. ;
Williams, R. O. ;
Paleolog, E. .
ANNALS OF THE RHEUMATIC DISEASES, 2010, 69 :97-99
[8]   Distinct and nonredundant in vivo functions of TNF produced by T cells and macrophages/neutrophils:: Protective and deleterious effects [J].
Grivennikov, SI ;
Tumanov, AV ;
Liepinsh, DJ ;
Kruglov, AA ;
Marakusha, BI ;
Shakhov, AN ;
Murakami, T ;
Drutskaya, LN ;
Förster, I ;
Clausen, BE ;
Tessarollo, L ;
Ryffel, B ;
Kuprash, DV ;
Nedospasov, SA .
IMMUNITY, 2005, 22 (01) :93-104
[9]   Modalities of Experimental TNF Blockade In Vivo: Mouse Models [J].
Kruglov, A. A. ;
Tumanov, A. V. ;
Grivennikov, S. I. ;
Shebzukhov, Yu. V. ;
Kuchmiy, A. A. ;
Efimov, G. A. ;
Drutskaya, M. S. ;
Scheller, J. ;
Kuprash, D. V. ;
Nedospasov, Sergei A. .
ADVANCES IN TNF FAMILY RESEARCH, 2011, 691 :421-431
[10]   Nonredundant Function of Soluble LTα3 Produced by Innate Lymphoid Cells in Intestinal Homeostasis [J].
Kruglov, Andrey A. ;
Grivennikov, Sergei I. ;
Kuprash, Dmitry V. ;
Winsauer, Caroline ;
Prepens, Sandra ;
Seleznik, Gitta Maria ;
Eberl, Gerard ;
Littman, Dan R. ;
Heikenwalder, Mathias ;
Tumanov, Alexei V. ;
Nedospasov, Sergei A. .
SCIENCE, 2013, 342 (6163) :1243-1246