Efalizumab

Talamonti, Mark S.; Spallone, Giulia; Stefani, Alessandro; Costanzo, Antonio; Chimenti, Sergio

doi:10.1517/14740338.2011.524925

Cited by 46 publications

(37 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…On day 7 after transfer or as indicated, recipient mice were analyzed for IL-17 production in CFSE labeled Tregs (n $ 3 per mouse line and per time point expression levels and the enhanced conversion of Tregs into Th17 cells enhancing the psoriasiform phenotype in CD18 hypo PL/J mice. Although a complete block of CD11a/CD18 (LFA-1), previously also used therapeutically by anti-psoriatic drugs such as the Ab efalizumab (34), primarily affects migration of autoreactive lymphocytes into the skin and may lead to symptoms of immunodeficiency comparable to human leukocyte adhesion deficiency as a consequence of decreased T cell activation, suboptimal CD18 function, and impaired interaction with its ICAM ligands on DCs-that is, mimicked in the CD18 hypo PL/J mouse model and potentially also occurs in psoriasis patients as a consequence of altered ICAM and or CD18 expression (17,35)results in the Treg dysfunction described in this study and in autoimmunity such as psoriasiform skin disease in mice. Notably, apart from sporadic cases of progressive multifocal leukoencephalopathy, severe relapses of pustular psoriasis were reported in patients treated with efazilumab (34), possibly indicating that under nonsaturating efazilumab conditions, activated Teffs rush into the skin, whereas Tregs may be still suppressed or may not have functionally recovered from efazilumab treatment yet.…”

Section: Discussionmentioning

confidence: 99%

Reduced CD18 Levels Drive Regulatory T Cell Conversion into Th17 Cells in the CD18hypo PL/J Mouse Model of Psoriasis

Singh

Gatzka

Peters

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Defective development and function of CD4+CD25high+Foxp3+ regulatory T cells (Tregs) contribute to the pathogenesis of psoriasis and other autoimmune diseases. Little is known about the influence of adhesions molecules on the differentiation of Foxp3+ Tregs into proinflammatory Th17 cells occurring in lesional skin and blood of psoriasis patients. In the CD18hypo PL/J mouse model of psoriasis, reduced expression of CD18/β2 integrin to 2–16% of wild-type levels is associated with progressive loss of Tregs, impaired cell–cell contact between Tregs and dendritic cells (DCs), as well as Treg dysfunction as reported earlier. In the present investigation, Tregs derived from CD18hypo PL/J mice were analyzed for their propensity to differentiate into IL-17–producing Th17 cells in vivo and in in vitro Treg–DC cocultures. Adoptively transferred CD18hypo PL/J Tregs were more inclined toward conversion into IL-17–producing Th17 cells in vivo in an inflammatory as well as noninflammatory environment compared with CD18wt PL/J Tregs. Addition of neutralizing Ab against CD18 to Treg–DC cocultures in vitro promoted conversion of CD18wt PL/J Tregs to Th17 cells in a dose-dependent manner similar to conversion rates of CD18hypo PL/J Tregs. Reduced thymic output of naturally occurring Tregs and peripheral conversion of Tregs into Th17 cells therefore both contribute to the loss of Tregs and the psoriasiform dermatitis observed in CD18hypo PL/J mice. Our data overall indicate that CD18 expression levels impact Treg development as well as Treg plasticity and that differentiation of Tregs into IL-17–producing Th17 cells is distinctly facilitated by a subtotal deficiency of CD18.

show abstract

Section: Discussionmentioning

confidence: 99%

Reduced CD18 Levels Drive Regulatory T Cell Conversion into Th17 Cells in the CD18hypo PL/J Mouse Model of Psoriasis

Singh

Gatzka

Peters

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Proof of principle for therapeutic antiadhesive T-cell strategies in autoimmunity comes in the form of biologics that block T-cell adhesion and were initially approved for clinical use (39). Unfortunately, these agents cause increased risk for infection, leading to their market withdrawal (40).…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic-T-Lymphocyte Antigen 4 Receptor Signaling for Lymphocyte Adhesion Is Mediated by C3G and Rap1

