krn-7000 and Arthritis--Rheumatoid

T cells reactive to lipids and restricted by major histocompatibility complex (MHC) class I-like molecules represent more than 15% of all lymphocytes in human blood. This heterogeneous population of innate cells includes the invariant natural killer T cells (iNK T), type II NK T cells, CD1a,b,c-restricted T cells and mucosal-associated invariant T (MAIT) cells. These populations are implicated in cancer, infection and autoimmunity. In this review, we focus on the role of these cells in autoimmunity. We summarize data obtained in humans and preclinical models of autoimmune diseases such as primary biliary cirrhosis, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, psoriasis and atherosclerosis. We also discuss the promise of NK T cell manipulations: restoration of function, specific activation, depletion and the relevance of these treatments to human autoimmune diseases.

Topics: Animals; Arthritis, Rheumatoid; Atherosclerosis; Autoimmunity; Clinical Trials, Phase I as Topic; Diabetes Mellitus, Type 1; Female; Galactosylceramides; Humans; Liver Cirrhosis, Biliary; Lupus Erythematosus, Systemic; Male; Mice; Multiple Sclerosis; Natural Killer T-Cells; Psoriasis

Topics: Adjuvants, Immunologic; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Autoimmune Diseases; Cytokines; Disease Models, Animal; Drug Evaluation, Preclinical; Galactosylceramides; Glycolipids; Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Neurokinin-1; T-Lymphocyte Subsets; Transforming Growth Factor beta; Transforming Growth Factor beta1

To investigate the role played by natural killer T (NKT) cells in osteoclastogenesis and their effects on inflammatory bone destruction.. Patients with rheumatoid arthritis (RA) (n = 25) and healthy controls (n = 12) were enrolled in this study. In vitro osteoclastogenesis experiments were performed using peripheral blood mononuclear cells (PBMCs) in the presence of macrophage colony-stimulating factor and RANKL. PBMCs were cultured in vitro with α-galactosylceramide (αGalCer), and proliferation indices of NKT cells were estimated by flow cytometry. In vivo effects of αGalCer-stimulated NKT cells on inflammation and bone destruction were determined in mice with collagen-induced arthritis.. In vitro osteoclastogenesis was found to be significantly inhibited by αGalCer in healthy controls but not in RA patients. Proliferative responses of NKT cells and STAT-1 phosphorylation in monocytes in response to αGalCer were impaired in RA patients. Notably, αGalCer-stimulated NKT cells inhibited osteoclastogenesis mainly via interferon-γ production in a cytokine-dependent manner (not by cell-cell contact) and down-regulated osteoclast-associated genes. Mice treated with αGalCer showed less severe arthritis and reduced bone destruction. Moreover, proinflammatory cytokine expression in arthritic joints was found to be reduced by αGalCer treatment.. This study primarily demonstrates that αGalCer-stimulated NKT cells have a regulatory effect on osteoclastogenesis and a protective effect against inflammatory bone destruction. However, it also shows that these effects of αGalCer are diminished in RA patients and that this is related to NKT cell dysfunction. These findings provide important information for those searching for novel therapeutic strategies to prevent bone destruction in RA.

Topics: Adult; Aged; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Case-Control Studies; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Female; Galactosylceramides; Humans; In Vitro Techniques; Interferon-gamma; Male; Mice; Mice, Inbred DBA; Middle Aged; Natural Killer T-Cells; Osteitis; Osteoclasts; Osteogenesis; Phosphorylation; STAT1 Transcription Factor

Mucosal-associated invariant T (MAIT) cells contribute to protection against certain microorganism infections and play an important role in mucosal immunity. However, the role of MAIT cells remains enigmatic in autoimmune diseases. In this study, we examined the level and function of MAIT cells in patients with rheumatic diseases. MAIT cell, cytokine, and programmed death-1 (PD-1) levels were measured by flow cytometry. Circulating MAIT cell levels were significantly reduced in systemic lupus erythematosus (SLE) and rheumatoid arthritis patients. In particular, this MAIT cell deficiency was more prominent in CD8(+) and double-negative T cell subsets, and significantly correlated with disease activity, such as SLE disease activity index and 28-joint disease activity score. Interestingly, MAIT cell frequency was significantly correlated with NKT cell frequency in SLE patients. IFN-γ production in MAIT cells was impaired in SLE patients, which was due to an intrinsic defect in the Ca(2+)/calcineurin/NFAT1 signaling pathway. In SLE patients, MAIT cells were poorly activated by α-galactosylceramide-stimulated NKT cells, thereby showing the dysfunction between MAIT cells and NKT cells. Notably, an elevated expression of PD-1 in MAIT cells and NKT cells was associated with SLE. In rheumatoid arthritis patients, MAIT cell levels were significantly higher in synovial fluid than in peripheral blood. Our study primarily demonstrates that MAIT cells are numerically and functionally deficient in SLE. In addition, we report a novel finding that this MAIT cell deficiency is associated with NKT cell deficiency and elevated PD-1 expression. These abnormalities possibly contribute to dysregulated mucosal immunity in SLE.

