Induction of oral tolerance in experimental antiphospholipid syndrome by feeding with polyclonal immunoglobulins

Abstract

Intravenous immunoglobulins (IVIG) contain a wide spectrum of anti-idiotypes associated with autoimmune diseases. Since part of these anti-idiotypes may bear an internal image of the eliciting antigen, IVIG might be suitable for induction of oral tolerance. In the current study we attempted to induce tolerance in an experimental model of anti-phospholipid syndrome (APS) by oral administration of IVIG. Naive mice were fed with IVIG, or anti-beta 2GPI-specific anti-idiotypic IVIG(alpha Id). Significantly diminished humoral response was noted in mice IVIG/ IVIG-F(ab')(2)or IVIG(alpha Id)-tolerized mice, accompanied by a significant attenuation of clinical manifestations. The maximal effect was achieved in the mice tolerized before disease induction. Abrogation of T lymphocyte proliferation to beta 2GPI was detected in the mice fed with IVIG prior to beta 2GPI immunization, mediated by TGFbeta and IL-10 secretion. The tolerance induced by IVIG-feeding was nonspecific and could be adoptively transferred to syngeneic mice by CD8alpha (+) cells. These CD8alpha (+) T cells, were found to secrete high levels of TGFbeta and IL-10. In summary, IVIG-induced oral tolerance has a nonspecific immunomodulatory effect in experimental APS, mediated by TGFbeta and IL-10-secreting CD8alpha (+) cells. Our results point to a possible application of IVIG in the induction of oral tolerance against various autoimmune diseases.

IVIg therapy in autoimmunity and related disorders: our experience with a large cohort of patients

“…This fact raised the possibility that IVIg might be suitable for induction of oral tolerance in various autoimmune states since it contains a wide range of anti-idiotypic antibodies mimicking a wide spectrum of possible sensitizing epitopes. [33]. Tolerance was induced in an experimental model of APS by oral administration of IVIg [33].…”

“…[33]. Tolerance was induced in an experimental model of APS by oral administration of IVIg [33]. Then APS was induced.…”

Induction of immune tolerance by oral IVIG

“…Furthermore, evidence was presented that the anti-idiotypic antibodies present in IVIG are responsible for the immunomodulatory activity of oral IVIG. Anti-idiotypic antibodies are very similar to the original antigen and therefore act like the antigen itself in the induction of oral tolerance [11]. In our study we show a different mechanism for the ability of IVIG to induce immunomodulatory effects after oral treatment.…”

“…Previously, evidence has been presented that orally applied IVIG can induce immune tolerance in an experimental model of anti-phospholipid syndrome [11]. Oral tolerance was achieved when mice were treated with IVIG before the onset of the disease.…”

“…The immunomodulatory effects of IVIG have been attributed to a range of different biologic functions of the polyvalent human IgG that are mediated by either International Immunopharmacology 7 (2007) 351 -359 www.elsevier.com/locate/intimp the Fc part or the antigen-binding F(ab′) 2 part of the IgG molecule [7][8][9][10]. Recently, evidence has been presented that feeding of mice with IVIG or F(ab') 2 fragments of IVIG induces a reduction in the antibody response against β2 glycoprotein I (β2GPI) and a significant attenuation of clinical symptoms in a murine model of experimental anti-phospholipid syndrome [11]. The therapeutic effect of oral IVIG in this model was due to an induction of oral tolerance by anti-idiotypic antibodies present in IVIG that were directed against anti-β2GPI autoantibodies.…”