Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis.

Cope, Andrew P.; Londei, Marco; Chu, Nina; Cohen, Stanley; Elliott, Michael J.; Brennan, Fionula M.; Maini, R. N.; Feldmann, Marc

doi:10.1172/jci117394

Cited by 231 publications

(155 citation statements)

References 58 publications

(37 reference statements)

Supporting

Mentioning

130

Contrasting

Unclassified

Order By: Relevance

“…A number of TCR-independent in vitro model systems have been developed, each of which recapitulates at least some phenotypic characteristics of RA synovial T cells. In both human PB T cells and in murine T cell hybridomas, chronic TNF-␣ or cytokine mixture exposure results in decreased CD3 protein expression and concomitant diminished proliferative responses to CD3/CD28 stimulation, yet promotes T cell activation of monocytes by cell-cell contact (19,30,33). Additionally, coincubation of RA SF T cells with IL-15 can induce IL-17 production (36), while a subset of RA synovial tissue and SF T cells respond to cytokine mixtures by producing IFN-␥ (54).…”

Section: Discussionmentioning

confidence: 99%

“…Many properties of RA T cells, including surface expression of activation markers and cell-cell contact-dependent activation of macrophages and FLS, can be recapitulated by peripheral blood (PB) T cell exposure to IL-15 or a combination of inflammatory cytokines (19,35,36). Similar effects are observed in PB T cells chronically exposed to TNF-␣ (20,30). Additionally, stimulation of PB T cells with a number of inflammatory cytokines, in combination with CD28 ligation, can reproduce oxidative stress observed in synovial T cells (37).…”

mentioning

confidence: 91%

“…Ex vivo, RA synovial tissue and SF T cells are hyporesponsive to stimulation by pharmacological mitogens and recall Ags, both in terms of proliferation and cytokine secretion (2, 3, 25, 30 -32). This may be a consequence of chronic T cell exposure to inflammatory cytokines and/or oxidative stress, which can lead to altered expression or misfolding of critical TCR signaling proteins, such as the CD3 chain (30,33) and linker for activation of T cells (31,32,34).…”

mentioning

confidence: 99%

See 2 more Smart Citations

The Presumed Hyporesponsive Behavior of Rheumatoid Arthritis T Lymphocytes Can Be Attributed to Spontaneous Ex Vivo Apoptosis rather than Defects in T Cell Receptor Signaling

Abreu

Grabiec²,

Krausz³

et al. 2009

The Journal of Immunology

View full text Add to dashboard Cite

Genetic associations and the clinical success of compounds targeting TCR costimulatory proteins suggest an active role for TCR signaling in the initiation and perpetuation of rheumatoid arthritis (RA). Paradoxically, T cells isolated from affected joints in RA show impaired proliferative and cytokine responses following stimulation with mitogens and recall Ags attributed in part to chronic T cell exposure to oxidative stress and inflammatory cytokines. Therefore, it is uncertain how local autoreactive TCR signaling contributes to pathology in established RA. Using single-cell analysis, we show that in contrast to results obtained in bulk culture assays, T cells from the synovial fluid of RA patients proliferate and produce cytokines (IL-2, TNF-α, and IFN-γ) as efficiently, if not more so, than T cells isolated from healthy donors and RA patient peripheral blood following TCR/CD28 stimulation. RA synovial fluid T cell hyporesponsiveness observed in bulk cultures can be attributed to spontaneous apoptosis ex vivo, which is associated with altered ratios of proapoptotic Noxa and anti-apoptotic Mcl-1 expression. The absence of RA synovial T cell proliferation and cytokine production in situ, despite the capacity of these cells to support productive TCR signaling, suggests that T cells contribute to local pathology in established RA by TCR-independent mechanisms.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 91%

mentioning

confidence: 99%

See 1 more Smart Citation

The Presumed Hyporesponsive Behavior of Rheumatoid Arthritis T Lymphocytes Can Be Attributed to Spontaneous Ex Vivo Apoptosis rather than Defects in T Cell Receptor Signaling

