F. van Wijk

Autologous bone marrow transplantation in autoimmune arthritis restores immune homeostasis through CD4+ CD25+ Foxp3+ regulatory T cells.

Despite the earlier use of potent immunosuppressive or cytostatic drugs and the recent emergence of biologicals as treatment for human autoimmune diseases (AIDs), some patients still remain unresponsive to treatment. To those severely ill patients, autologous bone marrow transplantation (aBMT) is applied as a last resource, leading to disease remission in a majority of patients. The underlying mechanism of action of aBMT is still largely unknown. Here, we showed that regulatory T cells (Tregs) play a role in the natural disease course of proteoglycan-induced arthritis (PGIA) and in disease remission by aBMT. aBMT led to an initial phase of rapid disease improvement corresponding with a relative increase in CD4(+)CD25(+) T cells. At this time, the CD4(+)CD25(+) cells did not yet show an increase in Foxp3 expression and showed less potent suppression. After this initial improvement, disease relapsed but stabilized at a level below the severity before aBMT. This second phase was actively regulated by potently suppressive CD4(+)CD25(+)Foxp3(+) Tregs. This work provided further insight into the role of Tregs in restoration of the immune balance by aBMT and can open the way to explore therapeutic interventions to further improve treatment of AID and disease relapses.

Mixed antibody and T cell responses to peanut and the peanut allergens Ara h 1, Ara h 2, Ara h 3 and Ara h 6 in an oral sensitization model

Background Peanut allergy is known for its severity and persistence through life. Several peanut proteins have been identified as allergenic and are indicated as Ara h 1–7. Very little is known about the mechanisms that underlie sensitization to peanut proteins.

CD4+CD25+ T cells regulate the intensity of hypersensitivity responses to peanut, but are not decisive in the induction of oral sensitization

Background Naturally occurring CD4+CD25+ regulatory T cells (Tregs) play a critical role in the maintenance of self‐tolerance and it has been suggested that these Tregs may also be involved in preventing allergic disease.

The CD28/CTLA-4-B7 signaling pathway is involved in both allergic sensitization and tolerance induction to orally administered peanut proteins

Dendritic cells are believed to play an essential role in regulating the balance between immunogenic and tolerogenic responses to mucosal Ags by controlling T cell differentiation and activation via costimulatory and coinhibitory signals. The CD28/CTLA-4-CD80/CD86 signaling pathway appears to be one of the most important regulators of T cell responses but its exact role in responses to orally administered proteins remains to be elucidated. In the present study, the involvement of the CD28/CTLA-4-CD80/CD86 costimulatory pathway in the induction of allergic sensitization and oral tolerance to peanut proteins was investigated. In both an established C3H/HeOuJ mouse model of peanut hypersensitivity and an oral tolerance model to peanut, CD28/CTLA-4-CD80/CD86 interactions were blocked using the fusion protein CTLA-4Ig. To examine the relative contribution of CD80- and CD86-mediated costimulation in these models, anti-CD80 and anti-CD86 blocking Abs were used. In the hypersensitivity model, CTLA-4Ig treatment prevented the development of peanut extract-induced cytokine responses, peanut extract-specific IgG1, IgG2a, and IgE production and peanut extract-induced challenge responses. Blocking of CD80 reduced, whereas anti-CD86 treatment completely inhibited, the induction of peanut extract-specific IgE. Normal tolerance induction to peanut extract was found following CTLA-4Ig, anti-CD86, or anti-CD80 plus anti-CD86 treatment, whereas blockade of CD80 impaired the induction of oral tolerance. We show that CD28/CTLA-4-CD80/CD86 signaling is essential for the development of allergic responses to peanut and that CD86 interaction is most important in inducing peanut extract-specific IgE responses. Additionally, our data suggest that CD80 but not CD86 interaction with CTLA-4 is crucial for the induction of low dose tolerance to peanut.

Correlation of CXCL10, Tumor Necrosis Factor Receptor Type II, and Galectin 9 With Disease Activity in Juvenile Dermatomyositis

Juvenile dermatomyositis (DM) is a systemic autoimmune disorder of unknown immunopathogenesis in which the immune system targets the microvasculature of skeletal muscles, skin, and other organs. The current mainstay of therapy is a steroid regimen in combination with other immunosuppressive treatments. To date, no validated markers for monitoring disease activity have been identified, which hampers personalized treatment. This study was undertaken to identify a panel of proteins specifically related to active disease in juvenile DM.

Regulatory T cells in autologous stem cell transplantation for autoimmune disease

Since a decade autologous stem cell transplantation (ASCT) is successfully performed to treat patients with severe autoimmune disease. However, the mechanism of action of this intervention remains largely unknown. Scarce data from animal studies and human clinical trials indicate that, besides extensive immune ablation, restoration of regulatory immune networks is of critical importance. This review focuses on the role of naturally occurring and induced regulatory T cells in controlling immune reconstitution and restoration of immune tolerance and in preventing relapses of disease following ASCT.

