Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis.

Abstract

SummaryThe role of epitope spreading in the pathology of relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) was examined. Using peripherally induced immunologic tolerance as a probe to analyze the neuropathologic T cell repertoire, we show that the majority of the immunopathologic reactivity during the acute phase of R-EAE in SJL/J mice induced by active immunization with the intact proteolipid (PLP) molecule is directed at the PLP139-151 epitope and that responses to secondary encephalitogenic PLP epitopes may contribute to the later relapsing phases of disease. Intermolecular epitope spreading was demonstrated by showing the development of T cell responses to PLP139-151 after acute disease in mice in which R-EAE was initiated by the transfer ofT cells specific for the non-cross-reactive MBP84-104 determinant. Intramolecular epitope spreading was demonstrated by showing that endogenous host T cells specific for a secondary encephalitogenic PLP epitope (PLP178-191) are demonstrable by both splenic T cell proliferative and in vivo delayed-type hypersensitivity responses in mice in which acute central nervous system damage was initiated by T cells reactive with the immunodominant, non-cross-reactive PLP139-151 sequence. The PLP178-191-specific responses are activated as a result of and correlate with the degree of acute tissue damage, since they do not develop in mice tolerized to the initiating epitope before expression of acute disease. Most importantly, we show that the PLP178-191-specific responses are capable of mediating R-EAE upon adoptive secondary transfer to naive recipient mice. Furthermore, induction of tolerance to intact PLP (which inhibits responses to both the initiating PLP139-151 epitope and to the PLP178-191 epitope) after the acute disease episode is sufficient to prevent relapsing disease. These results strongly support a contributory role ofT cell responses to epitopes released as a result of acute tissue damage to the immunopathogenesis of relapsing clinical episodes and have important implications for the design of antigenspecific immunotherapies for the treatment of chronic autoimmune disorders in humans.t~ lapsing experimental autoimmune encephalomyelitis (R-EAE) 1 is a CD4 + Thl-mediated demyelinating disease of the central nervous system (CNS) (1) that is inducible in genetically susceptible animals by immunization with myelin basic protein (MBP) or proteolipid protein (PLP) (2, 3) or synthetic peptides corresponding to the major encephalitogenic epitopes of MBP and PLP (4, 5). Alternatively, R-EAE The first two authors contributed equally to this work and should both be considered first authors.1 Abbreviations used in this paper: CNS, central nervous system; DTH, delayed-type hypersensitivity; ECDI, 1-ethyl-3-(3-dimethylaminopropyl)-carhodiimide HC1; MBP, myelin basic protein; MMS, mean maximal disease severity; MS, multiple sclerosis; PLP, proteolipid protein; K-EAE, relapsing experimental autoimmune encephalomyelitis; SP, splenocyte. may be transferred to naive rec...

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.…”

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.…”

“…This may in turn give rise to ongoing stimulation of the neuroantigen-specific T cells and drive their clonal expansion. Moreover, these induced lymphoid tissues within the CNS may represent the site in which the amplification of the autoimmune process via determinant spreading occurs (13)(14)(15)(16). In this study, we address the organ distribution and fate of the first wave of peripherally primed effector cells, and the site of engagement of the second wave effector cells.…”

Effective Antigen-Specific Immunotherapy in the Marmoset Model of Multiple Sclerosis

“…MP4 is processed into multiple determinants and can eliminate rodent EAE by promoting tolerance to different epitopes (19,20). This is important in view of epitope or determinant "spreading" in MS and EAE (19,20,(22)(23)(24)(25)(26)(27)(28). We previously documented epitope spreading in EAE in marmosets (29).…”