Abreu

Grabiec²,

Krausz³

et al. 2009

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Attualmente il FDA richiede che il trattamento sia temporaneamente sospeso in corso di episodi infettivi, e questa è la regola nella pratica clinica nell'AIG. D'altra parte, nell'AR, l'incontrollata attività di malattia, con l'esposizione cronica alla citochina pro-infiammatoria TNFα, sembra rendere deficitaria la risposta immune Tlinfocitaria, e l'efficacia di questa risposta sembra essere recuperata dopo l'instaurazione della terapia anti-TNFα (139). Infatti, nei pazienti con AR, la frequenza di gravi infezioni associate alla terapia anti-TNF è risultata bassa: circa il 2-5% (140).…”

Section: Eventi Avversi Dell'inibizione Del Tnfunclassified

Biological therapy with TNF-inhibitors in pediatric rheumatology. Review of the litterature and personal experience

Gerloni¹,

Pontikaki²,

Gattinara³

et al. 2011

Reumatismo

View full text Add to dashboard Cite

The therapeutic approach to JIA is sometimes very troublesome and progression to erosive polyarthritis may occur in all JIA categories. Only Methotrexate has shown efficacy and safety in a large controlled trial. Nevertheless, in many cases, drug resistance or intolerance has led to try other therapeutic options, with still debatable results. Therefore, there has been space, in the last few years, for new therapies as the TNF-inhibitors. This therapeutic approach has shown a dramatic clinical benefit in active polyarticular refractory JIA: the rate and rapidity of response have exceeded those of all other studied DMARDs. Preliminary data show that they are efficacious also for other pediatric rheumatic disease (spondyloarthropathies, autoimmune uveitis, dermatomyositis, Kawasaki syndrome and some auto- inflammatory diseases). TNF-inhibitors in JIA have demonstrated a favourable benefit-to-risk profile. However, as their use has increased worldwide, some unusual, usually not serious, adverse events have emerged. Severe infections, including TB, and deaths have been reported. Long-lasting active disease, systemic disease, concurrent and previous immunosuppressive therapies, all contribute to risk of infection and other serious AEs. Given the evidence that TNF has a primary role in the pathogenesis of JIA, particularly in joint destruction, neutralizing this cytokine early, within the window of opportunity, could halt or delay progression of joint damage and debilitating consequences of the disease. Thus, for JIA patients whose disease is not quickly controlled with MTX, TNF blockers may be considered as first-line treatment, although long-term safety data still need to be established

show abstract

“…Immun-mekanizma sebepli tablolar›n ortaya ç›kmas›, TNF'in yok edilmesi s›ras›nda artm›fl T ve B hücre aktivasyonunun, otoantijenler ve yabanc› antijenler ile reaksiyonlar›na ba¤lanm›flt›r. [125][126][127][128] TNF antagonistleri ile tedavi sonras›nda baflta anti-nukleer antikor ve antidsDNA antikor olmak üzere çeflitli otoantikorlar›n artt›¤› bilinmektedir. 129,130 Bu konuda yap›lan bir araflt›rmada 7700 infliksimab ve 3800 etanersept kullanan hasta grubunda lupus-benzeri tablo geliflen olgu say›s› yaln›z 22 (15 infliksimab ve 7 etanersept) olarak bildirilmifltir.…”

Section: Tnf Antagonistleriunclassified

New Treatment Alternatives in the Management of Non-İnfectious İntraocular İnflammations: Biologic Agents

