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T cell co-stimulation through the CD28 receptor on T cells is critical to the induction of experimental autoimmune encephalomyelitis (EAE). In this study, expression of the co-stimulatory ligands B7-1 (CD80) and B7-2 (CD86), as well as the receptors CD28 and CTLA-4, were quantitated in central nervous system (CNS) tissues from mice at various stages of EAE. Immunohistochemistry and flow cytometry of CNS-infiltrating cells revealed a high percentage of infiltrating T cells expressing B7-1 and B7-2 during acute, chronic and relapsing EAE. Of the infiltrating cells 10-20% were CTLA-4(+), most of which were CD4(+) T cells. B7-1 and B7-2 expression within the CNS during active EAE might increase the potential for local activation of autoimmune T cells; however, the high level of expression of B7 molecules may also provide a mechanism for the autoregulation of activated CTLA-4(+) T cells.

Several laboratories including ours have shown that T cell co-stimulation mediated through B7-1 or B7-2 is critical to the initiation of EAE. The role of T cell co-stimulation in ongoing EAE is less clear. In the present study, 32 mice with established EAE were randomly assigned to receive treatment with either CTLA-4-Fc or control Ig. Mice were followed daily by clinical scoring for 2 months post-immunization. A significant improvement in the degree of recovery following the acute episode and following relapses of EAE was observed in those mice randomized to CTLA-4-Fc treatment. Full clinical remission occurred twice as often in the CTLA-4-Fc group as in those mice receiving placebo, whereas placebo-treated mice were more likely to develop a stable prolonged neurologic deficit. Serial clinical scoring revealed no effect of CTLA-4-Fc upon relapse rate, with greater than 80% of the mice in each group displaying at least one clinical EAE relapse. In that the activation of memory T cells is relatively independent of T cell co-stimulation, these results indicate that development of chronic disease is associated with the activation of naive T cells and the recruitment of the latter cells into the disease process. Blocking B7 molecules may be beneficial in the treatment of established CNS inflammatory demyelinating diseases such as multiple sclerosis.

The highly regular pattern in which approximately 2000 small somatic cells and 16 large reproductive cells (or 'gonidia') are arranged in a typical asexual adult of Volvox carteri can be traced back to a stereotyped program of embryonic cleavage divisions. After five symmetrical divisions have produced 32 cells of equal size, the anterior 16 cells cleave asymmetrically, to produce one small somatic cell initial and one larger gonidial initial each. The gonidial initials then cease dividing before the somatic cell initials do. The significance of the visibly asymmetric divisions is underscored by genetic and experimental evidence that differences in size--rather than differences in cytoplasmic quality--are causally important in activating the programs that cause small cells to become mortal somatic cells and large cells to differentiate as reproductive cells. A number of loci, including at least five mul ('multiple gonidia') loci, appear to be responsible for determining where and when asymmetric divisions will occur, since mutations at these loci result in modified temporal and/or spatial patterns of asymmetric division in one or more portions of the life cycle. But the capacity to divide asymmetrically at all appears to require a function encoded by the gls (gonidialess) locus, since gls mutants fail to execute any asymmetric divisions. Second-site suppressors of gls that have been identified may encode other functions required for asymmetric division. Cytological and immunocytochemical studies of dividing embryos are being undertaken in an attempt to elucidate the mechanisms by which cell-division planes are established--and shifted--under the influence of such pattern-specifying genes. Studies to date clearly indicate a central role for the basal body apparatus, and particularly its microtubular rootlets, in establishing the orientation of both the mitotic spindle and the cleavage furrow; but it remains to be determined how behavior of the division apparatus becomes modified during asymmetric division.