Prevention of EAE by tolerogenic vaccination with PEGylated antigenic peptides.

Background: Therapeutic treatment options for chronic autoimmune disorders such as multiple sclerosis (MS) rely largely on the use of non-specific immunosuppressive drugs, which are not able to cure the disease. Presently, approaches to induce antigen-specific tolerance as a therapeutic approach; for example, by peptide-based tolerogenic 'inverse' vaccines have regained great interest. We have previously shown that coupling of peptides to carriers can enhance their capacity to induce regulatory T cells .

Tolerogenic Immunomodulation by PEGylated Antigenic Peptides.

Current treatments for autoimmune disorders rely on non-specific immunomodulatory and global immunosuppressive drugs, which show a variable degree of efficiency and are often accompanied by side effects. In contrast, strategies aiming at inducing antigen-specific tolerance promise an exclusive specificity of the immunomodulation. However, although successful in experimental models, peptide-based tolerogenic "inverse" vaccines have largely failed to show efficacy in clinical trials.

Facilitated Peptide Transport the Mucosal Epithelium: Impact on Tolerance Induction.

A hallmark of autoimmunity is the breakdown of tolerance and generation of effector responses against self-antigens. Re-establishment of tolerance in autoimmune disorders was always the most desired treatment option; however, despite many efforts, clinical trials have been largely unsuccessful. This also applies to the generation of oral tolerance, which seems to be a default response type of the mucosa-associated lymphoid tissues to harmless antigens.

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens.

Parasite proteins containing repeats are essential invasion ligands, important for their ability to evade the host immune system and to induce immunosuppression. Here, the intrinsic suppressive potential of repetitive structures within parasite proteins was exploited to induce immunomodulation in order to establish self-tolerance in an animal model of autoimmune neurological disease. We tested the tolerogenic potential of fusion proteins containing repeat sequences of parasites linked to self-antigens.

Identification of Targeting Peptides for Mucosal Delivery in Sheep and Mice.

In this study we identified and characterized a novel cyclic peptide that facilitates the rapid transportation of conjugated molecules across the epithelial layer of the small intestine. The peptide was initially selected from phage display libraries using a large animal experimental model, which employed consecutive in vitro and in vivo panning. The procedure was designed to enrich for peptides that facilitated transcytosis across the intestinal epithelium into the intestinal afferent lymphatic system.

Tolerogenic modulation of the immune response by oligoglycerol- and polyglycerol-peptide conjugates.

Peptide-based therapy is a promising strategy for antigen-specific immunosuppression to treat or even heal autoimmune diseases with significantly reduced adverse effects compared to conventional therapies. However, there has been no major success due to the drawbacks of native peptides, i.e.

miR-148a is upregulated by Twist1 and T-bet and promotes Th1-cell survival by regulating the proapoptotic gene Bim.

Repeatedly activated T helper 1 (Th1) cells present during chronic inflammation can efficiently adapt to the inflammatory milieu, for example, by expressing the transcription factor Twist1, which limits the immunopathology caused by Th1 cells. Here, we show that in repeatedly activated murine Th1 cells, Twist1 and T-bet induce expression of microRNA-148a (miR-148a). miR-148a regulates expression of the proapoptotic gene Bim, resulting in a decreased Bim/Bcl2 ratio.

Regulation and migratory role of P-selectin ligands during intestinal inflammation.

Dendritic cells from mesenteric lymph nodes (MLN) can convert retinal to retinoic acid (RA), which promotes induction of the gut-specific homing receptor α4β7. In contrast, priming within peripheral lymph nodes leads to upregulation of E- and P-selectin ligands (E- and P-lig). Apart from its α4β7 promoting effect, RA was shown to suppress E- and P-lig induction in vitro.

Accumulation and local proliferation of antigen-specific CD4+ T cells in antigen-bearing tissue.

Although activation and subsequent expansion of naive CD4(+) T cells within lymph nodes is well characterized, the fate of T effector cells activated within peripheral tissues during secondary reactions is poorly defined. Therefore, we studied the recruitment, proliferation and egress of antigen-specific Th1 effector cells in comparison with nonspecific Th1 cells throughout a delayed-type hypersensitivity reaction (DTH). Although we observed a high turnover of Th1 effector cells with unspecific high-rate recruitment and CCR7-dependent egress from the inflamed tissue in the early, acute DTH phase, a strong, selective accumulation of antigen-specific T cells occurred during the chronic, late DTH phase.

T cells as pioneers: antigen-specific T cells condition inflamed sites for high-rate antigen-non-specific effector cell recruitment.

Cellular infiltration is a classic hallmark of inflammation. Whereas the role of T cells in many types of inflammation is well established, the specific impact of antigen recognition on their migration into the site and on the accumulation of other effector cells are still matters of debate. Using a model of an inflammatory effector phase driven by T-cell receptor (TCR) transgenic T cells, we found (i) that antigen-specific T cells play a crucial role as 'pioneer cells' that condition the tissue for enhanced recruitment of further T effector cells and other leucocytes, and (ii) that the infiltration of T cells is not dependent on antigen specificity.

Murine CD146 is widely expressed on endothelial cells and is recognized by the monoclonal antibody ME-9F1.

The endothelium plays an important role in the exchange of molecules, but also of immune cells between blood and the underlying tissue. The endothelial molecule S-Endo 1 antigen (CD146) is preferentially located at endothelial junctions and has been claimed to support endothelial integrity. In this study we show that the monoclonal antibody ME-9F1 recognizes the extracellular portion of murine CD146.

Experience-driven development: effector/memory-like alphaE+Foxp3+ regulatory T cells originate from both naive T cells and naturally occurring naive-like regulatory T cells.

Naturally occurring Foxp3+CD25+CD4+ regulatory T cells (Treg) have initially been described as anergic cells; however, more recent in vivo studies suggest that Tregs vigorously proliferate under both homeostatic as well as inflammatory conditions. We have previously identified a subset of murine CD4+ Tregs, which is characterized by expression of the integrin alphaEbeta7 and which displays an effector/memory-like phenotype indicative of Ag-specific expansion and differentiation. In the present study, the alphaE+ Treg subset was found to contain a large fraction of cycling cells under homeostatic conditions in healthy mice.

Induction of organ-selective CD4+ regulatory T cell homing.

Compelling evidence suggests that Foxp3(+)CD25(+)CD4(+) Treg play a fundamental role in immunoregulation. We have previously demonstrated that Treg have to enter peripheral tissues to suppress ongoing inflammation. However, relatively little is known about how Treg acquire the expression of homing receptors required for tissue- or inflammation-specific migration.