Reduction of arthritis and pneumonitis in motheaten mice by soluble tumor necrosis factor receptor

Tumor necrosis factor-alpha (TNFα) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFα antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFα antibodies are effective in other IMIDs. Early efforts at understanding how TNFα antagonists act in IMIDs centered on their ability to neutralize soluble TNFα or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFα blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFα antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFα antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFα antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

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“…It did not, however, reduce the serum levels of IgM and IgM anti-dsDNA Abs in comparison to control mice [62].…”

Section: Mechanistic Lessons From Animal Modelsmentioning

confidence: 61%

TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

260

162

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“…Elevated levels of TNF or TNF mRNA have been reported in the sera and cells of Ptpn6 me-v/me-v relative to WT mice (15,(24)(25)(26). Anti-TNF antibody administration reduced lung tissue injury in Ptpn6 me/me bone marrow chimeras (25), and treatment with soluble TNF receptor reduced dermatitis, pneumonitis, and inflammatory lesions of the extremities in Ptpn6 me/me mice (27). SHP1 has also been implicated in the down-regulation of signaling elicited by type I IFN (e.g., JAK1 and STAT1 activation) (16).…”

Section: Discussionmentioning

confidence: 99%

Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger

Croker

Lawson

Berger

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

104

126

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A recessive phenotype called spin (spontaneous inflammation) was induced by N -ethyl- N -nitrosourea (ENU) mutagenesis in C57BL/6J mice. Homozygotes display chronic inflammatory lesions affecting the feet, salivary glands and lungs, and antichromatin antibodies. They are immunocompetent and show enhanced resistance to infection by Listeria monocytogenes . TLR-induced TNF and IL-1 production are normal in macrophages derived from spin mice. The autoinflammatory phenotype of spin mice is fully suppressed by compound homozygosity for Myd88 poc , Irak4 otiose , and Il1r1 -null mutations, but not Ticam1 Lps2 , Stat1 m1Btlr , or Tnf -null mutations. Both autoimmune and autoinflammatory phenotypes are suppressed when spin homozygotes are derived into a germ-free environment. The spin phenotype was ascribed to a viable hypomorphic allele of Ptpn6 , which encodes the tyrosine phosphatase SHP1, mutated in mice with the classical motheaten alleles me and me-v . Inflammation and autoimmunity caused by SHP1 deficiency are thus conditional. The SHP1-deficient phenotype is driven by microbes, which activate TLR signaling pathways to elicit IL-1 production. IL-1 signaling via MyD88 elicits inflammatory disease.

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“…In a murine model of autoimmune pneumonitis, TNF blockade with a soluble TNF receptor was therapeutic (10). On the other hand, because infliximab binds to TNF expressed on the surface of macrophages and CD4ϩ T cells, resulting in cell lysis (11), it is conceivable that the local release of macrophagederived proteolytic enzymes may contribute to MTX toxicity.…”

Section: Discussionmentioning

confidence: 99%