No abstract

Selective skewing of autoreactive interferon-gamma (IFN-gamma)-producing T helper cells (Th1) toward an interleukin-4 (IL-4)-producing (Th2) phenotype can in experimental animals alleviate autoimmune disease without inducing general immunosuppression. In a prospective dose escalation study, we assessed treatment with human IL-4 (rhuIL-4) in 20 patients with severe psoriasis. The therapy was well tolerated, and within six weeks all patients showed decreased clinical scores and 15 improved more than 68%. Stable reduction of clinical scores was significantly better at 0.2-0.5 microg rhuIL-4 than at < or =0.1 microg rhuIL-4 (P = 0.009). In psoriatic lesions, treatment with 0.2-0.5 microg/kg rhuIL-4 reduced the concentrations of IL-8 and IL-19, two cytokines directly involved in psoriasis; the number of chemokine receptor CCR5+ Th1 cells; and the IFN-gamma/IL-4 ratio. In the circulation, 0.2-0.5 microg/kg rhuIL-4 increased the number of IL-4+CD4+ T cells two- to three-fold. Thus, IL-4 therapy can induce Th2 differentiation in human CD4+ T cells and has promise as a potential treatment for psoriasis, a prototypic Th1-associated autoimmune disease.

Immune responses to heat shock proteins (Hsp) develop in virtually all inflammatory diseases; however, the significance of such responses is only now becoming clear. In experimental disease models, Hsp administration can prevent or arrest inflammatory damage, and in initial clinical trials in patients with chronic inflammatory diseases, Hsp peptides have been shown to promote the production of anti-inflammatory cytokines, indicating immunoregulatory potential of Hsp. Therefore, the presence of immune responses to Hsp in inflammatory diseases can be seen as an attempt of the immune system to correct the inflammatory condition. Hsp70 can modulate inflammatory responses in models of arthritis, colitis and graft rejection, and the mechanisms underlying this effect are now being elucidated. Incubation with microbial Hsp70 was seen to induce tolerogenic dendritic cells (DCs) and to promote a suppressive phenotype in myeloid-derived suppressor cells and monocytes. These DC could induce regulatory T cells (Tregs), independently of the antigens they presented. Some Hsp70 family members are associated with autophagy, leading to a preferential uploading of Hsp70 peptides in MHC class II molecules of stressed cells. Henceforth, conserved Hsp70 peptides may be presented in these situations and constitute targets of Tregs, contributing to downregulation of inflammation. Finally, an interfering effect in multiple intracellular inflammatory signaling pathways is also known for Hsp70. Altogether it seems attractive to use Hsp70, or its derivative peptides, for modulation of inflammation. This is a physiological immunotherapy approach, without the immediate necessity of defining disease-specific auto-antigens. In this article, we present the evidence on anti-inflammatory effects of Hsp70 and discuss the need for experiments that will be crucial for the further exploration of the immunosuppressive potential of this protein.

In industrialized countries the incidence of diseases caused by immune dysregulation has risen. Epidemiologic studies initially suggested this was connected to a reduction in the incidence of infectious diseases; however, an association with defects in immunoregulation is now being recognized. Effector T(H)1 and T(H)2 cells are controlled by specialized subsets of regulatory T cells. Some pathogens can induce regulatory cells to evade immune elimination, but regulatory pathways are homeostatic and mainly triggered by harmless microorganisms. Helminths, saprophytic mycobacteria, bifidobacteria and lactobacilli, which induce immunoregulatory mechanisms in the host, ameliorate aberrant immune responses in the setting of allergy and inflammatory bowel disease. These organisms cause little, if any, harm, and have been part of human microecology for millennia; however, they are now less frequent or even absent in the human environment of westernized societies. Deficient exposure to these 'old friends' might explain the increase in immunodysregulatory disorders. The use of probiotics, prebiotics, helminths or microbe-derived immunoregulatory vaccines might, therefore, become a valuable approach to disease prevention.

No abstract

Reestablishing self-tolerance in autoimmunity is thought to depend on self-reactive regulatory T cells (Tregs). Exploiting these antigen-specific regulators is hampered by the obscure nature of disease-relevant autoantigens. We have uncovered potent disease-suppressive Tregs recognizing Heat Shock Protein (Hsp) 70 self-antigens, enabling selective activity in inflamed tissues. Hsp70 is a major contributor to the MHC class II ligandome. Here we show that a conserved Hsp70 epitope (B29) is present in murine MHC class II and that upon transfer, B29-induced CD4 + CD25 + Foxp3 + T cells suppress established proteoglycan-induced arthritis in mice. These self-antigen–specific Tregs were activated in vivo, and when using Lymphocyte Activation Gene-3 as a selection marker, as few as 4,000 cells sufficed. Furthermore, depletion of transferred Tregs abrogated disease suppression. Transferred cells exhibited a stable phenotype and were found in joints and draining lymph nodes up to 2 mo after transfer. Given that ( i ) B29 administration by itself suppressed disease, ( ii ) our findings were made with wild-type (T-cell receptor nontransgenic) Tregs, and ( iii ) the B29 human homolog is presented by HLA class II, we are nearing translation of antigen-specific Treg activation as a promising intervention for chronic inflammatory diseases.

Especially since the (re-)discovery of T cell subpopulations with specialized regulatory activities, mechanisms of anti-inflammatory T cell regulation are studied very actively and are expected to lead to the development of novel immunotherapeutic approaches, especially in chronic inflammatory diseases. Heat shock proteins (Hsp) are possible targets for regulatory T cells due to their enhanced expression in inflamed (stressed) tissues and the evidence that Hsp induce anti-inflammatory immunoregulatory T cell responses. Initial evidence for an immunoregulatory role of Hsp in chronic inflammation was obtained through analysis of T cell responses in the rat model of adjuvant arthritis and the findings that Hsp immunizations protected against the induction of various forms of autoimmune arthritis in rat and mouse models. Since then, immune reactivity to Hsp was found to result from inflammation in various disease models and human inflammatory conditions, such as rheumatoid arthritis (RA), type 1 diabetes, and atherosclerosis. Now, also in the light of a growing interest in T cell regulation, it is of interest to further explore the mechanisms through which Hsp can be utilized to trigger immunoregulatory pathways, capable of suppressing such a wide and diversified spectrum of inflammatory diseases.

Bovine paratuberculosis is caused by infection of young calves with Mycobacterium avium subsp. paratuberculosis. In some of the chronically infected cows the long asymptomatic stage (2 to 4 years) is followed by a rapid progression to a clinical stage due to protein-losing enteropathy, which will ultimately be fatal. The current dogma is that in early stages of disease the cell-mediated responses predominate, whereas in the clinical stage of the disease the humoral responses prevail, possibly signaling a switch in immune reactivity related to disease progression. We developed immunoglobulin M (IgM)-, IgA-, and IgG1-and IgG2-isotype-specific enzymelinked immunosorbent assays for M. avium subsp.