The clinical utility of inhibiting CD28‐mediated costimulation

Linsley, Peter S.; Nadler, Steven G.

doi:10.1111/j.1600-065x.2009.00780.x

Cited by 142 publications

(127 citation statements)

References 93 publications

(111 reference statements)

Supporting

Mentioning

124

Contrasting

Unclassified

Order By: Relevance

“…First, we report that abatacept inhibited T cell priming, which is consistent with previous in vivo studies showing that abatacept reduced T cell proliferation and proinflammatory cytokine levels (21). Importantly, we showed that abatacept treatment during priming did not induce functional anergy of T cells.…”

Section: Discussionsupporting

confidence: 92%

“…To confirm the ability of abatacept to inhibit T cell priming (21,22), we investigated the activation status of T cells derived from the draining LNs of nonimmunized (naive), primed, primed and treated with abatacept or control IgG, and orally tolerized mice and analyzed the expression of CD44, CD62L, ICOS, and CD71 (Figure 1). Abatacept reduced the proportion of activated T cells (CD44 high CD62L-) and inhibited the up- Figure 1.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Patakas

Weir

et al. 2016

Arthritis & Rheumatology

Self Cite

View full text Add to dashboard Cite

Objective. To determine at the phenotypic, functional, and transcriptional levels whether abatacept, a CTLA-4Ig molecule that binds with high affinity to CD80/86 on antigen-presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of immunologic tolerance in T cells and dendritic cells in mice.Methods. We investigated the capacity of abatacept to regulate the development of antigen-specific immunologic tolerance in vivo using murine models of priming and tolerance to generate highly purified antigen-specific T cell populations and CD11c1 APCs. These were combined with detailed immunologic and full genome transcriptional analyses.Results. We found that abatacept inhibited T cell activation, but did not render T cells anergic or lead to the generation of Treg cells. However, it induced a sustained inhibition of T cell activation due to the inability of these cells to progress through the cell cycle following T cell receptor stimulation. We also observed that this state was accompanied by an inhibition of dendritic cell activation due to their reduced licensing by T cells.Conclusion. This study provides detailed insight into the mode of action of abatacept, demonstrating that its effectiveness is not due to the induction of T cell tolerance, but rather to a sustained inhibition of T cell activation that results in reduced functionality of APCs, with significant implications for its clinical application.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Patakas

Weir

et al. 2016

Arthritis & Rheumatology

Self Cite

View full text Add to dashboard Cite

show abstract

“…T cell activation and proliferation are important factors in the initiation and perpetuation of arthritis. The possibility of treating arthritis by interfering with the interaction between the costimulatory molecules CD28 on T cells and CD80 (B7-1) and CD86 (B7-2) on APCs has raised interest in the field of rheumatology (111,112). CTLA-4 (CD152) is a homolog of CD28.…”

Section: From Animal Models Toward the Clinicmentioning

confidence: 99%

Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?

Bevaart¹,

Vervoordeldonk²,

Tak³

2010

Arthritis & Rheumatism

228

193

View full text Add to dashboard Cite

There are accumulating data describing the association between diabetes and cancer mortality from Westernised populations. There are no data describing the relationship between diabetes and cancer mortality in African or South Asian populations from developing countries. We explored the relationship of abnormal glucose tolerance and diabetes on cancer mortality risk in a large, multi‐ethnic cohort from the developing nation of Mauritius. Population‐based surveys were undertaken in 1987, 1992 and 1998. The 9559 participants comprised 66% of South Asian (Indian), 27% of African (Creole), and 7% of Chinese descent. Cox's proportional hazards model with time varying covariates was used to obtain hazard ratios (HRs) and 95% confidence intervals (95% CI) for risk of cancer mortality, after adjustment for confounding factors. In men, but not women, cancer mortality risk increased with rising 2h‐PG levels with HR for the top versus bottom quintile of 2.77 (95%CI: 1.28 to 5.98). South Asian men with known diabetes had a significantly greater risk of cancer mortality than those with normal glucose tolerance (NGT) HR: 2.74 (95%CI: 1.00‐7.56). Overall, impaired glucose tolerance was associated with an elevated risk of cancer mortality compared to NGT (HR: 1.47, 95% CI: 0.98–2.19), though this was not significant. We have shown that the association between abnormal glucose tolerance and cancer extends to those of African and South Asian descent. These results highlight the importance of understanding this relationship in a global context to direct future health policy given the rapid increase in type 2 diabetes, especially in developing nations.

