ACCLAIM: A randomized trial of abatacept (CTLA4-Ig) for relapsing-remitting multiple sclerosis

Khoury, Samia J.; Rochon, James; Ding, Linna; Byron, Margaret; Ryker, Kristin; Tosta, Patti; Gao, Wendy; Freedman, Mark S.; Arnold, Douglas L.; Sayre, Peter H.; Smilek, Dawn E.

doi:10.1177/1352458516662727

Cited by 48 publications

(48 citation statements)

References 27 publications

(36 reference statements)

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“…In a recent study, patients treated with abatacept, a B7 antagonist, did not see a therapeutic effect. 128 These results are in direct contrast to previous findings suggesting abatacept is a potential therapeutic regulator of neuroinflammation. 129,130 These contradictory findings may be explained by low disease activity prior to treatment.…”

Section: Associations Between Ms and The B7/t-cell Costimulatory Pathwaycontrasting

confidence: 79%

Involvement of Immune Regulation in Multiple Sclerosis

Spagnuolo

Piavis

Williams

2017

Immunol Immunogenet Insights

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Multiple sclerosis (MS) is a neurodegenerative disease characterized by neuroinflammation and demyelination that results in axon loss. Multiple sclerosis has been shown to be the result of an autoimmune response caused by a mixture of genetic and environmental factors. Dendritic cells are prominent antigen-presenting cells that interact with various molecules to regulate the immune system. The dysfunction of various features of immune regulation, including interleukins (ILs), CD4 + T cells, and suppressor of cytokine signaling (SOCS1), has been implicated in the pathogenesis of MS. T cells, particularly through the malfunction of B7-costimulatory pathways, have been shown to affect the progression of the disease. SOCS1 is important in regulating the function of T cells through its interactions with other nearby genes, especially CLEC16A, with abnormal decreases in SOCS1 expression leading to the exhibition of MS symptoms. The activation of IL-23 receptors on CD4 + T cells is pivotal to their differentiation into pathogenic T H 17 cells. Several promising compounds that downregulate gene expression of IL-23 and IL-23R have been discovered but require further investigation for efficacy and safety. Given their role in the severity and progression of MS, therapies that decrease these dysregulations may ultimately decrease symptoms and in turn improve patients' quality of life.

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Section: Associations Between Ms and The B7/t-cell Costimulatory Pathwaycontrasting

confidence: 79%

Involvement of Immune Regulation in Multiple Sclerosis

Spagnuolo

Piavis

Williams

2017

Immunol Immunogenet Insights

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“…Deletion of CTLA‐4 on regulatory T cells in mature animals leads to resistance to EAE., indicating that selective expression of checkpoint inhibitory molecules on effector versus regulatory cells makes it difficult to predict the therapeutic response of modulating these molecules in autoimmune disorders (Liu et al, ; Paterson et al, ). A Phase 2 clinical trial (ACCLAIM) did not demonstrate efficacy of abatacept, a CTLA4‐Ig fusion protein, in reducing the number of new gadolinium enhanced MRI lesions or clinical measures of disease activity in relapsing remitting MS (RRMS) (Khoury et al, ). Boosting the immune responses using checkpoint inhibitors is receiving increasing consideration for therapies of gliomas.…”

Section: Comparison Of the Role Of Inflammation In Physiologic And Pamentioning

confidence: 99%

“…Inhibits disease (Klinkert et al, 1997) Exacerbates disease (Kemanetzoglou and Andreadou 2017) IL-12 (p40/−35) and IL-23 (p40/p19) Abs Ameliorated by anti-IL-23 not IL-12 Abs (Cua et al, 2003;Grifka-Walk et al, 2015) No efficacy (Segal et al, 2008) IL-17Ab (secukinumab) Inhibits disease (Komiyama et al, 2006) Nonsignificant lesion reduction (effective in psoriasis and RA) (Havrdova et al, 2016) IL-27 Abs + (inhibits GM-CSF) (Casella et al, 2017) n/a GM-CSFR blockade Prevents relapses (Nissen et al, 2018) Ameliorates progression (Ifergan et al, 2017) No alteration of initial clinical course; limits extent of chronic CNS injury (Duncker et al, 2018) Abbreviations: Abs, antibodies; EAE, experimental autoimmune encephalomyelitis; GM-CSFR, granulocyte-macrophage colony-stimulating factor receptor; MS, multiple sclerosis; RA, rheumatoid arthritis. gadolinium enhanced MRI lesions or clinical measures of disease activity in relapsing remitting MS (RRMS) (Khoury et al, 2017). Boosting the immune responses using checkpoint inhibitors is receiving increasing consideration for therapies of gliomas.…”

