CD6 synergistic co-stimulation promoting proinflammatory response is modulated without interfering with the activated leucocyte cell adhesion molecule interaction

Abstract

SummaryThe CD6 membrane-proximal scavenger receptor cysteine-rich domain (SRCR3) includes the activated leucocyte cell adhesion molecule (ALCAM) binding site. CD6-ALCAM mediates a low-affinity interaction and their longterm engagement contributes to the immunological synapse. Their ligation may play a dual function, facilitating stable adhesion between the antigenpresenting cells and T cells during the early activation phase and later in the proliferative phase of the immune response. This study explored the strength of the CD6 co-stimulatory effect and whether CD6 co-stimulation with its natural ligand ALCAM also contributes to the lymphocyte effector differentiation. It was found that CD6-ALCAM interaction in vitro induced a synergistic co-stimulation of normal human peripheral blood mononuclear cells, defined by Bliss analysis. CD6 co-stimulation enhanced the CD3 proliferative efficacy by 23-34%. Moreover, a fivefold increment in the CD25 molecules number with a distinct gene transcription profile associated with cell activation, differentiation, survival and adhesion molecules was observed over CD3 single activation. Additionally, CD6 co-stimulation in excess interleukin (IL)-2 promotes a preferentially proinflammatory response. Besides, a CD6 membrane-distal domain (SRCR1)-specific non-depleting monoclonal antibody (mAb) inhibited the induced proliferation in the presence of ALCAM, reducing interferon-g, IL-6 and tumour necrosis factor-a production. These results suggest that CD6 co-stimulation enhances the intrinsic activity of the CD3 activation pathway and contributes to the T helper type 1 subset commitment, enhancing the IL-2 sensitivity of recent activated human lymphocytes. It supports the role of CD6 as a susceptibility gene for pathological autoimmunity leading to tissue inflammation, and its relevance for targeted therapy.

Immunological and histological evaluation of clinical samples from psoriasis patients treated with anti-CD6 itolizumab

“…When these cells were treated with itolizumab, a decrease in the transcription of these genes was observed. 28 In our study, itolizumab treatment reduced T cell proliferation capacity and decreased frequency of IFN-γ-secreting T cells in patients treated with the two schemes, indicating the modulation of the CD6-mediated activation of T cells. This is the first evidence of the action of this antibody on cells from treated patients.…”

“…27 In experiments in vitro with peripheral blood mononuclear cells (PBMC) from healthy donors, itolizumab inhibited proliferation in the presence of soluble ALCAM and IL-2; downregulated the phosphorylation of intracellular proteins involved in the CD6-mediated activation pathway; and reduced IFN-γ, IL-6 and TNF production. 28 The mouse version of this antibody was effective in reducing CD6+ T cell infiltration in the epidermis and dermis of psoriasis patients, thus showing its potential not only in symptom control, but also in the modification of pathogenic elements of the disease. 29 Itolizumab registration is currently in process.…”

Antibody-based therapeutics to watch in 2011

“…CD6 is a co-stimulatory receptor on T cells and T1h binds in the membrane-distal domain (SRCR1) of its target. 24 Phase 2 studies have or are, evaluating T1h in combination with methotrexate as a treatment for active rheumatoid arthritis and T1h as a single agent in active moderate-to-severe psoriasis. In a dose-finding, single-blind, randomized Phase 2 study, 40 patients with moderate-to-severe psoriasis were administered three different IV doses of T1h once a week, biweekly or every four weeks for eight weeks.…”

Immunological evaluation of rheumatoid arthritis patients treated with itolizumab

“…33 In experiments in vitro with peripheral blood mononuclear cells (PBMC) from healthy donors, itolizumab reduced IFN-g, IL-6 and TNF production. 34 Recently, we found a significant decrease in T cell proliferation and reduction in circulating proinflammatory cytokine levels in psoriasis patients treated with itolizumab. 35 For the study presented here, clinical samples taken from 30 RA patients participating in a clinical trial to evaluate the safety and efficacy of itolizumab in combination with MTX were analyzed for lymphocyte counts and cytokine levels.…”