Tumor necrosis factor blockade and the risk of viral infection

Kim, Seo Young; Solomon, Daniel H.

doi:10.1038/nrrheum.2009.279

Cited by 174 publications

(139 citation statements)

References 112 publications

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“…Surprisingly, TNF-α, a potent amplifier of RANKL-induced osteoclastogenesis (21-23), was not seen to be up-regulated in the serum of HIV-1 Tg rats, and neutralization of TNF-α failed to suppress the enhanced basal and RANKL-stimulated osteoclastogenesis ex vivo. TNF-α is reported to be up-regulated in the serum of human patients with HIV and may play a critical role in the clinical progression of HIV infection (30). It is possible that the transgenic expression of HIV-1 proteins in this model bypasses or negates the requirement for TNF-α in disease progression.…”

Section: Discussionmentioning

confidence: 95%

“…TNF-α is a cytokine known to amplify the osteoclastogenic activity of RANKL (21)(22)(23). Serum levels of TNF-α have been reported to be elevated in patients with HIV, and are suggested to play a critical role in the clinical progression of HIV infection (30). To determine whether elevated levels of TNF-α play a role in the enhanced osteoclastogenic activity in HIV-1 Tg rats, we cultured OCs ex vivo in the presence of a subsaturating dose of RANKL (15 ng/mL) in the presence or absence of a saturating dose of neutralizing TNF-α antibody (20 μg/mL).…”

Section: Hiv-1 Tg Rats Have Reduced Bone Mass As a Consequence Of Incmentioning

confidence: 99%

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Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats

Vikulina¹,

Fan

Yamaguchi³

et al. 2010

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

128

117

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Osteoporosis and bone fractures are increasingly recognized complications of HIV-1 infection. Although antiretroviral therapy itself has complex effects on bone turnover, it is now evident that the majority of HIV-infected individuals already exhibit reduced bone mineral density before therapy. The mechanisms responsible are likely multifactorial and have been difficult to delineate in humans. The HIV-1 transgenic rat recapitulates many key features of human AIDS. We now demonstrate that, like their human counterparts, HIV-1 transgenic rats undergo severe osteoclastic bone resorption, a consequence of an imbalance in the ratio of receptor activator of NF-κB ligand, the key osteoclastogenic cytokine, to that of its physiological decoy receptor osteoprotegerin. This imbalance stemmed from a switch in production of osteoprotegerin to that of receptor activator of NF-κB ligand by B cells, and was further compounded by a significantly elevated number of osteoclast precursors. With the advancing age of individuals living with HIV/AIDS, low bone mineral density associated with HIV infection is likely to collide with the pathophysiology of skeletal aging, leading to increased fracture risk. Understanding the mechanisms driving bone loss in HIV-infected individuals will be critical to developing effective therapeutic strategies.AIDS | osteoprotegerin | osteoporosis | receptor activator of NF-κB ligand | osteoclast

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Section: Discussionmentioning

confidence: 95%

Section: Hiv-1 Tg Rats Have Reduced Bone Mass As a Consequence Of Incmentioning

confidence: 99%

Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats

Vikulina¹,

Fan

Yamaguchi³

et al. 2010

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

128

117

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“…Current therapies, such as cytokine antagonists, have shown great promise in treating many of these diseases. TNF-α antagonists have changed the course of rheumatoid arthritis, and other cytokine antagonists are showing impressive efficacy in various other diseases (1,2). However, most of the current therapeutic agents target the terminal phase of inflammation and do not address the fundamental problems that are responsible for the initiation and progression of the autoimmune process.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of human autoimmunity

