Neonatal Exposure to a Self-Peptide–Immunoglobulin Chimera Circumvents the Use of Adjuvant and Confers Resistance to Autoimmune Disease by a Novel Mechanism Involving Interleukin 4 Lymph Node Deviation and Interferon γ–mediated Splenic Anergy

A gene therapy model has been designed to induce tolerance to multiple epitopes expressed in-frame on a soluble IgG fusion protein scaffold. Tolerance to the λ repressor cI sequence p1-102 or its immunodominant epitopes (p12-26, p73-88) can be elicited when bone marrow (BM) or LPS blasts are transduced and injected into naive or even primed recipients. To explore the mechanism of tolerance, class II−/− (knockout, KO) BM cells were transduced with p1-102-IgG and transferred to irradiated recipients. These cells failed to induce tolerance to challenge with p1-102 epitopes, whereas transduced +/+ BM cells did. This supports the importance of class II MHC on the tolerogenic APC rather than secretion and representation in tolerogenesis. When BM cells from μMT KO mice were transfected with p12-26-IgG and injected into irradiated mice, these transduced BM cells also failed to induce tolerance to an immunodominant epitope. These results suggest the direct involvement of B cells in tolerance to p1-102 epitopes. IL-10 KO BM cells infected with a p12-26-IgG construct were still tolerogenic. Importantly, anti-CTLA-4 injections reversed tolerance in primed, but not in naive, recipients of transduced LPS blasts. These data emphasize the importance of MHC class II presentation, B cell involvement, and CTLA-4 engagement in induction and/or maintenance of tolerance.

Section: Discussionmentioning

confidence: 99%

Mechanisms of Tolerance Induction by a Gene-Transferred Peptide-IgG Fusion Protein Expressed in B Lineage Cells

El-Amine

Melo

Kang

et al. 2000

“…First, although newborn mice are able to mount strong CTL responses (51-53), differentiation of type 2 cytokine-secreting T cells is preferentially induced by systemic Ag during the neonatal period (54,55). Several factors could contribute to this phenomenon: 1) differences in the function of APCs (56 -60); 2) lower frequency of T cells (61); 3) greater requirements for accessory cell factors (62); and 4) the high relative Ag dose (54).…”

Section: Discussionmentioning

confidence: 99%

Systemic Administration of Agonist Peptide Blocks the Progression of Spontaneous CD8-Mediated Autoimmune Diabetes in Transgenic Mice Without Bystander Damage

Bercovici

Heurtier

Vízler

et al. 2000

Insulin-dependent diabetes is an autoimmune disease targeting pancreatic β-islet cells. Recent data suggest that autoreactive CD8+ T cells are involved in both the early events leading to insulitis and the late destructive phase resulting in diabetes. Although therapeutic injection of protein and synthetic peptides corresponding to CD4+ T cell epitopes has been shown to prevent or block autoimmune disease in several models, down-regulation of an ongoing CD8+ T cell-mediated autoimmune response using this approach has not yet been reported. Using CL4-TCR single transgenic mice, in which most CD8+ T cells express a TCR specific for the influenza virus hemagglutinin HA512–520 peptide:Kd complex, we first show that i.v. injection of soluble HA512–520 peptide induces transient activation followed by apoptosis of Tc1-like CD8+ T cells. We next tested a similar tolerance induction strategy in (CL4-TCR × Ins-HA)F1 double transgenic mice that also express HA in the β-islet cells and, as a result, spontaneously develop a juvenile onset and lethal diabetes. Soluble HA512–520 peptide treatment, at a time when pathogenic CD8+ T cells have already infiltrated the pancreas, very significantly prolongs survival of the double transgenic pups. In addition, we found that Ag administration eliminates CD8+ T cell infiltrates from the pancreas without histological evidence of bystander damage. Our data indicate that agonist peptide can down-regulate an autoimmune reaction mediated by CD8+ T cells in vivo and block disease progression. Thus, in addition to autoreactive CD4+ T cells, CD8+ T cells may constitute targets for Ag-specific therapy in autoimmune diseases.

“…IL-12 blocked/reversed UV radiation-induced immunosuppression (32)(33)(34), experimental autoimmune thyroiditis (35), neonatal tolerance in proteolipid protein-induced EAE (36) and in transplantation (37), and OVA-induced tolerance (38, 39), by promoting Th1 response and/or inhibiting Th2 polarization.…”

Section: Discussionmentioning

confidence: 99%

The Role of IL-12 in the Induction of Intravenous Tolerance in Experimental Autoimmune Encephalomyelitis

Zhang

Kusumoto

et al. 2002

Intravenous administration of autoantigen is an effective method to induce Ag-specific tolerance against experimental autoimmune encephalomyelitis (EAE). IL-12 is a potent Th1 stimulator and an essential cytokine in the induction of EAE. The role of IL-12 in the induction of i.v. tolerance is not clear. In this study, we induced tolerance by i.v. administering myelin basic protein (MBP) peptide Ac1–11 (MBP1–11) in EAE. We observed significant suppression of IL-12 production by the lymph node cells of MBP1–11-injected mice. To see whether the low level of IL-12 is the cause or effect of tolerance, we administered IL-12 to the EAE mice at the time of i.v. MBP1–11 injection. Exogenous IL-12 abrogated the suppression of clinical and pathological EAE by i.v. tolerance. IL-12 blocked the suppressive effect of i.v. tolerance on the proliferative response to MBP1–11 and MBP1–11-induced production of IL-12 and IFN-γ. Furthermore, IL-12 completely blocked the i.v. tolerance-induced type 1 T regulatory cell response. These data suggest that i.v. administration of autoantigen results in the suppression of endogenous IL-12 and the consequent switching of the immune response from an immunogenic to a tolerogenic form.