Co-stimulatory modulation in rheumatoid arthritis: The role of (CTLA4-Ig) abatacept

Fiocco, Ugo; Sfriso, Paolo; Oliviero, Francesca; Pagnin, Elisa; Scagliori, Elena; Campana, Carla; Dainese, Serena; Cozzi, L.; Punzi, Leonardo

doi:10.1016/j.autrev.2008.07.035

Cited by 65 publications

(37 citation statements)

References 38 publications

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“…The expression patterns of HHLA2 and its putative counter receptor coupled with its coinhibitory function suggest that this pathway may be a potent regulator of human immune responses at both the very early and late stages. In the clinic, CTLA-4-Ig fusion proteins (Abatacept and Belatacept) inhibit T-cell functions and have already been used to treat adult rheumatoid arthritis and to prevent acute kidney transplant rejection (43,44), respectively. A mAb that blocks CTLA-4 functions (Ipilimumab) was recently approved for treatment of metastatic melanoma (45,46).…”

Section: Discussionmentioning

confidence: 99%

HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function

Zhao

Chinai²,

Buhl

et al. 2013

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

169

287

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T-cell costimulation and coinhibition generated by engagement of the B7 family and their receptor CD28 family are of central importance in regulating the T-cell response, making these pathways very attractive therapeutic targets. Here we describe HERV-H LTRassociating protein 2 (HHLA2) as a member of the B7 family that shares 10-18% amino acid identity and 23-33% similarity to other human B7 proteins and phylogenetically forms a subfamily with B7x and B7-H3 within the family. HHLA2 is expressed in humans but not in mice, which is unique within the B7 and CD28 families. HHLA2 protein is constitutively expressed on the surface of human monocytes and is induced on B cells after stimulation with LPS and IFN-γ. HHLA2 does not interact with other known members of the CD28 family or the B7 family, but does bind a putative receptor that is constitutively expressed not only on resting and activated CD4 and CD8 T cells but also on antigen-presenting cells. HHLA2 inhibits proliferation of both CD4 and CD8 T cells in the presence of T-cell receptor signaling. In addition, HHLA2 significantly reduces cytokine production by T cells including IFN-γ, TNF-α, IL-5, IL-10, IL-13, IL-17A, and IL-22. Thus, we have identified a unique B7 pathway that is able to inhibit human CD4 and CD8 T-cell proliferation and cytokine production. This unique human T-cell coinhibitory pathway may afford unique strategies for the treatment of human cancers, autoimmune disorders, infection, and transplant rejection and may help to design better vaccines. Interactions between members of the B7 ligand and CD28 receptor families generate positive costimulation and negative coinhibition, which are of central importance in regulating T-cell responses (1-3). B7-1/B7-2/CD28/CTLA-4 is the most extensively characterized of these pathways. Ligands B7-1 (CD80) and B7-2 (CD86) on antigen-presenting cells (APCs) bind to CD28 on naïve T cells and provide a major costimulatory signal to activate naïve T cells. After the initial activation, coinhibitory molecule cytotoxic T lymphocyte antigen-4 (CTLA-4, CD152) is induced on T cells and engages the same B7-1 and B7-2 ligands to restrain T-cell function. In contrast to the costimulatory activity of CD28, the interaction of B7-1 or B7-2 with CTLA-4 is essential for limiting the proliferative response of recently activated T cells to antigen and CD28-mediated costimulation.During the past decade, several new pathways in the B7 and CD28 families have been identified, including B7h/ICOS, PD-L1/PD-L2/PD-1, B7-H3/receptor, and B7x/receptor. B7h (4) (also called ICOS-L, B7RP-1 (5), GL50 (6), B7H2 (7), LCOS (8), and CD275) binds to the inducible costimulator (ICOS, CD278) on activated T cells (9), which induces strong phosphatidylinositol 3-kinase activity (10, 11) and leads to the expression of transcription factors involved in follicular helper CD4 T (Tfh) differentiation (12). Therefore, the B7h/ICOS pathway provides critical T-cell help to B cells. Deficiencies in this pathway result in substantially reduced numbers of mem...

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Section: Discussionmentioning

confidence: 99%

HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function

Zhao

Chinai²,

Buhl

et al. 2013

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

169

287

View full text Add to dashboard Cite

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“…Synthetic peptides to competitively block autoantigen presentation [46][47][48][49][50]; the administration of a recombinant human fusion protein of cytotoxic lymphocyte antigen 4 to dampen immunocyte activation [51][52][53][54]; monoclonal antibodies [55][56][57] and recombinant molecules [58][59][60] to counter-regulate cytotoxic cytokine pathways; vaccination programs to eliminate or inhibit clones of cytotoxic T lymphocytes [61,62]; oral tolerance regimens to suppress or ablate detrimental cytokine expressions [63,64]; and gene silencing techniques to suppress the production of deleterious gene products [65][66][67][68][69] have already been used successfully in animal models and patients with various liver and non-liver immune-mediated diseases. These efforts reflect the common desire for a more effective, safe, and durable treatment than currently available for the autoimmune diseases.…”

