Antigen-specific immunotherapy with apitopes suppresses generation of FVIII inhibitor antibodies in HLA-transgenic mice.

Hemophilia A (HA) is a blood clotting disorder that is caused by various genetic deficiencies in the factor VIII (FVIII)-encoding F8 gene. Patients receiving FVIII-replacement therapy are at risk for developing neutralizing antibodies (FVIII inhibitors), rendering the FVIII-replacement therapy ineffective. Immunological tolerance toward FVIII can be achieved through immune tolerance induction protocols in some patients, but this is a lengthy and costly desensitization program.

Negative feedback control of the autoimmune response through antigen-induced differentiation of IL-10-secreting Th1 cells.

Regulation of the immune response to self- and foreign antigens is vitally important for limiting immune pathology associated with both infections and hypersensitivity conditions. Control of autoimmune conditions can be reinforced by tolerance induction with peptide epitopes, but the mechanism is not currently understood. Repetitive intranasal administration of soluble peptide induces peripheral tolerance in myelin basic protein (MBP)-specific TCR transgenic mice.

Natural and induced regulatory T cells: targets for immunotherapy of autoimmune disease and allergy.

Recent advances in immunology have greatly increased our understanding of immunological tolerance. In particular, there has been a resurgence of interest in mechanisms of immune regulation. Immune regulation refers to the phenomenon, previously known as immune suppression, by which excessive responses to infectious agents and hypersensitivities to otherwise innocuous antigens such as self antigens and allergens are avoided.

Persistent antigenic stimulation alters the transcription program in T cells, resulting in antigen-specific tolerance.

Repetitive antigen stimulation induces peripheral T cell tolerance in vivo. It is not known, however, whether multiple stimulations merely suppress T cell activation or, alternatively, change the transcriptional program to a distinct, tolerant state. In this study, we have discovered that STAT3 and STAT5 were activated in response to antigen stimulation in vivo, in marked contrast to the suppression of AP-1, NF-kappaB and NFAT.

Antigen-induced IL-10+ regulatory T cells are independent of CD25+ regulatory cells for their growth, differentiation, and function.

Recent studies have emphasized the importance of T cells with regulatory/suppressor properties in controlling autoimmune diseases. A number of different types of regulatory T cells have been described with the best characterized being the CD25(+) population. In addition, it has been shown that regulatory T cells can be induced by specific Ag administration.

Natural and induced regulatory T cells.

Mucosal antigen delivery can induce tolerance, as shown by suppression of subsequent responses to antigen. Our previous work showed that both intranasal and oral routes of antigen delivery were effective but indicated that the intranasal route might be more reliable. Intranasal peptide administration induced cells that could mediate bystander suppression of responses to associated antigenic epitopes.

IL-2 overcomes the unresponsiveness but fails to reverse the regulatory function of antigen-induced T regulatory cells.

Intranasal administration of peptide Ac1-9[4Y], based on the N-terminal epitope of myelin basic protein, can induce CD4(+) T cell tolerance, and suppress experimental autoimmune encephalomyelitis induction. The peptide-induced regulatory T (PI-T(Reg)) cells failed to produce IL-2, but expressed IL-10 in response to Ag and could suppress naive T cell responses in vitro. Analysis of Jak-STAT signaling pathways revealed that the activation of Jak1, STAT3, and STAT5 were induced in tolerant T cells after Ag stimulation in vivo.

Regulatory CD4+ T cells and the control of autoimmune disease.

The immune system is a delicately balanced network of interacting cells. In recent years, the concept of immune regulation/suppression has been firmly established, and both natural and induced regulatory cells play vital roles in protection from autoimmune disease. Recent work has revealed the diverse nature of regulatory CD4+ T (Treg) cells and the molecules involved in their function.

Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo.

Regulatory CD4(+) T cells were induced in the Tg4 TCR transgenic mouse specific for the N-terminal peptide (Ac1-9) of myelin basic protein by intranasal administration of a high-affinity MHC-binding analog (Ac1-9[4Y]). Peptide-induced tolerant cells (PItol) were anergic, failed to produce IL-2, but responded to Ag by secretion of IL-10. PItol cells were predominantly CD25(-) and CTLA-4(+) and their anergic state was reversed by addition of IL-2 in vitro.

Induction of experimental autoimmune encephalomyelitis in the absence of c-Jun N-terminal kinase 2.

Experimental autoimmune encephalomyelitis (EAE) is a CD4(+) T cell-dependent, organ-specific autoimmune model commonly used to investigate mechanisms involved in the activation of autoreactive T(h)1 cells. Mitogen-activated protein kinases such as c-Jun N-terminal kinase (Jnk) 1 and 2 play an important role in the differentiation of naive precursors into T(h)1 or T(h)2 effector cells. To investigate the role of Jnk2 on autoimmunity, Jnk2(-/-) and wild-type mice were immunized with the myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide and the onset of EAE studied.

Experimental autoimmune encephalomyelitis induction in naive mice by dendritic cells presenting a self-peptide.

Self-reactive T cells escape deletion in the thymus and are found in the peripheral repertoire. Because bone-marrow-derived dendritic cells (BM-DC) are potent activators of antigen-specific T cells, these cells could theoretically activate self-reactive T cells leading to autoimmunity. We investigated whether BM-DC could induce the autoimmune disease experimental autoimmune encephalomyelitis (EAE).