No abstract

Multiple sclerosis (MS) can be divided into 4 clinical forms: relapsing‐remitting (RR), primary progressive (PP), secondary progressive (SP), and progressive relapsing (PR). Since PP‐MS is notably different from the other forms of MS, both clinically and pathologically, the question arises whether PP‐MS is immunologically similar to the other forms. The pathogenesis of the PP‐MS remains unclear, partly due to a lack of highly relevant animal models. Using an encephalitogenic peptide from myelin oligodendrocyte glycoprotein (MOG)92–106, we have established animal models that mimic different forms of MS in 2 strains of H‐2s mice, SJL/J and A.SW. We induced experimental allergic encephalomyelitis (EAE) using MOG92‐106 in the presence or absence of supplemental Bordetella pertussis (BP). Although, SJL/J mice developed RR‐EAE whether BP was given or not, A.SW mice developed PP‐EAE without BP and SP‐EAE with BP. Histologically, SJL/J mice developed mild demyelinating disease with T cell infiltration, while A.SW mice developed large areas of plaque‐like demyelination with immunoglobulin deposition and neutrophil infiltration, but with minimal T cell infiltration. In A.SW mice without BP, high titer serum anti‐MOG antibody was detected and the anti‐MOG IgG2a/IgG1 ratio correlated with survival times of mice. We hypothesized that, in A.SW mice, a Th2 response favors production of myelinotoxic antibodies, leading to progressive forms with early death. Our new models indicate that a single encephalitogen could induce either RR‐, PP‐, or SP‐ forms of demyelinating disease in hosts with immunologically different humoral immune responses.

Relapsing-remitting experimental allergic encephalomyelitis (R-EAE) is an animal model for multiple sclerosis (MS). Many potential immunomodulatory strategies for MS have been used first in EAE to assess their effectiveness. Recently, the injection of plasmid DNA has been shown to induce potent humoral and cellular immune responses. The primary aim of our experiments reported here was to determine if vaccination with cDNAs encoding myelin proteolipid protein (PLP) could prime for a PLP-specific immune response and affect subsequent R-EAE. We constructed cDNAs encoding whole PLP (pPLP(all)) or encephalitogenic epitopes PLP(139-151) (pPLP(139-151)) and PLP(178-191) (pPLP(178-191)). Following DNA injection, we induced R-EAE in SJL/J mice using PLP(139-151) or PLP(178-191) peptides in adjuvant. All 3 plasmid constructs enhanced R-EAE induced with PLP(139-151), and injection of mice with pPLP(all) increased R-EAE induced with PLP(178-191). DNA immunization induced higher PLP peptide-specific lymphoproliferative responses than did vector alone following R-EAE induction with IgG1 or IgG2b antibody responses. These data suggest that DNA immunization of PLP can modulate immune responses, leading to enhancement of R-EAE.

No abstract

The mechanism(s) responsible for generating the different forms of multiple sclerosis, primary progressive (PP) and secondary progressive (SP) versus relapsing-remitting (RR), is not well understood. Using myelin oligodendrocyte glycoprotein (MOG)(92-106), we have established animal models that mimic the different types of multiple sclerosis. A.SW mice develop PP or SP-experimental allergic encephalomyelitis (EAE) with large areas of demyelination and high titers of MOG antibody whereas SJL/J mice develop RR-EAE with perivascular T cells and mild demyelination. In A.SW progressive EAE, we found atrophy of the thymus, spleen, and lymph nodes with depletion of T and B cells and massive apoptosis, as demonstrated by immunohistochemistry, terminal dUTP nick-end labeling, and DNA agarose gel electrophoresis. To test whether lymphoid apoptosis itself contributes to disease progression, we injected SJL/J mice with apoptotic thymocytes. Injection of apoptotic cells resulted in greater than 20% of mice developing SP-EAE with ataxia. SJL/J mice with SP-EAE had large areas of demyelination, high MOG antibody titers and atrophic lymphoid organs. Spleen cells from mice with progressive EAE produced less interferon-gamma than those from RR-EAE when stimulated with mitogen. We suggest that induction of lymphoid apoptosis alters the balance of Th1 versus Th2 immune responses and increases MOG antibody production, leading to exacerbation of demyelination and subsequent disease progression.