Pathologic Role and Temporal Appearance of Newly Emerging Autoepitopes in Relapsing Experimental Autoimmune Encephalomyelitis

Abstract

Relapsing experimental autoimmune encephalomyelitis (R-EAE) is a CD4+ T cell-mediated demyelinating disease model for multiple sclerosis. Myelin destruction during the initial relapsing phase of R-EAE in SJL mice initiated by immunization with the proteolipid protein (PLP) epitope PLP139–151 is associated with activation of T cells specific for the endogenous, non-cross-reactive PLP178–191 epitope (intramolecular epitope spreading), while relapses in R-EAE induced with the myelin basic protein (MBP) epitope MBP84–104 are associated with PLP139–151-specific responses (intermolecular epitope spreading). Here, we demonstrate that T cells specific for endogenous myelin epitopes play the major pathologic role in mediating clinical relapses. T cells specific for relapse-associated epitopes can serially transfer disease to naive recipients and are demonstrable in the CNS of mice with chronic R-EAE. More importantly, induction of myelin-specific tolerance to relapse-associated epitopes, by i.v. injection of ethylene carbodiimide-fixed peptide-pulsed APCs, either before disease initiation or during remission from acute disease effectively blocks the expression of the initial disease relapse. Further, blockade of B7-1-mediated costimulation with anti-B7-1 F(ab) during disease remission from acute PLP139–151-induced disease prevents clinical relapses by inhibiting activation of PLP178–191-specific T cells. The protective effects of anti-B7-1 F(ab) treatment are long-lasting and highly effective even when administered following the initial relapsing episode wherein spreading to a MBP epitope (MBP84–104) is inhibited. Collectively, these data indicate that epitope spreading is B7-1 dependent, plays a major pathologic role in disease progression, and follows a hierarchical order associated with the relative encephalitogenic dominance of the myelin epitopes (PLP139–151 > PLP178–191 > MBP84–104).

Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis

“…These results can be interpreted in light of studies on epitope spreading where induction of EAE with the MBP 84-101 epitope results in the generation of PLP 139-151-specific T cells after the initial attack. 25,26 Thus, it is not surprising that our PLP-secreting fibroblasts are able to protect MBP-induced EAE mice against relapse by silencing PLP-specific T cells as we have described previously. 30 However, mice receiving the MBP-secreting fibroblasts were also protected from relapse despite the fact that the MBP 84-101 epitope is less encephalogenic than is PLP 139-151.…”

“…[22][23][24] In subsequent relapses, T cells specific for other encephalogenic epitopes, such as myelin basic protein (MBP) amino acids 84-104, have been demonstrated. 25,26 This diversification of epitope specificity as disease progresses has been defined as epitope spreading. [27][28][29] In order to halt or ameliorate EAE disease in SJL/J mice, we have used a gene therapy approach in which continuous exposure to low levels of PLP antigen in the absence of a co-stimulatory signal -conditions believed to render T cells unresponsive -resulted in a striking abrogation of both clinical and histological signs of disease.…”

Peripheral Tolerance Induction Using Ethylenecarbodiimide-Fixed APCs Uses both Direct and Indirect Mechanisms of Antigen Presentation for Prevention of Experimental Autoimmune Encephalomyelitis

“…One hallmark of the ECDI-Ag-coupled-cell tolerance regimen is its exquisite Ag specificity when used in both preventative and treatment modes in relapsing-remitting EAE (5,12,13,36). In light of the potential contribution of indirect tolerance to Ag-SP in our model system, we revisited the specificity of Ag-SP tolerance under conditions favoring indirect tolerance.…”

Frequencies of Neuroantigen-Specific T Cells in the Central Nervous System Versus the Immune Periphery During the Course of Experimental Allergic Encephalomyelitis

“…Furthermore, we show that the first wave of effector cells (the PLP 139 -151 -specific T cells engaged by peripheral immunization) eventually exhausts without undergoing a Th2 switch. Finally, our data suggest that second wave immunity to the endogenous PLP 178 -191 peptide (15,26) is engaged in the CNS itself.…”