The stress response (SR) can block in¯ammatory gene expression by preventing activation of transcription factor nuclear factor-kappa B (NF-kB). As in¯ammatory gene expression contributes to the pathogenesis of demyelinating diseases, we tested the effects of the SR on the progression of the demyelinating disease experimental autoimmune encephalomyelitis (EAE). EAE was actively induced in C57BL/6 mice using an encephalitogenic myelin oligodendrocyte glycoprotein (MOG 35255 ) peptide. Whole body hyperthermia was used to induce a heat shock response (HSR) in immunized mice 2 days after the booster MOG 35255 peptide injection. The HSR reduced the incidence of EAE by 70%, delayed disease onset by 6 days, and attenuated disease severity. The HSR attenuated leukocyte in®ltration into CNS assessed by quantitation of perivascular in®ltrates, and by reduced staining for CD4 and CD25 immunopositive T-cells. T-cell activation, assessed by the production of interferon g (IFNg) in response to MOG 35255 , was also decreased by the HSR. The HSR reduced in¯ammatory gene expression in the brain that normally occurs during EAE, including the early increase in RANTES (regulated on activation of normal T-cell expressed and secreted) expression, and the later expression of the inducible form of nitric oxide synthase. The early activation of transcription factor NF-kB was also blocked by the HSR. The ®nding that the SR reduces in¯ammation in the brain and the clinical severity of EAE opens a novel therapeutic approach for prevention of autoimmune diseases. Keywords: cytokines, demyelinating disease, heat shock, in¯ammation, nitric oxide.The stress response (SR) is a protective mechanism elicited by a variety of stimuli, including thermal, chemical, oxidative, graft rejection, and physical trauma, and is thought to confer resistance against subsequent and more lethal stress (Welch 1992). Due to initial studies using hyperthermia to induce the SR, and the reproducibility of using heat as an inducer, the SR is more commonly referred to as the heat shock response (HSR). The HSR causes a general down-regulation of cellular RNA and protein synthesis, and the rapid expression of a speci®c set of proteins termed HS proteins (HSPs) which can protect cells by facilitating re-naturation of denatured proteins and transport to subcellular organelles (Morimoto and Santoro 1998).In addition to protective and chaperoning functions, the HSR also functions in an anti-in¯ammatory mode (Moseley 1998;Santoro 2000). The HSR protects cells from in¯ammatory damage incurred as a consequence of synovitis (Otremski et al. 1994), pulmonary in¯ammation , and endotoxemia (Hotchkiss et al. 1993;Ribeiro et al. 1994). In some cases the HSR was shown to Abbreviations used: EAE, experimental autoimmune encephalomyelitis; HSP, HS protein; HSR, heat shock response; IFNg, interferon g; iNOS, the inducible form of nitric oxide synthase; LPS, lipopolysaccharide; MOG, myelin oligodendrocyte glycoprotein; NF-kB, nuclear factor kappa B; NSAIDs, non-steroidal anti-in¯am...

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A bifunctional alkylating agent, 3-[Bis(2-chloroethyl) amino]-4-methylbenzoic acid (NSC-146171; IOB-82) was administered in HR-18 rat ascites cell cultures (which presented 2 morphologic cellular types: A and B type cells, genetically, 2 cellular populations having 41-45 and 85-86 chromosomes and cells with high ploidy), and the morphological and cytogenetical effects were related to the compound concentration. Thus, 24 h after IOB-82 administration in small doses (3.62 X 10(-4) micron/ml), important morphological changes were observed: nuclear changes (denuded nuclei, pyknosis) and cytoplasmic alterations (breaks at the exoplasm level, followed by cytoplasmic extrusions in extracellular spaces, cytoplasmic vacuolization). In addition to these changes, other abnormalities were observed when IOB-82 was administered in large doses (3.62 X 10(-3) micron/ml), i.e., nuclear changes (nuclear residues, granulation of the nuclear material and spreading of the nuclear content into cytoplasm) and cytoplasmic alterations (cytoplasmic shades and accentuated cytoplasmic vacuolization). Generally, the large A-type cells were more affected. Twenty-four h after IOB-82 treatment (with small or large doses), the chromatid and chromosome aberrations (gaps, breaks, deletions, fragments) were also observed. These aberrations were more numerous when IOB-82 was administered in large doses. Both morphological and cytogenetical changes indicate that the effect of IOB-82 could be radiomimetic. Changes produced and their incidence appear to depend on the concentration of IOB-82 employed and the morphological type of ascites cells. These are expressed in terms of multiple abnormality production in these cells. IOB-82 treatment produced changes in chromosome numbers and especially the disappearance of polyploid cells and cell populations with 85-86 chromosomes. These results indicate a possible correlation between the increased sensitivity of HR-18 rat ascites cells and changes in ploidy.