In Vivo Antiidiotypic Therapy In Autoimmune Diseases

Anti-idiotypic therapy has not been tried in human autoimmune diseases directly. One study used the approach of passage of plasma over an anti-idiotype column which removes antibodies bearing the common idiotype [51], In this study, an anti-3I Id column was used to remove anti-ds DNA antibodies bearing the 31 Id from patients with SLE. There were no significant side effects. The recent development of 'humanized' murine or rat monoclonal antibodies opens the way for direct injection of Id-bearing or anti-idiotypic antibodies into patients.

Intravenous immune globulin (IVIG) exhibits a number of immunomodulatory properties that are mediated by the Fc portion of IgG and by the spectrum of variable (V) regions contained in the immune globulin preparations. Significant progress has been made in understanding the mechanisms by which IVIG exert immunomodulatory effects in the treatment of autoimmune diseases [52, 53] (see Table 3).

Table 3. Possible mechanisms of action accounting for the immunomodulatory effects of IVIG

• Neutralization of circulating autoantibodies by anti-idiotypic antibodies in IVIG.

• Selection of immune repertoires.

• Functional blockage of Fc receptors on splenic macrophages.

• Inhibition of complement-mediated damage.

• Modulation of the production of cytokines and cytokine antagonists.

Much attention has been given in recent years to the possibility that the immunomodulating effects seen in autoimmune diseases treated with IVIG (intravenous immunoglobulin) may be applied by anti-idiotypic antibodies present in the gammaglobulin preparations. Indeed, recent studies strengthen the likelihood that anti-idiotypic antibodies present in IVIG preparations may control autoimmune reactions. Patients who developed antibodies to their own circulating factor VIII can bleed severely. IVIG can block the secretion of such antibodies and this property has been attributed to the presence of naturally occurring anti-Id antibody to the antibody against factor VIII [54-55], Subsequently IVIG, prepared from large pools of plasma from normal donors, were found to contain specific anti-idiotypes against a number of disease-related autoantibodies, including antibodies to DNA, thyroglobulin, gastric intrinsic factor [56, 57], peripheral nerve [58], neutrophil cytoplasmic antigens [59], platelet gpIIb/IIIa [60], and membrane antigen of erythroblasts [61].

Dietrich and Kazatchkine [57] found that antiidiotypes in IVIG recognize a cross-reactive idiotype on human anti-thyroglobulin (TG) autoantibodies that was defined by heterologous anti-idiotypic antibodies, termed anti-T44 antibodies. The idiotype was expressed on anti-thyroglobulin IgG of 8 out of 9 patients with Hashimoto's disease but on no IgG of 5 healthy individuals who were tested. Antithyroglob-ulin autoantibodies expressing the T44 idiotype exhibited restricted epitopic specificity against human thyroglobulin, thus, IVIG contain anti-idiotypic antibodies directed against an immunodominant cross-reactive idiotype of human anti-TG autoantibodies. Evans and Abdou [62] have demonstrated that anti-idiotypic antibody and its (ab')2 fragments prepared from pooled normal human IgG had a partial inhibitory effect on the spontaneous in vitro secretion of anti-DNA antibodies from blood mononuclear cells of lupus patients.

The inhibitory effect was specific for anti-DNA secretion as the anti-idiotype failed to inhibit the spontaneous secretion of anti-tetanus toxoid, in the same culture supernatants [62].

Several lines of evidence demonstrate the presence in IVIG of anti-idiotypes against autoantibodies. These include:

1. F(ab')2 fragments from IVIG inhibit the binding of autoantibodies to their autoantigens [54, 58, 63],

2. F(ab')2 fragments with autoantibody activity are specifically retained on affinity columns of sepharose-bound F(ab')2 fragments from IVIG [59, 63, 64],

3. IVIG contain no antibody specificities against the most common allotypes expressed in the F(ab')2 region of human IgG [63].

4. The binding of IVIG to affinity-purified autoantibodies is specifically displaced by F(ab')2 fragments from heterologous polyclonal antiautoanti-body anti-idiotypes [56].

The high number of donors contributing to IVIG endows the preparation with anti-idiotypic specificities that may not necessarily be detectable in plasma from single healthy individuals. The IVIG may be efficient in some autoimmune diseases by providing a source of anti-idiotypes with a wide range of specificities brought as interconnected antibody species that may compensate for altered connectivity of the immune network of patients with autoimmune diseases [56],

Indeed, Bakimer et al. [65] have examined the effect of IVIG on the obstetric complication of experimental antiphospholipid syndrome (APS). After showing the binding of IVIG to mouse and human anti-cardiolipin antibodies (ACA) (e.g., the existence of natural anti-idiotypic autoantibodies to ACA), they infused 36 mu-g of IVIG to the tail vein of mice in which experimental APLS was induced by passive transfer of monoclonal mouse ACA (CAR). Mice treated with IVIG had significantly less fetal resorptions when mated, in comparison to untreated mice. The best results were achieved when IVIG was given 2 days after induction of the disease (on day 6 of pregnancy) [65].

Arnout et al. [66] have described an interesting patient with a history of habitual abortion, deep venous thrombosis, thrombocytopenia, high titer IgG anticar-

diolipin antibodies and a clear positive lupus anticoagulant. She was treated during her seventh pregnancy with high dose IVIG from the third month onwards. Every month, a daily infusion of 400 mg immunoglobulins per kg body weight was given during five consecutive days. The patient's pregnancy ended preterm with a live birth, delivered by caesarian section because of a placental abruption. Each treatment with IVIG resulted in a slight reduction of both anticardi-olipin antibodies and lupus anticoagulant levels and in an increase in platelet count. During the six-month observation period, a gradual decline in antiphospho-lipid antibodies and an increase in platelet count was found. The potential role of anti-idiotypic antibodies present in the IVIG used for treatment was studied. In vitro IVIG were able to reduce the binding of the patient's anticardiolipin antibodies to cardiolipin coated microti ter plates. The presence of anti-idiotypic antibodies in IVIG was further documented by affinity chromatography and by real-time biospecific interaction analysis (BIA) on a BIA-core instrument. Affinity purified anticardiolipin antibodies were retarded on a column of insolubilized IVIG and a weak interaction was found between IVIG and affinity purified patient antiphospholipid antibodies, coupled to the BIA-core biosensor. In addition, the same technology revealed increased levels of anti-antiphospholipid antibodies in the patient's plasma following IVIG therapy. The partial and transient reduction of anti-phospholipid antibody levels observed immediately following each treatment course seems compatible with low affinity complexation of idiotype-antiidiotypes, resulting in an accelerated clearance of the autoantibodies. Despite the low affinity for the patient's idiotypes, the beneficial long term effects observed could be related to an immune regulatory role of these anti-idiotypic antibodies on the synthesis of antiphospholipid antibodies [66],

Lockwood had shown the beneficial effect of IVIG in the management of vasculitis [67], The author has shown the importance of ANCA idiotypic-anti-idiotypic reactions in vitro and demonstrated that these could be influenced by anti-idiotypic determinants present in IVIG. Thus F(ab')2 fragments of IVIG could block ANCA binding to antigen, in a dose-dependent fashion. The degree of inhibition was variable, ranging up to 100% for the ANCA-containing sera of certain patients. Similar inhibitory activity could be found in the sera of patients in remission after treat ment, as well as in occasional patients whose disease remitted spontaneously, without drugs being used [67],

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