Emre¹,

Tutkun²

2011

tjo

View full text Add to dashboard Cite

ÖzetEnfeksiyöz olmayan üveitlerin tedavisinde son y›llara kadar genel olarak immün sistemi bask›layan ilaçlar kullan›lmak-tayd›. Ancak gen mühendisli¤indeki geliflmeler, inflamatuar süreçte yer alan özgün molekülleri hedefleyen proteinlerin sentezini ve bu proteinlerin terapötik olarak kullan›lmalar›n› mümkün k›lm›flt›r. Genel olarak protein yap›s›ndaki bu ajanlar biyolojik ajanlar olarak adland›r›lm›fllard›r. Oftalmologlar›n biyolojik ajanlar ile tecrübeleri s›n›rl› olsa da, bu ajanlar romatoloji ve dermatoloji baflta olmak üzere di¤er disiplinler taraf›ndan yo¤un biçimde kullan›lmaktad›rlar. ‹nterferon, infliksimab ve adalimumab baflta olmak üzere birçok biyolojik ajan›n üveit hastalar›nda kullan›m› ile ilgili literatür verisi olmas›na ra¤men henüz bu endikasyonda ruhsatl› kullan›mlar› yoktur. Ayr›ca bu ajanlar›n kullan›m› s›ras›nda dikkat edilmesi gereken güvenlik önlemleri ve önemli risk faktörleri mevcuttur. Bu derlemenin amac›, dirençli üveit hastalar›nda kullan›labilen biyolojik ajanlar konusunda güncel ve kapsaml› bilgi sunmakt›r. ( SummaryConventional immunosuppressive agents have been traditionally used for the treatment of noninfectious uveitis. Recent developments in genetic engineering have made it possible to synthesize proteins that target specific molecules playing role in the inflammatory response. These agents are generally in protein structure and are named biologic agents. While there is limited experience with biologics in the field of ophthalmology, they are commonly used in other disciplines such as rheumatology and dermatology. Although considerable data have accumulated in the uveitis literature regarding the use of biologic agents, including mainly interferon, infliximab, and adalimumab, their use for this indication is still off-label. Moreover, there are certain precautions that have to be taken into account, as well as important safety issues associated with their use. The purpose of this paper is to present an updated comprehensive review of biologic agents that may be used for the treatment of refractory uveitis. (Turk J Ophthalmol 2011; 41: 243-55 GiriflEnfeksiyöz olmayan üveitlerin tedavisinde kullan›lmakta olan immunsupresan ajanlar, ba¤›fl›kl›k sistemini genel olarak bask›lamakta veya sapt›rmaktad›rlar. Bu tedavi yöntem-lerinin sebep olduklar› ciddi yan etkiler ile tedaviye dirençli olgular, hekimleri yeni tedavi aray›fllar›na itmektedir. Son y›llarda araflt›r›lan biyolojik ajanlar, inflamatuar süreçteki öz-gün molekülleri (proteinleri) etkileyerek ba¤›fl›kl›k sisteminde daha s›n›rl› ancak etkin bir tedavi sa¤lamaktad›rlar. Biyolojik ajanlar, moleküler rekombinant DNA teknolojisi kullan›larak elde edilen proteinlerdir. Bu ajanlar›n büyük ço¤un-lu¤u monoklonal antikorlard›r. fiu an için enfeksiyöz olmayan üveitlerin tedavisinde bafll›ca kullan›lan biyolojik ajanlar 3 grupta s›n›fland›r›labilir; i. Interferon-α, ii. TNF-α antagonistleri ve iii. Çeflitli sitokin veya yüzey membran proteini gibi farkl› hedeflere yönelik antikorlar veya füzyon proteinleri.

show abstract

Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis.

Abstract: Experiments were designed to test the hypothesis that chronic exposure to tumor necrosis factor alpha (TNF)

Cited by 231 publications

References 58 publications

The Presumed Hyporesponsive Behavior of Rheumatoid Arthritis T Lymphocytes Can Be Attributed to Spontaneous Ex Vivo Apoptosis rather than Defects in T Cell Receptor Signaling

The Presumed Hyporesponsive Behavior of Rheumatoid Arthritis T Lymphocytes Can Be Attributed to Spontaneous Ex Vivo Apoptosis rather than Defects in T Cell Receptor Signaling

Biological therapy with TNF-inhibitors in pediatric rheumatology. Review of the litterature and personal experience

New Treatment Alternatives in the Management of Non-İnfectious İntraocular İnflammations: Biologic Agents

Contact Info

Product

Resources

About