No abstract

SummaryThe zona pellucida (ZP), an ovarian extracellular structure, contains three major glycoproteins: ZP1, ZP2, and ZP3. A ZP3 peptide contains both an autoimmune oophoritis-inducing T cell epitope and a B cell epitope that induces autoantibody to ZP. This study investigates two major T cell costimulation pathways in this disease model. Herein we show that blockage of glycoprotein (gp)39 and CD40 interaction with gp39 monoclonal antibody (mAb) results in the failure to induce both autoimmune oophoritis and autoantibody production. Inhibition of hgand binding to the CD28 receptor with the fusion protein, murine CTLA4-immunoglobulin (Ig), also results in failure to generate antibody to ZP and significantly reduces disease severity and prevalence. Surprisingly, the frequencies of antigen-specific T cells in anti-gp39 mAbtreated mice, CTLA4-Ig treated mice, and in mice given control hamster IgG or control fusion protein L6, were equivalent as determined by hmiting dilution analysis (--~ 1 : 5,000). These T cells, which produced comparable amounts ofinterleukin 4 and interferon ~/in vitro, were able to transfer oophoritis to normal recipients. When anti-gp39 mAb and CTLA4-Ig were given together, the effect was additive, leading to inhibition of T cell activation as determined by in vitro prohferation and bruiting dilution analysis (-~1:190,000); disease and antibody responses were absent in these mice. By studying these two costimulatory pathways in parallel, we have shown that autoimmune disease and autoantibody production are inhibitable by blocking either the gp39 or the CD28 pathway, whereas inhibition of clonal expansion of the effector T cell population occurs only when both pathways are blocked.

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In 1993, the published reports of four different laboratories (for review see reference 1) characterized one form of hyper IgM (HIM) syndrome as resulting from a defect in the ligand for CD40 ligand (CD40L) on T cells. In The report by Conley and co-workers (2) establishes that mutations which affect CD40 signalling in B cells mirror mutations in the CD40 ligand on T cells and cause severe immunodeficiency. The concordant data provided by HIM as well as the CD40-and CD40L-deficient mice provide conclusive evidence of the essential role of this receptor-ligand pair in T-dependent humoral immune responses. The extensive redundancy in the immune system is such that the existence of a single receptorligand pair absolutely required for T cell-dependent humoral immunity is indeed remarkable. As such, the unique nonredundant feature of the CD40-CD40L interaction makes it a singularly attractive candidate for therapeutic intervention in autoimmune disease.

A cDNA library was prepared from the murine Th cell line Th2 D.10 and used to clone the murine homologue of Ox40 by polymerase chain reaction. Comparison of the mouse sequence with the rat revealed greater than 90% homology between the two sequences at both the DNA and protein level. Northern blot analysis found that, as in the rat, Ox40 expression appears to be restricted to activated T cells. A chimeric receptor globulin was prepared to include the mouse Ox40 extracellular domain coupled to the hinge-CH2-CH3 domains of human IgG1 (Ox40-Ig). This soluble form of the molecular was then used to identify cells bearing a ligand for Ox40. FACS analysis revealed that Ox40-Ig bound to a subset of peritoneal B cells as well as to a fraction of LPS-activated splenic B cells. Immunostaining of spleen sections using an Ag-specific conjugate and Ox40-Ig found a significant proportion of antibody-forming cells co-stained with Ox40-Ig. Immunoprecipitation of cell-surface radiolabeled peritoneal B cells suggests a specific interaction with a protein of 70 kDa.