show abstract

“…Thus, inhibition of T cell activation may lead to clinical benefits in patients with PsA. Full antigen-induced activation of naive T cells requires 2 discrete signals from the antigen-presenting cell (23). Antigen is presented to the T cell receptor in the context of a major histocompatibility complex molecule, but full activation occurs only when the binding of CD80 or CD86 to the CD28 molecule on the T cell produces a second costimulatory signal.…”

mentioning

confidence: 99%

Abatacept in the treatment of patients with psoriatic arthritis: Results of a six‐month, multicenter, randomized, double‐blind, placebo‐controlled, phase II trial

Mease¹,

Genovese²,

Gladstein³

et al. 2011

Arthritis & Rheumatism

269

166

View full text Add to dashboard Cite

Objective. To assess the safety and efficacy of abatacept, a selective T cell costimulation modulator, in patients with psoriatic arthritis (PsA).Methods. In this 6-month, multicenter, randomized, double-blind, placebo-controlled, phase II study, 170 PsA patients with a psoriasis target lesion (TL) >2 cm who had previously taken disease-modifying antirheumatic drugs (DMARDs), including anti-tumor necrosis factor (anti-TNF) agents, were randomized (1:1: 1:1) to receive placebo or abatacept at doses of 3 mg/kg, 10 mg/kg, or 30/10 mg/kg (2 initial doses of 30 mg/kg, followed by 10 mg/kg) on days 1, 15, and 29 and then once every 28 days thereafter. The primary end point was the American College of Rheumatology 20% criteria for improvement (ACR20 response) on day 169. Other key end points were magnetic resonance imaging (MRI) scores for joint erosion, osteitis, and synovitis, scores on the Health Assessment Questionnaire (HAQ) and the Short Form-36 (SF-36) health survey, the investigator's global assessment of psoriasis, the TL score, and the Psoriasis Area and Severity Index (PASI) score.Results. Proportions of patients achieving an ACR20 response were 19%, 33%, 48%, and 42% in the placebo, the abatacept 3 mg/kg, the abatacept 10 mg/kg, and the abatacept 30/10 mg/kg groups, respectively. Compared with placebo, improvements were significantly higher for the abatacept 10 mg/kg (P ‫؍‬ 0.006) and 30/10 mg/kg (P ‫؍‬ 0.022) groups, but not for 3 mg/kg group (P ‫؍‬ 0.121). All abatacept regimens resulted in improved MRI, HAQ, and SF-36 scores, with 10 mg/kg showing the greatest improvements. Improvements in the TL and PASI scores were observed in all abatacept arms; a response according to the investigator's global assessment was seen only with 3 mg/kg of abatacept. The safety profiles were similar among the treatment arms.Conclusion. The results of this study suggest that 10 mg/kg of abatacept, the approved dosage for rheumatoid arthritis and juvenile idiopathic arthritis, may be an effective treatment option for PsA.Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by both arthritis and psoriasis ClinicalTrials.gov identifier: NCT00534313.

show abstract

The clinical utility of inhibiting CD28‐mediated costimulation

Cited by 142 publications

References 93 publications

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?

Abatacept in the treatment of patients with psoriatic arthritis: Results of a six‐month, multicenter, randomized, double‐blind, placebo‐controlled, phase II trial

Contact Info

Product

Resources

About