Section: Precedents For Targeted Site-specific Therapies In Autoimmunmentioning

confidence: 99%

“…CTLA-4 is a homologue of the CD28 molecule, and its binding with the B7 ligands on the surface of the APC naturally dampens immunocyte activation by attenuating the ligation of the B7 glycoproteins with the CD28 [52,54], mismatched marrow transplants [51], multiple sclerosis [115] High; soluble fusion molecule available [108,113]; approved by FDA for rheumatoid arthritis [113] Anti-TNF-a Impair cytotoxic type 1 cytokine pathway Effective in Crohn disease [56], rheumatoid arthritis [141,142] Low; diverse serious toxicities [147][148][149][150][151] Multiple preparations [152] Recombinant IL-10…”

Section: Co-stimulatory Signaling Pathways For Immunocyte Activationmentioning

confidence: 99%

“…Fusion of CTLA-4 with immunoglobulin creates a dimeric recombinant human fusion protein (CTLA-4Ig) which is soluble and can be used to abrogate or attenuate ongoing inflammatory and immunemediated processes [52,53,112]. Soluble CTLA-4Ig (abatacept) has already been used successfully in animal models [52,107,112] and patients with rheumatoid arthritis [53,54,113], patients with juvenile idiopathic arthritis [114], individuals with mismatched bone marrow transplantations [51], and patients with multiple sclerosis [115]. Abatacept was approved by the Food and Drug Administration of the United States in 2006 [113] and the European Medicines Agency in 2007 [108] for treatment of rheumatoid arthritis.…”

Section: Co-stimulatory Signaling Pathways For Immunocyte Activationmentioning

confidence: 99%

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Emerging Opportunities for Site-Specific Molecular and Cellular Interventions in Autoimmune Hepatitis

Czaja

2010

Dig Dis Sci

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Current corticosteroid-based treatments of autoimmune hepatitis frequently have incomplete or unsatisfactory outcomes, side effects, and excessive immune suppression. The goal of this review is to describe the advances in developing animal models of autoimmune hepatitis and in treating diverse immune-mediated diseases that make pursuit of site-specific molecular and cellular inventions in autoimmune hepatitis feasible. Prime source and review articles in English were selected by a Medline search through October 2009. A murine model infected with an adenovirus expressing human CYP2D6 is a resource for evaluating new therapies because of its histological and serological features, persistence, and progressive hepatic fibrosis. Synthetic analog peptides that block autoantigen expression, a dimeric recombinant human fusion protein of cytotoxic T lymphocyte antigen-4, monoclonal antibodies against tumor necrosis factor-alpha, recombinant interleukin 10, tolerization techniques for disease-triggering autoantigens, T regulatory cell transfer, vaccination against antigen-specific cytotoxic CD8+ T cells, and gene silencing methods using small inhibitory RNAs are feasible interventions to explore. Treatments directed at dampening immunocyte activation with soluble cytotoxic T lymphocyte antigen-4, inhibiting immunocyte differentiation with recombinant interleukin 10, and improving immunosuppressive activity with regulatory T cell modulation have the most immediate promise. Progress in the development of an animal model of autoimmune hepatitis and experiences in other immune-mediated diseases justify the evaluation of site-specific molecular and cellular interventions in this disease.

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“…[10][11][12] Three anti-TNF drugs are available for clinical use: infliximab (chimerical anti-TNF monoclonal antibody -human/murine) 13 , etanercept (fusion protein composed by the TNF soluble receptor region Fc of the IgC) 14 and adalimumab (human antibody against TNF). 15 Other biological therapies being used include the IL-1 receptor antagonist (anakinra) 16 , anti-lymphocytes B -anti-CD20 antibodies (rituximab) [17][18][19] , inhibitors of costimulatory molecules, as CTLA4-IgG fusion proteins (abatacept) [20][21][22] and anticytokines, as the interleukin-6 soluble antireceptor antibody (tocilizumab). [23][24][25] All the biological agents are effective in controlling articular manifestation and hindering the disease's radiological progression, although there may be a therapeutic failure, especially with continuous treatment, in as much as 30 to 40% of the patients.…”

Section: Introductionmentioning

confidence: 99%

Princípios gerais do tratamento da artrite reumatoide inicial

Mota¹,

Laurindo²,

Neto³

2010

Rev. Assoc. Med. Bras.

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Co-stimulatory modulation in rheumatoid arthritis: The role of (CTLA4-Ig) abatacept

Cited by 65 publications

References 38 publications

HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function

HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function

Emerging Opportunities for Site-Specific Molecular and Cellular Interventions in Autoimmune Hepatitis

Princípios gerais do tratamento da artrite reumatoide inicial

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