Section: Glia As Immune-therapeutic Targetsmentioning

confidence: 99%

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

Healy

Yaqubi

Ludwin

et al. 2019

Glia

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Cells of the adaptive and innate immune systems in the brain parenchyma and in the meningeal spaces contribute to physiologic functions and disease states in the central nervous system (CNS). Animal studies have demonstrated the involvement of immune constituents, along with major histocompatibility complex (MHC) molecules, in neural development and rare genetic disorders (e.g., colony stimulating factor 1 receptor [CSF1R] deficiency). Genome wide association studies suggest a comparable role of the immune system in humans. Although the CNS can be the target of primary autoimmune disorders, no current experimental model captures all of the features of the most common human disorder placed in this category, multiple sclerosis (MS). Such features include spontaneous onset, environmental contributions, and a recurrent/progressive disease course in a genetically predisposed host. Numerous therapeutic interventions related to antigen and cytokine specific therapies have demonstrated effectiveness in experimental autoimmune encephalomyelitis (EAE), the animal model used to define principles underlying immune‐mediated mechanisms in MS. Despite the similarities in the two diseases, most treatments used to ameliorate EAE have failed to translate to the human disease. As directly demonstrated in animal models and implicated by correlative studies in humans, adaptive and innate immune constituents within the systemic compartment and resident in the CNS contribute to the disease course of neurodegenerative and neurobehavioral disorders. The expanding knowledge of the molecular properties of glial cells provides increasing insights into species related variables. These variables affect glial bidirectional interactions with the immune system as well as their own production of “immune molecules” that mediate tissue injury and repair.

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“…efficacy in some immune-mediated disease, CTLA4-Ig failed to show clinical benefit for the treatment of recent-onset type one diabetes (8), lupus nephritis (9), and relapsing-remitting multiple sclerosis (RRMS) (10). The reasons for these divergent results are currently unclear and warrant further interrogation of abatacept's mode of action.…”

mentioning

confidence: 99%

Abatacept Targets T Follicular Helper and Regulatory T Cells, Disrupting Molecular Pathways That Regulate Their Proliferation and Maintenance

Glatigny

Höllbacher²,

Motley³

et al. 2019

The Journal of Immunology

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Abatacept is a CTLA-4-Ig fusion protein that binds to the costimulatory ligands CD80 and CD86 and blocks their interaction with the CD28 and CTLA-4 receptors expressed by T cells, therefore inhibiting T cell activation and function. Abatacept has shown clinical efficacy in treating some autoimmune diseases but has failed to show clinical benefit in other autoimmune conditions. The reasons for these disparate results are not clear and warrant further investigation of abatacept’s mode of action. Longitudinal specimens from the Immune Tolerance Network's A Cooperative Clinical Study of Abatacept in Multiple Sclerosis trial were used to examine the effects of abatacept treatment on the frequency and transcriptional profile of specific T cell populations in peripheral blood. We found that the relative abundance of CD4+ T follicular helper (Tfh) cells and regulatory T cells was selectively decreased in participants following abatacept treatment. Within both cell types, abatacept reduced the proportion of activated cells expressing CD38 and ICOS and was associated with decreased expression of genes that regulate cell-cycle and chromatin dynamics during cell proliferation, thereby linking changes in costimulatory signaling to impaired activation, proliferation, and decreased abundance. All cellular and molecular changes were reversed following termination of abatacept treatment. These data expand upon the mechanism of action of abatacept reported in other autoimmune diseases and identify new transcriptional targets of CD28-mediated costimulatory signaling in human regulatory T and Tfh cells, further informing on its potential use in diseases associated with dysregulated Tfh activity.

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ACCLAIM: A randomized trial of abatacept (CTLA4-Ig) for relapsing-remitting multiple sclerosis

Cited by 48 publications

References 27 publications

Involvement of Immune Regulation in Multiple Sclerosis

Involvement of Immune Regulation in Multiple Sclerosis

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

Abatacept Targets T Follicular Helper and Regulatory T Cells, Disrupting Molecular Pathways That Regulate Their Proliferation and Maintenance

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