Topics: Active Transport, Cell Nucleus; Adult; Arthritis, Rheumatoid; Autoimmune Diseases; Calcineurin; Calcium Signaling; CD8-Positive T-Lymphocytes; Cytokines; Escherichia coli; Escherichia coli Infections; Female; Galactosylceramides; Humans; Immunity, Mucosal; Interferon-gamma; Lupus Erythematosus, Systemic; Lymphocyte Activation; Lymphocyte Count; Male; Middle Aged; Natural Killer T-Cells; NFATC Transcription Factors; Programmed Cell Death 1 Receptor; Synovial Fluid; T-Lymphocyte Subsets

Invariant NKT (iNKT) cells are a distinctive subtype of CD1d-restricted T cells involved in regulating autoimmunity and capable of producing various T helper type 1 (Th1), Th2 and Th17 cytokines. Activation of iNKT cells by their exogenous ligand alpha-galactosylceramide (alpha-GalCer) exerts therapeutic effects in autoimmune diseases such as rheumatoid arthritis (RA). However, the pathophysiological role of iNKT cells in RA, in the absence of exogenous stimulation, is incompletely understood. We investigated the potential pathophysiological effects of iNKT cells in mice with collagen-induced arthritis (CIA), a model of RA. We found that iNKT cells underwent activation only in the early phases of the disease (6 days post-induction). In the liver, but not the spleen or lymph nodes, this early activation led to the release of interleukins -4, -17A and -10 and of interferon-gamma; and an increased CD69 expression. Importantly, clinical and histological signs of arthritis were improved by the functional blockade of iNKT cells by a monoclonal antibody to CD1d at the early phase of the disease. This improvement was associated on day 6 post-induction with decreased expression of co-stimulatory molecules (CD80, CD86, CD40) on splenic dendritic cells and macrophages, whereas regulatory T-cell suppressive effects and proportions were not modified. Taken in concert, these findings suggest that iNKT cells are activated early in the course of CIA and contribute to the pathogenesis of arthritis. Therefore, iNKT-cell activation may be a valid treatment target in RA.

Topics: Animals; Antibodies, Monoclonal; Antigens, CD; Antigens, CD1d; Antigens, Differentiation, T-Lymphocyte; Arthritis, Experimental; Arthritis, Rheumatoid; Collagen; Cytokines; Galactosylceramides; Gene Expression Regulation; Humans; Lectins, C-Type; Lymphocyte Activation; Male; Mice; Mice, Inbred DBA; Natural Killer T-Cells; Th1 Cells; Th2 Cells; Time Factors

Data from rodent models indicate that invariant natural killer T (iNKT) cells are key regulators of many immune responses including autoimmune arthritis, but their role in human diseases is unclear. The aims of this study are to determine whether iNKT cell frequency and function are altered in patients with rheumatoid arthritis (RA), and the clinical significance of such iNKT cell abnormalities.. Peripheral blood iNKT cell frequency and proliferative response to an iNKT cell-specific agonist, α-galactosylceramide were measured in 46 RA patients (including 23 untreated, newly diagnosed patients), 22 healthy controls and 27 patients presenting with recent-onset joint pain. The relationship between iNKT cell frequency and clinical characteristics and the effects of immunosuppressive treatment was examined.. Compared with healthy controls, RA patients had a decreased frequency of peripheral blood iNKT cells (median 0.001% vs 0.021%, p<0.001) and the proliferative response of this subset to α-galactosylceramide was also diminished in the patient group (median fold-expansion 31 vs 121, p=0.037). These abnormalities preceded the initiation of disease-modifying or immunosuppressive therapy, whose effect was to increase the circulating iNKT cell frequency (p=0.037). Furthermore, iNKT cell frequency correlated inversely with the systemic inflammatory marker, C-reactive protein (p=0.008). Finally, in patients presenting with recent-onset joint symptoms, normal peripheral blood iNKT cell frequency predicted a non-inflammatory cause of joint pain.. iNKT cell deficiency is present in patients with RA and other inflammatory arthropathy. Normal iNKT cell frequency predicts non-inflammatory causes of joint pain.

Topics: Adult; Aged; Aged, 80 and over; Antirheumatic Agents; Arthralgia; Arthritis, Rheumatoid; C-Reactive Protein; Cell Proliferation; Cells, Cultured; Diagnosis, Differential; Female; Galactosylceramides; Humans; Immunosuppressive Agents; Lymphocyte Count; Male; Methotrexate; Middle Aged; Natural Killer T-Cells; Osteoarthritis; Young Adult

Invariant natural killer T (iNKT) cells are a unique lymphocyte subtype implicated in the regulation of autoimmunity and a good source of protective Th2 cytokines. Agonist alpha-galactosylceramide (alpha-GalCer) of iNKT cells exert a therapeutical effect in type 1 diabetes. We investigated whether iNKT activation with alpha-GalCer was protective in collagen-induced arthritis (CIA) in DBA/1 mice, a standard model of rheumatoid arthritis. Here, we have shown that in vivo iNKT cell function was altered in DBA/1 mice since stimulation with alpha-GalCer led to decreased IL-4 and IFN-gamma levels in sera, as compared with C57BL/6 mice. alpha-GalCer induced a clear-cut diminution of clinical and histological arthritides. An anti-IL-10 receptor antibody abrogated the protective effect of alpha-GalCer, suggesting a key role for IL-10 in the protection against CIA by activated iNKT cells. Confirming these data, disease protection conferred by alpha-GalCer correlated with the ability of LN CD4+ cells to secrete larger amounts of IL-10. These findings suggest that in CIA susceptibility to autoimmunity is associated with dysfunctions of iNKT cells. Our demonstration that iNKT cell activation by alpha-GalCer remains efficient in CIA-prone DBA/1 mice to provide protective IL-10 suggests that this could be used therapeutically to treat autoimmune arthritis.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Galactosylceramides; Genetic Predisposition to Disease; Interleukin-10; Killer Cells, Natural; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; T-Lymphocyte Subsets