Yasuhiko Kita

Common T cell receptor clonotype in lacrimal glands and labial salivary glands from patients with Sjögren's syndrome.

Sjogrens syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration into lacrimal and salivary glands leading to symptomatic dry eyes and mouth. Immunohistological studies have clarified that the majority of infiltrating lymphocytes around the lacrimal glands and labial salivary glands are CD4 positive alphabeta T cells. To analyze the pathogenesis of T cells infiltrating into lacrimal and labial salivary glands, we examined T cell clonotype of these cells in both glands from four SS patients using PCR-single-strand conformation polymorphism (SSCP) and a sequencing method. SSCP analysis showed that some infiltrating T cells in both glands expand clonally, suggesting that the cells proliferate by antigen-driven stimulation. Intriguingly, six to sixteen identical T cell receptor (TCR) Vbeta genes were commonly found in lacrimal glands and labial salivary glands from individual patients. This indicates that some T cells infiltrating into both glands recognize the shared epitopes on autoantigens. Moreover, highly conserved amino acid sequence motifs were found in the TCR CDR3 region bearing the same TCR Vbeta family gene from four SS patients, supporting the notion that the shared epitopes on antigens are limited. In conclusion, these findings suggest that some autoreactive T cells infiltrating into the lips and eyes recognized restricted epitopes of a common autoantigen in patients with SS.

The first double-blind, randomised, parallel-group certolizumab pegol study in methotrexate-naive early rheumatoid arthritis patients with poor prognostic factors, C-OPERA, shows inhibition of radiographic progression

Objectives To evaluate efficacy and safety of combination therapy using certolizumab pegol (CZP) and methotrexate (MTX) as first-line treatment for MTX-naive, early rheumatoid arthritis (RA) with poor prognostic factors, compared with MTX alone. Methods MTX-naive, early RA patients with ≤12 months persistent disease, high anti-cyclic citrullinated peptide, and either rheumatoid factor positive and/or presence of bone erosions were enrolled in this multicentre, double-blind, randomised placebo (PBO)-controlled study. Patients were randomised 1:1 to CZP+MTX or PBO+MTX for 52 weeks. Primary endpoint was inhibition of radiographic progression (change from baseline in modified Total Sharp Score (mTSS CFB)) at week 52. Secondary endpoints were mTSS CFB at week 24, and clinical remission rates at weeks 24 and 52. Results 316 patients randomised to CZP+MTX (n=159) or PBO+MTX (n=157) had comparable baseline characteristics reflecting features of early RA (mean disease duration: 4.0 vs 4.3 months; Disease Activity Score 28-joint assessment (DAS28)) (erythrocyte sedimentation rate (ESR)): 5.4 vs 5.5; mTSS: 5.2 vs 6.0). CZP+MTX group showed significantly greater inhibition of radiographic progression relative to PBO+MTX at week 52 (mTSS CFB=0.36 vs 1.58; p<0.001) and week 24 (mTSS CFB=0.26 vs 0.86; p=0.003). Clinical remission rates (Simple Disease Activity Index, Boolean and DAS28 (ESR)) of the CZP+MTX group were significantly higher compared with those of the PBO+MTX group, at weeks 24 and 52. Safety results in both groups were similar, with no new safety signals observed with addition of CZP to MTX. Conclusions In MTX-naive early RA patients with poor prognostic factors, CZP+MTX significantly inhibited structural damage and reduced RA signs and symptoms, demonstrating the efficacy of CZP in these patients. Trial registration number (NCT01451203).

Characteristics of T-cell receptor Vα24JαQ T cells, a human counterpart of murine NK1 + T cells, from normal subjects

Abstract Background: In mice, natural killer (NK) T cells are specialized subsets of T cells that express an invariate T cell receptor (TCR) α chain and NK markers. In particular, murine NK1 ± T cells rapidly produce IL-4 and function as regulatory T cells. Objective: We investigated the distribution of invariate TCR Vα24JαQ T cells in CD4 – CD8 – double-negative (DN) and CD4 + T cell populations of healthy individuals. We also studied the NK phenotypes and IL-4 production of Vα24JαQ T cells. Methods: The frequency of Vα24 ± DN or CD4 ± T cells was determined by three-color FACS analysis, and subsequently the frequency of Vα24JαQ rearrangement among Vα24 ± DN or CD4 ± T cells was determined by sequencing. Results: While the majority of DN Vα24 + T cells (68% to 88%) possessed TCR Vα24JαQ, few of CD4 + Vα24 + T cells (0.4% to 4%) did, indicating that Vα24JαQ T cells are a major population of DN T cells, but not of CD4 + T cells, in healthy subjects. The DN Vα24JαQ T cells expressed a natural killer surface receptor NKR-P1A and CD56, but not CD16, on the cell surface. Moreover, DN Vα24JαQ T cells promptly expressed IL-4 mRNA by stimulation with anti-Vα24 monoclonal antibody in vitro. Conclusion: From these phenotypic and functional similarities of human DN Vα24JαQ T cells with murine NK1 + Vα14Jα281 T cells, we conclude that DN Vα24JαQ T cells are a counterpart of murine NK1 + T cells, suggesting that they may play a regulatory role in autoimmune responses in vivo. (J Allergy Clin Immunol 1999;103:S445-51.)

Clinical benefit of 1-year certolizumab pegol (CZP) add-on therapy to methotrexate treatment in patients with early rheumatoid arthritis was observed following CZP discontinuation: 2-year results of the C-OPERA study, a phase III randomised trial

Objectives To investigate the clinical impact of 1-year certolizumab pegol (CZP) therapy added to the first year of 2-year methotrexate (MTX) therapy, compared with 2-year therapy with MTX alone. Methods MTX-naïve patients with early rheumatoid arthritis (RA) with poor prognostic factors were eligible to enter Certolizumab-Optimal Prevention of joint damage for Early RA (C-OPERA), a multicentre, randomised, controlled study, which consisted of a 52-week double-blind (DB) period and subsequent 52-week post treatment (PT) period. Patients were randomised to optimised MTX+CZP (n=159) or optimised MTX+placebo (PBO; n=157). Following the DB period, patients entered the PT period, receiving MTX alone (CZP+MTX→MTX; n=108, PBO+MTX→MTX; n=71). Patients who flared could receive rescue treatment with open-label CZP. Results 34 CZP+MTX→MTX patients and 14 PBO+MTX→MTX patients discontinued during the PT period. From week 52 through week 104, significant inhibition of total modified total Sharp score progression was observed for CZP+MTX versus PBO+MTX (week 104: 84.2% vs 67.5% (p<0.001)). Remission rates decreased after CZP discontinuation; however, higher rates were maintained through week 104 in CZP+MTX→MTX versus PBO+MTX→MTX (41.5% vs 29.3% (p=0.026), 34.6% vs 24.2% (p=0.049) and 41.5% vs 33.1% (p=0.132) at week 104 in SDAI, Boolean and DAS28(erythrocyte sedimentation rate) remission. CZP retreated patients due to flare (n=28) showed rapid clinical improvement. The incidence of overall adverse events was similar between groups. Conclusions In MTX-naïve patients with early RA with poor prognostic factors, an initial 1 year of add-on CZP to 2-year optimised MTX therapy brings radiographic and clinical benefit through 2 years, even after stopping CZP. Trial registration number NCT01451203.