Search

In experimental arthritis, glucocorticoid secretion is inadequate relative to inflammation. We hypothesized that IL-1 is a key factor for inadequate glucocorticoid secretion in arthritic rats. Collagen type II—induced arthritis (CIA) in DA rats was the model to study effects of IL-1 on adrenal function. In the CIA model, an increase of intraadrenal MHCII-positive cells was observed. MHCII-positive cells or bone marrow-derived dendritic cells inhibited glucocorticoid secretion of adrenal gland cells. IL-1, but also IL-18 and the inflammasome were critical in glucocorticoid inhibition. Arthritic compared to control adrenal gland cells produced higher amounts of CXC chemokines from MHCII+ adrenal cells, particularly CINC-2, which is strongly dependent on presence of IL-1. In CIA, macrophages and/or dendritic cells inhibit glucocorticoid secretion via IL-1 in adrenal glands. These findings show that activated macrophages and/or dendritic cells inhibit glucocorticoid secretion in experimental arthritis and that IL-1β is a decisive factor.

Objectives: The appearance of endogenous tyrosine hydroxylase-positive cells (TH+ cells) in collagen-induced arthritis was associated with an anti-inflammatory effect. Here we investigated putative anti-inflammatory and antinociceptive effects of the transfer of induced, bone marrow stem cell-derived TH+ cells (iTH+ cells) on murine antigen-induced arthritis (AIA). Methods: Bone marrow-derived stem cells were differentiated into iTH+ cells. These cells were transferred to mice immunized against methylated bovine serum albumin (mBSA) 2 days before AIA was induced by injection of mBSA into one knee joint. In AIA control mice and iTH+-treated mice the severity of AIA, pain-related behavior, humoral and cellular responses, and the invasion of macrophages into the dorsal root ganglia were assessed. Results: The intravenous transfer of iTH+ cells before AIA induction did not cause a sustained suppression of AIA severity but significantly reduced inflammation-evoked pain-related behavior. The iTH+ cells used for transfer exhibited enormous production of interleukin-4. A major difference between AIA control mice and iTH+-treated AIA mice was a massive invasion of the dorsal root ganglia by iNOS-negative, arginine 1-positive macrophages corresponding to an M2 phenotype. The differences in other cellular and humoral immune parameters such as release of cytokines from stimulated lymphocytes between AIA control mice and iTH+-treated mice were small. Conclusions: The transfer of iTH+ cells may cause a long-lasting reduction of arthritis-induced pain even if it does not ameliorate inflammation. The invasion of M2 macrophages into the dorsal root ganglia is likely to be an important mechanism of antinociception.

OBJECTIVE Patients with chronic inflammatory autoimmune diseases benefit from a broad spectrum of immunosuppressive and antiproliferative medication available today. However, nearly all of these therapeutic compounds have unwanted toxic side effects. Recent knowledge about the neurobiology of placebo responses indicates that associative learning procedures can be utilized for dose reduction in immunopharmacotherapy while simultaneously maintaining treatment efficacy. This study was undertaken to examine whether and to what extent a 75% reduction of pharmacologic medication in combination with learned immunosuppression affects the clinical outcome in a rodent model of type II collagen-induced arthritis. METHODS An established protocol of taste-immune conditioning was applied in a disease model of chronic inflammatory autoimmune disease (type II collagen-induced arthritis) in rats, where a novel taste (saccharin; conditioned stimulus [CS]) was paired with an injection of the immunosuppressive drug cyclosporin A (CSA) (unconditioned stimulus [US]). Following conditioning with 3 CS/US pairings (acquisition), the animals were immunized with type II collagen and Freund's incomplete adjuvant. Fourteen days later, at the first occurrence of clinical symptoms, retrieval was started by presenting the CS together with low-dose CSA as reminder cues to prevent the conditioned response from being extinguished. RESULTS This "memory-updating" procedure stabilized the learned immune response and significantly suppressed disease progression in immunized rats. Clinical arthritis score and histologic inflammatory symptoms (both P < 0.05) were significantly diminished by learned immunosuppression in combination with low-dose CSA (25% of the full therapeutic dose) via β-adrenoceptor-dependent mechanisms, to the same extent as with full-dose (100%) pharmacologic treatment. CONCLUSION These results indicate that learned immunosuppression appears to be mediated via β-adrenoceptors and might be beneficial as a supportive regimen in the treatment of chronic inflammatory autoimmune diseases by diminishing disease exacerbation.

Objectives In collagen type II-induced arthritis (CIA), early activation of the sympathetic nervous system (SNS) is proinflammatory. Here, we wanted to find new target organs contributing to proinflammatory SNS effects. In addition, we wanted to clarify the importance of SNS-modulated immunocyte migration. Methods A new technique termed spatial energy expenditure configuration (SEEC) was developed to demonstrate bodily areas of high energy demand (to find new targets). We studied homing of labeled cells in vivo, lymphocyte expression of CCR7, supernatant concentration of CCL21, and serum levels of sphingosine-1-phosphate (S1P) in sympathectomized control/arthritic animals. Results During the course of arthritis, SEEC identified an early marked increase of energy expenditure in draining lymph nodes and spleen (nowhere else!). Although early sympathectomy ameliorated later disease, early sympathectomy increased energy consumption, organ weight, and cell numbers in arthritic secondary lymphoid organs, possibly a sign of lymphocyte retention (also in controls). Elimination of the SNS retained lymph node cells, elevated expression of CCR7 on lymph node cells, and increased CCL21. Serum levels of S1P, an important factor for lymphocyte egress, were higher in arthritic than control animals. Sympathectomy decreased S1P levels in arthritic animals to control levels. Transfer of retained immune cells from draining lymph nodes of sympathectomized donors to sympathectomized recipients markedly increased arthritis severity over weeks. Conclusions By using the SEEC technique, we identified draining lymph nodes and spleen as major target organs of the SNS. The data show that the SNS increases egress of lymphocytes from draining lymph nodes to stimulate arthritic inflammation.