Rosenblum¹,

Remedios²,

Abbas³

2015

J. Clin. Invest.

391

258

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R e v i e w S e R i e S : A u t o i m m u n i t y2 2 2 9 jci.org Volume 125 Number 6 June 2015theories have been proposed to explain this association, including epitope spreading, antigenic complementarity, and excessive innate/pattern recognition receptor activation. For example, evidence of EBV infection in postmortem brain tissue has been associated with MS but not other inflammatory disorders (17). Additionally, systemic infections have been reported to trigger relapses in patients with relapsing-remitting MS through enhancement of myelin-specific T cell responses (15). Another example of the association of infections with autoimmunity is that of periodontal infections and rheumatoid arthritis (18). In contrast, infections are also postulated to protect against some autoimmune diseases. For example, infection of germ-free mice with Bacteroides fragilis has been reported to protect against experimental autoimmune encephalomyelitis, the mouse model of MS, through induction of Treg cells (19). Additionally, a higher incidence of MS and type 1 diabetes is correlated with a decreased number of infections in developed countries (20). Recent interest has focused on the possible role of the microbiome in influencing local and systemic immune responses. Much of the emphasis has been on the gut microbiome. It is now believed that inflammatory bowel disease (IBD) is initiated by dysregulated and exaggerated immune responses to intestinal commensal microbes. In fact, the major manifestations of IBD may be caused by antimicrobial immune reactions and not by true autoimmunity (i.e., directed at tissue self-antigens). There are also several studies in mice that implicate commensal microbes in autoimmune disease, including type 1 diabetes (reviewed in ref. 21).A well-recognized nonmicrobial environmental trigger is UV irradiation for cutaneous lupus. A possible explanation for this connection is that UV radiation induces apoptotic death of many cell types and increases the burden of nuclear antigens, especially if the dead cells cannot be efficiently cleared (22). It has been suggested that low-level natural cell death in tissues is a mechanism for maintaining peripheral tolerance to tissue antigens through tolerance-promoting dendritic cell populations (23). It is plausible that lupus patients have a genetic predisposition for this system to become easily overwhelmed and are thus unable to maintain tolerance in the presence of continual UV exposure.Defective regulation as the cause of autoimmunity. If failure of self-tolerance is the fundamental abnormality in autoimmune diseases, the central question becomes -which mechanisms of tolerance fail in specific diseases, and why? In patients with SLE, defects in deletion of immature B cells in the bone marrow, in receptor editing, and in control of mature B cells in peripheral tissues have all been proposed (24). In humans with SLE, mature naive B cells can produce autoantibodies even before encounter with antigen, suggesting that defects in early B cell tolerance checkpoints m...

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“…Neutralising these cytokines therefore necessarily significantly compromises the host's natural ability to effectively combat infections. This explains why anti-TNF therapy recipients are at serious risk of more severe acute virus infections [131], and reactivation of chronic viral or bacterial infection, especially tuberculosis [132]. This explains why there are numerous reports of reactivation of chronic virus infections such as varicella zoster virus ('shingles') in patients using anti-TNF mAbs [133].…”

Section: Adverse Events Related To Cytokine Neutralisationmentioning

confidence: 99%

Therapeutic Antibody‐Based Drugs in the Treatment of Human Inflammatory Disorders

Sedger¹,

Ranasinghe²,

McDermott³

et al. 2017

Immunotherapy - Myths, Reality, Ideas, Future

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Inflammation causes debilitating human conditions and older treatments rely on global immunosuppression that non-specifically alleviates symptoms. Currently, several monoclonal antibodies (mAbs) are available that specifically block pro-inflammatory cytokines. These include mAbs specific to tumour necrosis factor (TNF), interleukin (IL)-1β,I L -6 , IL-17 and IL-12/IL-23. The chapter summarises the key elements in human inflammatory disease conditions, including various forms of arthritis, psoriasis, Crohn's disease and ulcerative colitis, plus pyrin-associated inflammatory syndromes and periodic fevers, to explain the benefit of cytokine neutralisation through mAb-type reagents. The chapter reviews the efficacy and safety of the current repertoire of anti-cytokine/cytokine receptor mAbs. It also discusses the known side effects and adverse events that are sometimes associated with systemic blockade of cytokines in vivo, and concludes that the accumulating knowledge of treatment failures can reveal unappreciated aspects of cytokine biology and even new treatment opportunities. The chapter includes mention of the rapidly expanding cohort of biosimilar mAbs and the mAbs to IL-4, IL-5 and IL-13 that are now emerging, in addition to the need for treatments for disorders that remain refractory to the current repertoire of anti-cytokine mAbs and conventional treatments. Thus, here we summarise the current status of anti-cytokine mAbs for human inflammatory diseases.

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Tumor necrosis factor blockade and the risk of viral infection

Cited by 174 publications

References 112 publications

Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats

Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats

Mechanisms of human autoimmunity

Therapeutic Antibody‐Based Drugs in the Treatment of Human Inflammatory Disorders

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