Pathogenic and protective functions of TNF, produced by T lymphocytes, in autoimmune diseases
Final Report Abstract
Tumor necrosis factor (TNF, TNF-α) is a potent immunomodulatory and proinflammatory cytokine produced by many types of immunocytes. Its most likely evolutionary significance related to protection against bacterial infections. However, rather unexpectedly the same “good” molecule was implicated in the pathogenesis of several autoimmune diseases, including rheumatoid arthritis (RA) and multiple sclerosis (MS). During the first phase of this project we have discovered and documented the contrasting and opposite contributions of TNF produced by myeloid cells and T cells in disease development. In particular, TNF produced by T cells in its transmembrane form appeared to provide protection in experimental arthritis (and in Mycobacterium tuberculosis infection) through yet unknown mechanisms. This paradoxical discovery led us to the development of a prototype myeloid cell-restricted TNF blocker that inhibits the “bad” TNF from myeloid cells but spares beneficial TNF functions produced by T lymphocytes (European patent). 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, for drug development. In the second (extended) phase of the project we developed additional animal models that allowed us to dissect several molecular mechanisms of TNF pathogenicity in diseases, such as antibody-mediated experimental arthritis, in a novel type of experimental colitis and in experimental autoimmune encephalomyelitis (EAE). The most interesting result relates to the function of TNFR2 expressed by Tregs that provides intrinsic signalling critical for protective Treg functions in EAE. Overall, we found that myeloid cell-derived TNF is pathogenic in two models of arthritis as well as in EAE, but T cell-derived TNF can be protective (in one form of arthritis) but can be deleterious (in colitis). TNFR2 on Tregs is protective in EAE. The results of the project DFG led to the development of a prototype of novel type of TNF blocker that can be further modified for use in humans (European patent).
Publications
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(2018). Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity. Proc. Natl. Acad. Sci. USA, 115(51):13051-13056
Atretkhany, K-S.N., Mufazalov, I.A., Dunst, J., Kuchmiy, A.A., Gogoleva, V.S., Andruszewski, D., Drutskaya, M.S., Faustman, D.L., Schwabenland, M., Prinz, M., Kruglov, A.A., Waisman, A., and Nedospasov, S.A.
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(2019) Modulation of bioavailability of proinflammatory cytokines produced by myeloid cells. Semin Arthritis Rheum. 49(3S):S39-S42
Nosenko, M.A., Atretkhany, K.N., Mokhonov, V.V., Vasilenko, E.A., Kruglov, A.A., Tillib, S.V., Drutskaya , M.S., and Nedospasov, S.A.
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(2020) Contrasting contributions of TNF from distinct cellular sources in arthritis. Annals Rheum. Dis. 79(11):1453-1459
Kruglov, A.A, Drutskaya, M.S., Schlienz, D., Gorshkova, E.A., Kurz, K., Morawietz, L. and Nedospasov, S.A.
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(2020) Effects of myeloid cellrestricted TNF inhibitors in vitro and in vivo. J Leukoc Biol. 107(6):933-939
Drutskaya, M.S., Nosenko, M.A,, Gorshkova, E.A., Mokhonov, V.V., Zvartsev, R.V., Polinova, A.I., Kruglov, A.A., and Nedospasov, S.A.
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(2022) TNF hampers intestinal tissue repair in colitis by restricting IL-22 bioavailability. Mucosal Immunol. 2022 Apr 5
Ninnemann J, Winsauer C, Bondareva M, Kühl AA, Lozza L, Durek P, Lissner D, Siegmund B, Kaufmann SHE, Mashreghi MF, Nedospasov SA, Kruglov AA
