Factors that contribute to resistance and susceptibility to EAE in the rat

Naomi Vishnupad

doi:10.17918/00007665

Multiple sclerosis (MS) is a complex autoimmune disease, and both genetic and environmental factors contribute to its etiology. Evidence suggests that there are multiple genes involved in disease susceptibility. Many of these loci remain elusive, and the study of animal models has provided a way to investigate potential causes of resistance and susceptibility. LEW rats are susceptible to the induction of experimental allergic encephalomyelitis (EAE), the rodent model for MS. The F344 rat is resistant to the active induction of EAE. Studies of EAE in the rat have been difficult due to the effects of complete Freund's adjuvant (CFA) used to induce EAE. We have eliminated these effects by demonstrating that a purified oligonucleotide is capable of acting as an adjuvant for inducing EAE in LEW rats, with the same efficacy as CFA. After eliminating the effects of CFA, we demonstrate that LEW draining lymph nodes have a greater number of cells in response to immunization with myelin basic protein (MBP) or peptide 68-88 (EP) compared to lymph nodes of F344 rats. We show that there is no difference in the cell number after immunization with adjuvant alone or with ovalbumin, which indicates that the major difference between the strains is myelin antigen-specific. Upon examining the cell types in the draining lymph nodes plus adjuvant-treated rats, we show that LEW rats have more non-T cells, while F344 rats have a greater proportion of CD3+ cells. Additionally, F344 rats have a greater proportion of NKRP+ cells. All of these differences observed in the lymph node could play a role in the EAE-resistance and susceptibility. Upon further examination of the T cells in these rat strains, we establish that LEW rats produce more Th1 cells than F344 rats, which produce more Th2 cells. We investigate the expression of CD45RC and RT6 to determine the Th1 and Th2 subsets, which is of particular interest in the rat, since the reagents to study cytokines are so limited. Using these cell surface markers, we show a difference between these two strains, with or without antigen in the adjuvant preparation. The CD45RC/RT6 expression can be correlated with IL-10 production. In the study of autoimmune diseases, the specific autoantigen is often unknown, which prevents the isolation of the antigen-specific cells. In our model, we have demonstrated that there is a difference in the response to immunization with MBP or EP between LEW and F344 rats. In order to identify the antigen-specific cells, we investigated the ability to select a CD4 high subset of CD4+ T cells and hypothesized that this subset would expand after immunization with antigen. The results did not show and expansion of this population in response to antigen. The expression of the homing molecule, CD44, which is expressed on T cells and has been implicated in the development of EAE was also investigated, but no significant differences in CD44 expression between LEW and F344 rats were seen at time points that were chosen to be relevant to the function of this molecule on T lymphocytes. Based on the observed differences in the cellular immune response to MBP and its encephalitogenic peptide, the highly significant recruitment and expansion seen in the lymph node, the likely differences in the Th1 and Th2 subsets, we propose a model for EAE resistance and susceptibility in the rat.

Factors that contribute to resistance and susceptibility to EAE in the rat

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Factors that contribute to resistance and susceptibility to EAE in the rat

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