Mesenchymal stem cell therapy in proteoglycan induced arthritis

Objectives To explore the immunosuppressive effect and mechanism of action of intraperitoneal (ip) and intra-articular (ia) mesenchymal stem cell (MSC) injection in proteoglycan induced arthritis (PGIA). Methods MSC were administered ip or ia after establishment of arthritis. We used serial bioluminescence imaging (BLI) to trace luciferase-transfected MSC. Mice were sacrificed at different time points to examine immunomodulatory changes in blood and secondary lymphoid organs. Results Both ip and local ia MSC injection resulted in a beneficial clinical and histological effect on established PGIA. BLI showed that MSC ip and ia in arthritic mice are largely retained for several weeks in the peritoneal cavity or injected joint respectively, without signs of migration. Following MSC treatment pathogenic PG-specific IgG2a antibodies in serum decreased. The Th2 cytokine IL-4 was only upregulated in PG-stimulated lymphocytes from spleens in ip treated mice and in lymphocytes from draining lymph nodes in ia treated mice. An increase in production of IL-10 was seen with equal distribution. Although IFN-γ was also elevated, the IFN-γ/IL-4 ratio in MSC treated mice was opposite to the ratio in (untreated) active PGIA. Conclusions MSC treatment, both ip and ia, suppresses PGIA, a non-collagen induced arthritis model. MSC are largely retained for weeks in the injection region. MSC treatment induced at the region of injection a deviation of PG-specific immune responses, suggesting a more regulatory phenotype with production of IL-4 and IL-10, but also of IFN-γ, and a systemic decrease of pathogenic PG-specific IgG2a antibodies. These findings underpin the potential of MSC treatment in resistant arthritis.

Autologous stem cell transplantation leads to a change in proinflammatory plasma cytokine profile of patients with juvenile dermatomyositis correlating with disease activity.

Juvenile dermatomyositis (JDM) is a rare autoimmune disorder, affecting mainly muscles and skin. The mainstay of treatment is high dose corticosteroids, combined with other immunosuppressive drugs.1 In about 30% of patients, the disease cannot be controlled despite multiple treatment interventions. Autologous stem cell transplantation (aSCT) has been reported as a last resort treatment in refractory patients with autoimmune diseases.2 The main hypothesis for the underlying immunological mechanism is that aSCT resets the immune system and restores immune tolerance following profound lymphodepletion and immune suppression.3 Here, we report three patients with refractory JDM that received aSCT (Clinical information, table 1). A short-term follow-up with detailed clinical information (including imaging before and after aSCT, and immune reconstitution after aSCT) of two patients describing complete remission was reported previously.4 The current follow-up of these patients is more than 5 years showing sustained remission. A third patient (#3) has a follow-up of nearly 3 years. Indication of aSCT for patient 3 was refractory muscle and skin inflammation comparable to the other two patients. Whole body MRI prior to aSCT confirmed active myositis. As muscle tests improved substantially after aSCT, MRI was not repeated post aSCT in this patient. Immune reconstitution …

Allergen-specific Th2 responses in young children precede sensitization later in life.

Allergic sensitization is initiated by allergen‐specific Th2‐cell responses. Data on early allergen‐specific T‐cell responses in allergic children are scarce. We hypothesized that allergen‐specific Th2‐cell responses can be detected preceding sensitization. Therefore, peripheral blood mononuclear cells (PBMC) of nonsensitized, ‘not‐yet’ sensitized or sensitized children were cultured with highly purified allergens. Cytokine levels in supernatant were determined using multiplex assay and GATA3 expression by flow cytometry. PBMC of sensitized children aged 3 and 5 years showed higher production of IL4, IL5 and IL13 and higher expression of GATA3 in response to purified allergens compared to nonsensitized children. PBMC of children that were ‘not‐yet’ sensitized already showed higher levels of IL5 and IL13 and higher GATA3 expression at age 3 years. This shows that allergen‐specific in vitro Th2 responses precede the detection of allergen‐specific IgE, which can provide a window of opportunity for novel therapeutic interventions.

PReS-FINAL-1019: Inflammatory monocytes induce resistance of effector t cells to suppression

Ever since their discovery research has focused on whether deficiencies in FOXP3+ regulatory T cells (Treg) underlie human autoimmune pathology. Very recently however, the topic of Treg extrinsic factors as the cause of regulatory defects in chronic autoimmune inflammation has become more prominent in the discussion. It has become clear that resistance of effector cells (Teff) to suppression contributes to disturbed immune regulation in autoimmune inflammation, especially at the site of inflammation. Therefore, targeting this unresponsiveness to suppression could be a promising treatment option for patients with autoimmune disease. It remains unknown how resistance of T cells to suppression is induced.