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*
Research Unit of Autoimmune Diseases, Department of Medicine B, Sheba Medical Center, Tel-Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;
Immunology Laboratory for Diagnosis, Oncology Department, Hadassah Medical Center, Jerusalem, Israel;
Clinical Immunology Unit, Spedali Civili, Brescia, Italy; and
§
Department of Medicine II, Hokkaido University School of Medicine, Sapporo, Japan
Oral tolerance was induced in BALB/c mice by feeding low dose ß2-glycoprotein I (ß2GPI). The ß2GPI-fed mice did not develop serologic and clinical markers of experimental antiphospholipid syndrome (APS) upon immunization with the autoantigen. The treated group was characterized by low titers of serum anti-ß2GPI and anticardiolipin Abs in the serum, lack of fetal resorptions, low incidence of thrombocytopenia, and normal aPTT (activated partial thromboplastin time) values. ß2GPI given orally before priming with ß2GPI resulted in complete prevention of experimental APS development; ß2GPI given at an early stage of the disease reduced clinical manifestations. However, administration of ß2GPI 70 days postimmunization had a less significant effect on disease expression. Tolerized mice exhibited a diminished T lymphocyte proliferation response to ß2GPI in comparison with ß2GPI-immunized mice fed with OVA. When nontolerant ß2GPI-primed T lymphocytes were mixed with T lymphocytes derived from tolerized mice, a significant inhibition of proliferation upon exposure to ß2GPI was observed. The induction of suppression was ß2GPI specific and driven, as well as TGF-ß mediated. The ß2GPI-specific response of T lymphocytes from the ß2GPI-fed mice was reversed by anti-TGF-ß Abs. The tolerance was adoptively transferred by CD8+ T cells from the tolerized mice into naive mice. Those CD8+ cells were MHC class I restricted, found to secrete TGF-ß, and had no cytolytic activity. Oral administration of ß2GPI suppressed priming of CTLs in the recipient mice. In sum, ß2GPI-induced oral tolerance has an immunomodulatory effect in experimental APS, demonstrating the importance of ß2GPI in the pathogenesis of the disease.
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