Kloog

Mor

2014

Molecular and Cellular Biology

View full text Add to dashboard Cite

bT-lymphocyte adhesion plays a critical role in both inflammatory and autoimmune responses. The small GTPase Rap1 is the key coordinator mediating T-cell adhesion to endothelial cells, antigen-presenting cells, and virus-infected cells. We describe a signaling pathway, downstream of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor, leading to Rap1-mediated adhesion. We identified a role for the Rap1 guanine nucleotide exchange factor C3G in the regulation of T-cell adhesion and showed that this factor is required for both T-cell receptor (TCR)-mediated and CTLA-4-mediated T-cell adhesion. Our data indicated that C3G translocates to the plasma membrane downstream of TCR signaling, where it regulates activation of Rap1. We also showed that CTLA-4 receptor signaling mediates tyrosine phosphorylation in the C3G protein, and that this is required for augmented activation of Rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (LFA-1). Zap70 is required for C3G translocation to the plasma membrane, whereas the Src family member Hck facilitates C3G phosphorylation. These findings point to C3G and Hck as promising potential therapeutic targets for the treatment of T-cell-dependent autoimmune disorders.

show abstract

“…Another T cell modulating agent, efalizumab, that targets multiple stages of T cell activation by interacting with CD11a, has been voluntarily withdrawn from the US market because of the risk of PML [86,87]. The question whether alefacept that is also a T cells modulating agent will introduce a risk to HIV infected individuals for PML during treatment remains to be seen.…”

Section: Alefacept In Reducing Hiv Reservoir: Challengesmentioning

confidence: 99%

Can We Repurpose FDA-Approved Alefacept to Diminish the HIV Reservoir?

Zaidi¹,

Meng²

2016

Immunother Open Acc

View full text Add to dashboard Cite

Current anti-retroviral treatment (ART) for HIV is effective in maintaining HIV at undetectable levels. However, cessation of ART results in immediate and brisk rebound of viremia to high levels. This rebound is driven by an HIV reservoir mainly enriched in memory CD4 + T cells. In order to provide any form of functional HIV Cure, elimination of this viral reservoir has become the focus of current HIV cure strategies. Alefacept was initially developed for the treatment of chronic plaque psoriasis. Alefacept is a chimeric fusion protein consisting of the CD2-binding portion of human leukocyte function antigen-3 (LFA3) linked to the Fc region of human IgG1 (LFA3-Fc). Alefacept was designed to inhibit memory T cell activation that contributes to the chronic autoimmune disease psoriasis by blocking the CD2 coreceptor. However, it was found to deplete memory T cells that express high levels of CD2 via NK cellmediated antibody dependent cell cytotoxicity (ADCC) in vivo. Phase II and phase III clinical trials of alefacept with psoriasis patients demonstrated promising results and an excellent safety profile. Subsequently, alefacept has been successfully repurposed for other memory T cell-mediated autoimmune diseases including skin diseases other than psoriasis, organ transplantation and type I diabetes (T1D). Herein, we review our specific strategy to repurpose the FDA approved biologic alefacept to decrease and hopefully someday eliminate the HIV reservoir, for which CD2 hi memory CD4 + T cells are a significant contributor.

show abstract

Efalizumab

Abstract: Although initially favorable, the safety profile of efalizumab revealed the appearance of severe adverse events in long-term treated patients. Therefore, post-marketing surveillance is essential for correct evaluation of drug potential.

Cited by 46 publications

References 75 publications

Reduced CD18 Levels Drive Regulatory T Cell Conversion into Th17 Cells in the CD18hypo PL/J Mouse Model of Psoriasis

Reduced CD18 Levels Drive Regulatory T Cell Conversion into Th17 Cells in the CD18hypo PL/J Mouse Model of Psoriasis

Cytotoxic-T-Lymphocyte Antigen 4 Receptor Signaling for Lymphocyte Adhesion Is Mediated by C3G and Rap1

Can We Repurpose FDA-Approved Alefacept to Diminish the HIV Reservoir?

Contact Info

Product

Resources

About