Genetic influence on disease course and cytokine response in relapsing experimental allergic encephalomyelitis

A protracted and relapsing form of experimental allergic encephalomyelitis(EAE) develops in the DA rat after immunization with rat spinal cordhomogenate (SCH) emulsified in incomplete Freund's adjuvant (IFA). Thegenetic influence on this model has been analyzed by immunizing MHCcongenic strains on both LEW and DA genetic backgrounds, and recombinantinbred strains between DA and E3 rats. An in situ hybridization assay wasused to examine the expression of mRNA for IFN-gamma, IL-4, IL-10 andtransforming growth factor (TGF)-beta both in sections of spinal cords andthe antigen-induced expression for these cytokines by splenocytes after invitro stimulation with encephalitogenic MBP peptides. The susceptibility ofrelapsing EAE after immunization with SCH in IFA in the DA strain, but notthe E3 strain, was correlated with a lack of expression for TGF-beta in thespinal cord. The recombinant inbred DXEB rats developed a severe EAE whilesurprisingly no signs of disease were observed in the DXEA strain, whichshares the MHC region with the DXEB strain, after immunization with the MBP63-87 peptide. Resistance to relapsing EAE in the DXEA strain correlatedwith increased non-MHC controlled expression for TGF-beta and lack ofIFN-gamma in the spinal cord. The same pattern of cytokine expression wasseen in splenocytes after stimulation in vitro with the MBP 63-87 peptide.A spreading of the immune response to the MBP 87-110 peptide was seen.Non-MHC genes controlled the quality of this response: splenocytes from MBP63-87 immunized DXEB rats responded in vitro towards the MBP 87-110 peptideby expressing mRNA for IFN-gamma, IL-10 and IL-4, whereas in the DXEAstrain the corresponding response involved IL-4 and TGF-beta. Takentogether these data show that non-MHC controlled expression of mRNA forTGF-beta is associated with resistance to EAE.