Usefulness of daily folic acid supplementation during methotrexate treatment of Japanese patients with rheumatoid arthritis.

OBJECTIVES: We investigated the effect of daily folic acid supplementation on methotrexate (MTX) toxicity and efficacy in Japanese patients with rheumatoid arthritis (RA). METHODS: We followed 19 patients treated with MTX who switched from taking weekly 5 mg folic acid supplementation (weekly regimen) to 1.25 mg daily (daily regimen). White blood cell (WBC) and platelet (PLT) counts, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels were collected for 24 weeks following the change. RESULTS: We observed no significant changes in WBC or PLT counts. AST and ALT levels, which had exceeded the upper limits of their normal ranges at the beginning of the study, were improved significantly at weeks 4 and 8, no subsequent deterioration in liver function was found. Further, no significant changes in ESR and CRP levels were observed. CONCLUSION: Our data indicate that supplementing 1.25 mg of folic acid daily rather than 5 mg weekly reduces toxicity caused by MTX without affecting its efficacy.

CD5-NK1.1+ γδ T Cells that Develop in a Bcl11b-Independent Manner Participate in Early Protection against Infection.

We recently found that a unique subset of innate-like γδ T cells develops from the DN2a stage of the fetal thymus independently of the zinc-finger transcription factor B cell leukemia/lymphoma 11b (Bcl11b). Herein, we characterize these Bcl11b-independent γδ T cells in the periphery as CD5-NK1.1+ and Granzyme B+, and we show that they are capable of producing interferon (IFN)-γ upon T cell receptor stimulation without Ca2+ influx. In wild-type mice, these cells were sparse in lymphoid tissues but abundant in non-lymphoid tissues, such as the liver. Bcl11b-independent CD5-NK1.1+ γδ T cells appeared and contributed to early protection before Bcl11b-dependent CD5+NK1.1- γδ T cells following Listeria monocytogenes infection, resembling their sequential appearance during development in the thymus.

Two Types of Interleukin 17A-Producing γδ T Cells in Protection Against Pulmonary Infection With Klebsiella pneumoniae.

BACKGROUND: Klebsiella pneumoniae frequently causes life-threatening infection in children. Interleukin 17A (IL-17A) is known to be involved in protection against K. pneumoniae infection through activation of neutrophils. METHODS AND RESULTS: We found that IL-17A-producing γδ T cells existed more frequently in younger mice on examination of IL-17A-producing lymphocytes in the lung of naive mice at various ages. We hence compared the protective role of IL-17A-producing γδ T cells against pulmonary K. pneumoniae infection in young (3 weeks old) and adult (8-12 weeks old) mice. IL-17A-deficient mice were susceptible to K. pneumonia regardless of age. Cγ-, Vγ4/6-, or Vδ1-deficient mice were susceptible to K. pneumonia at young age, while interleukin 23p19 (IL-23p19)-deficient mice were susceptible at adult age. IL-17A-producing Vγ1-Vγ4- γδ T cells expressing canonical Vγ6/Vδ1 genes were dominant over IL-17A-producing Vγ4+ γδ T cells in the lungs of young mice after infection. The IL-17A-producing Vγ1-Vγ4- γδ T cells expressed an activation marker, CD69, and proliferated in an IL-23-independent manner, while the IL-17A-producing Vγ4+ γδ T cells expressing IL-23 receptor but no CD69 proliferated in IL-23-dependent manner. CONCLUSIONS: These results suggest that 2 types of IL-17A-producing γδ T cells are activated for host defense against K. pneumoniae infection by IL-23-dependent or independent mechanism.

IL-21 inhibits IL-17A-producing γδ T-cell response after infection with Bacillus Calmette-Guérin via induction of apoptosis.

Innate γδ T cells expressing Vγ6 produce IL-17A at an early stage following infection with Mycobacterium bovis Bacillus Calmette-Guérin (BCG). In this study, we used IL-21 receptor knockout (IL-21R KO) mice and IL-21-producing recombinant BCG mice (rBCG-Ag85B-IL-21) to examine the role of IL-21 in the regulation of IL-17A-producing innate γδ T-cell response following BCG infection. IL-17A-producing Vγ6+ γδ T cells increased in the peritoneal cavity of IL-21R KO mice more than in wild type mice after BCG infection. In contrast, the number of IL-17A-producing Vγ6+ γδ T cells was significantly lower after inoculation with rBCG-Ag85B-IL-21 compared with control rBCG-Ag85B. Notably, exogenous IL-21 selectively induced apoptosis of IL-17A-producing Vγ6+ γδ T cells via Bim. Thus, these results suggest that IL-21 acts as a potent inhibitor of a IL-17A-producing γδ T-cell subset during BCG infection.