Oral tolerance to low dose beta 2-glycoprotein I: immunomodulation of experimental antiphospholipid syndrome.

Oral tolerance was induced in BALB/c mice by feeding low dose beta2-glycoprotein I (beta2GPI). The beta2GPI-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-beta2GPI and anticardiolipin Abs in the serum, lack of fetal resorptions, low incidence of thrombocytopenia, and normal aPTT (activated partial thromboplastin time) values. Beta2GPI given orally before priming with beta2GPI resulted in complete prevention of experimental APS development; beta2GPI given at an early stage of the disease reduced clinical manifestations. However, administration of beta2GPI 70 days postimmunization had a less significant effect on disease expression. Tolerized mice exhibited a diminished T lymphocyte proliferation response to beta2GPI in comparison with beta2GPI-immunized mice fed with OVA. When nontolerant beta2GPI-primed T lymphocytes were mixed with T lymphocytes derived from tolerized mice, a significant inhibition of proliferation upon exposure to beta2GPI was observed. The induction of suppression was beta2GPI specific and driven, as well as TGF-beta mediated. The beta2GPI-specific response of T lymphocytes from the beta2GPI-fed mice was reversed by anti-TGF-beta 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-beta, and had no cytolytic activity. Oral administration of beta2GPI suppressed priming of CTLs in the recipient mice. In sum, beta2GPI-induced oral tolerance has an immunomodulatory effect in experimental APS, demonstrating the importance of beta2GPI in the pathogenesis of the disease.