Treatment of Recalcitrant Plaque Psoriasis with a Humanized Non-depleting Antibody to CD4

Bachelez, Hervé; Flageul, B.; Dubertret, Louis; Fraïtag, Sylvie; Grossman, Rachel; Brousse, Nicole; Poisson, Dominique; Knowles, Robert W.; Wacholtz, Mary C.; Haverty, Thomas P.; Chatenoud, Lucienne; Bach, Jean‐François

doi:10.1006/jaut.1997.0175

Cited by 59 publications

(27 citation statements)

References 32 publications

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“…The changes in lesional T-cell numbers correlated with reductions in epidermal proliferation, epidermal thickness, reversion of keratinocyte maturational abnormalities, and clinical improvement of psoriasis. The highly selective nature of this therapeutic intervention supports prior findings and suggests that activated T cells, and the cytokines that they elaborate, are the prime effectors in the pathogenesis of psoriasis (2)(3)(4)(5)(6)(7)(8).…”

Section: Discussionsupporting

confidence: 75%

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris

et al. 1999

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Psoriasis is a multifactorial disease of uncertain etiology that affects approximately 2% of the population (1). Psoriatic lesions are characterized by a clinical triad consisting of skin induration, scaling, and erythema. The histologic correlates of these clinical findings include inflammation, abnormal keratinocyte proliferation/terminal differentiation, and dermal angiogenesis. The inflammatory infiltrate, particularly pronounced at the dermal-epidermal junction, consists largely of activated T cells and antigen-presenting cells (APCs) and precedes the development of epidermal hyperproliferation (2). Increased levels of inflammatory cytokines have been detected in lesional psoriatic epidermis, which may result in the potentiation of T-cell activation (3) as well as hyperproliferation and accelerated differentiation of keratinocytes (4, 5). These and other data derived from T cell-based therapeutics (6-8) suggest that activated T cells play an important role in triggering and perpetuating the disease. Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage φX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.

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Section: Discussionsupporting

confidence: 75%

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris

et al. 1999

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“…In Belgian trial centres flow cytometry was used to quantify peripheral lymphocyte subsets. [12] Statistical analysis Data were stored at the Belgian Diabetes Registry and analysed by a statistician (L. Kaufman) who was not a member of the trial team. The extension study followed all variables that had been predefined for the 18 month study [5].…”

Section: Methodsmentioning

confidence: 99%

Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass

et al. 2010

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Aims/hypothesis The aim of the study was to examine the 48 month outcome of treating recent-onset type 1 diabetic patients for 6 days with humanised CD3-antibody, ChAglyCD3. Methods Eighty patients, aged 12-39 years, were recruited for a phase 2 multicentre trial and randomised to placebo (n=40) or ChAglyCD3 (n=40) treatment by a third party member; participants and care-givers were blinded. The change in insulin dose (U kg −1 day −1 ) over 48 months was chosen as primary endpoint and compared in 31 placeboand 33 ChAglyCD3-treated patients. Adverse events were followed in 35 and 38 patients, respectively. Results Treatment with ChAglyCD3 delayed the rise in insulin requirements of patients with recent-onset diabetes and reduced its amplitude over 48 months (+0.09 vs +0.32 U kg −1 day −1 in the placebo group). Using multivariate analysis this effect was correlated with higher baseline residual beta cell function and a younger age. It was associated with better outcome variables in subgroups selected according to these variables. In the ChAglyCD3 subgroup with higher initial beta cell function, 0/11 patients became C-peptide-negative over 48 months vs 4/9 in the corresponding placebo subgroup. In the subgroup aged <27 years old, antibody treatment preserved initial beta cell function for 36 months (vs >80% decline within 24 months in the placebo subgroup <27 years old), resulted in lower HbA 1c concentrations and tended to reduce glycaemic variability (p=0.08). No longterm adverse events were observed. Conclusions/interpretation A 6 day ChAglyCD3 treatment can suppress the rise in insulin requirements of recent-onset type 1 diabetic patients over 48 months, depending on their age and initial residual beta cell function. In younger patients this effect is associated with reduced deterioration of metabolic variables. These observations help to define inclusion criteria for prevention trials.

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“…The rheumatoid synovium has increased levels of CD4 ϩ T cells, which are hypothesized to both initiate and perpetuate the deleterious effects of inflammatory cells (15)(16)(17)(18). Similarly the dermal lesions of psoriasis are dominated by cell infiltrates of activated CD4 ϩ T cells (19,20). Furthermore, injection of CD4 ϩ T cells in a SCID mouse engrafted with symptomless psoriatic skin induced psoriatic plaques (21).…”

Section: Introductionmentioning

confidence: 99%

Modification of the Fc Region of a Primatized IgG Antibody to Human CD4 Retains Its Ability to Modulate CD4 Receptors but Does Not Deplete CD4+ T Cells in Chimpanzees

Newman¹,

Hariharan²,

Reff³

et al. 2001

Clinical Immunology

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Treatment of Recalcitrant Plaque Psoriasis with a Humanized Non-depleting Antibody to CD4

Cited by 59 publications

References 32 publications

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris

Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass

Modification of the Fc Region of a Primatized IgG Antibody to Human CD4 Retains Its Ability to Modulate CD4 Receptors but Does Not Deplete CD4+ T Cells in Chimpanzees

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