Objective. Treg cells modulate immune responses and can suppress the development of autoimmune diseases. Tumor necrosis factor receptor II (TNFRII) has been recognized as a key receptor on these cells that facilitates expansion and stabilization of CD4+ Treg cells. The purpose of the present study was to investigate the therapeutic activity of a novel TNFRII agonist in experimental arthritis as well as the role of different Treg cell subsets. Methods. A novel mouse TNFRII-selective fusion protein (EHD2-sc-mTNF(R2)) was generated by genetic engineering. Mouse T cells were incubated together with interleukin-2 and/or EHD2-sc-mTNF(R2), and the effects on Treg cells were analyzed by flow cytometry. Mice with collagen-induced arthritis (CIA) were treated with EHD2-sc-mTNF(R2) or saline, and the therapeutic effects were monitored and characterized. Results. Selective activation of TNFRII was found to expand both CD4+ and CD8+ Treg cells. Moreover, TNFRII activation elevated the number of CD4+CD25+ and CD8+CD25+ Treg cells and increased the number of FoxP3-expressing cells in CD8+, but not CD4+, Treg cells, indicating different mechanisms of TNFRII-induced expansion of diverse T cell subsets with suppressive activity. In the CIA model, we demonstrated that administration of the TNFRII agonist EHD2-sc-mTNF(R2) led to the expansion of both CD4+ and CD8+ Treg cells invivo and induced anti-inflammatory responses that alleviated arthritis. Conclusion. Our findings support the use of TNFRII-selective therapeutics as an effective approach to the treatment of arthritic disease and possibly other inflammatory and autoimmune diseases.

In rheumatoid and collagen-induced arthritis (CIA) relative insufficiency of adrenal glands (AG) in later stages of the disease is known. Additionally, migration of macrophages and dendritic cells (DCs) into AG has been described. We hypothesized that these cells contribute to inadequate glucocorticoid secretion. CIA was induced in DA rats. Cytokines in supernatants from whole AG cells, AG cells after magnetic bead separation for macrophage/DC markers MHCII and CD11b, and from bone marrow-derived DCs (BMDC) were quantified with ELISA. The corticosterone secretion from whole AG cells in co-culture with BMDCs was quantified with ELISA. BMDCs generated from arthritic rats expressed significantly more IL-1b, CINC-1,-2,-3, and LIX (all p

Introduction: Density of sympathetic nerve fibers decreases in inflamed arthritic tissue tested by immunoreactivity towards tyrosine-hydroxylase (TH, catecholaminergic key enzyme). Since sympathetic nerve fibers can change phenotype from catecholaminergic to cholinergic (example: sweat glands, periosteum),[for full text, please go to the a.m. URL], 43. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 29. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 25. wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

In an established paradigm of taste-immune conditioning in the rat, the novel taste saccharine (conditioned stimulus/CS) is combined with an i.p. injection of the immunosuppressive drug cyclosporine A (CsA; unconditioned stimulus/US). With this paradigm we analyzed in two experimental settings conditioned immunosuppressive effects on collagen type II induced arthritis as a model of chronic inflammatory autoimmune diseases. In both experiments, four different groups of rats were conditioned with three CS/US pairings starting nine days prior to induction of arthritis. During the first experiment animals were re-exposed to the CS at day 13 after immunization. Our data show that CS re-exposure led to a significant reduction of the clinical and histological arthritis score. This effect was accompanied by an inhibition of splenic CD3 stimulated T cell cytokine production. In the second experiment retrieval started one day after immunization before emergence of the first arthritis symptoms. Significant differences in the clinical score between conditioned animals and controls where only seen in the acute phase of the disease. These results essentially indicated that in conditioned immunosuppression the time point of retrieval is important for the beneficial outcome on inflammatory joint diseases. Moreover, in a third upcoming experiment, retrieval of the conditioned response will be initiated after the first symptoms occur, analyzing more clinically relevant aspects.

Sympathetic nerve fibers innervate bone and tissue adjacent to joints. They play an important role in bone and tissue homeostasis. Under certain conditions, sympathetic nerve fibers can change their phenotype from catecholaminergic to cholinergic. This can be important because anti-inflammatory effects of acetylcholine have been described (alpha-7-nicotinic receptor). We asked whether this transition might occur in the joint during collagen-induced arthritis (CIA) in mice or during rheumatoid arthritis (RA) and osteoarthritis (OA) in humans. Sections of limbs from 30 immunized mice and synovial tissue samples obtained from 30 OA and 12 RA patients were stained for tyrosine hydroxylase (noradrenergic fibers), and for vesicular acetylcholine transporter (cholinergic fibers). In mouse joint area, an increase in the ratio of cholinergic to catecholaminergic nerve fibers appeared at day 35 after immunization. Most of the nerve fibers were located in joint-adjacent skin or muscle tissue, and only very few were detected in synovial tissue or near erosions. In human tissue sections, we were able to show cholinergic fibers in the synovium of four OA patients but in none of the RA patients. Co-culture of sympathetic ganglia and osteoclast progenitors from healthy mice showed more catecholaminergic-to-cholinergic transition when compared to experiments with osteoclast progenitors from arthritic mice. In mice and men, catecholaminergic-to-cholinergic transition is possible in less synovial inflamed tissue but not in highly inflamed arthritic tissue.