Novel anti-idiotype antibody therapy for lipooligosaccharide-induced experimental autoimmune neuritis: Use relevant to Guillain-Barré syndrome

Guillain-Barre syndrome (GBS) is an immune-mediated peripheral neuropathy characterized by neuromuscular weakness and frequently accompanied by flaccid paralysis and may occasionally lead to death. The major pathological hallmarks involve demyelination, axonal degeneration, and/or impairment of neurotransmission by ion channel blockage (Rinaldi and Willison, 2008; van Doorn et al., 2008; Kaida et al., 2009). The etiology of GBS is complex and is not fully known. A growing body of evidence, however, indicates that aberrant immune responses triggered by an infectious agent or vaccination allow disease development and the underlying pathogenetic mechanisms (Langmuir et al., 1984; Kuwabara, 2004; Souayah et al., 2007). The most commonly identified microbial agents are Campylobacter jejuni (C. jejuni), Haemophilus influenzae, cytomegalovirus (CMV), Epstein-Barr virus, and Mycoplasma pneumoniae (Hughes et al., 1999; Hadden et al., 2001; Sivadon-Tardy et al., 2006, 2009). A preceding infectious event and patient-related host factors also seem to be related to certain subtypes of GBS and may affect the severity of the disease (Geleijns et al., 2005; Caporale et al., 2006; Yuki, 2007). C. jejuni infection frequently induces antiganglioside antibodies in the patient's serum (Yuki et al., 1990; Usuki et al., 2006b). Thus, despite the possibility of other pathogenic mechanisms, an antibody-mediated process is one of the major insults to the nerve, causing both conduction block and velocity loss and the ensuing clinical symptoms (Rinaldi and Willison, 2008; van Doorn et al., 2008; Kaida et al., 2009). The etiology of GBS has been not been fully clarified; one possibility is based on molecular mimicry and cross-reacting antiglycolipid antibody induction during the postinfectious phase (Yu et al., 2006; Yuki, 2007). For this reason, an elevated level of serum antiganglioside antibodies in GBS is the most important serological marker for disease diagnosis (Ariga and Yu, 2005; Kaida et al., 2009). Conventional treatment strategies rely heavily on removal of pathogenic antiglycolipid antibodies from the blood circulation. In practice, plasmapheresis and intravenous immunoglobulin (IVIG) have been used extensively for treatment (Buchwald et al., 2002; Kieseier et al., 2008). Both strategies, however, are invasive and remove both nonpathogenic and pathogenic antibodies from circulation, with attendant risk of undesirable side effects. One of IVIG's mechanisms is neutralization by antiidiotype antibodies (Dalakas, 2004a). For this reason, we have devised a novel therapeutic strategy to remove specific pathogenic antiglycolipid antibodies by using antiidiotype antibodies. This molecular mimic would serve as a specific competitive inhibitor for antigangioside antibodies in the circulation. According to the idiotype network in autoimmunity, antiidiotype mAbs are produced in syngenic mice against a mouse mAb recognizing GD3 ganglioside (mAb R24; Chapman and Houghton, 1991). BEC2, an antiidiotypic mAb that recognizes the GD3 binding site of R24, mimics GD3 and can be used as an immunogen in mice and humans to induce anti-GD3 antibodies. Thus, the structure of BEC2 mirrors that of GD3. Previously, we reported a model of GBS-like neuromuscular disorder by sensitizing rats with a crude lipooligosaccharide (LOS) fraction of C. jejuni (Usuki et al., 2006b). Interestingly, immunization produced polyclonal antibodies for GD3, GM1, GM2, GD1a, and GQ1b in response to ganglioside-like antigens found in the crude LOS. We have validated that the anti-GD3 antibody is one of the cross-reacting antibodies found in rats that have been sensitized by the crude LOS that contains many ganglioside-like carbohydrate epitopes (Usuki et al., 2006b). This finding was further confirmed by isolation of a purified GD3-like LOS (LOSGD3) and a GM1-like LOS (LOSGM1). Previously, we reported anti-GD3 antibody in two patients with acute and chronic inflammatory demyelinating polyneuropathy (AIDP/CIDP; Usuki et al., 2005). Anti-GD3 antibody is known to be elevated in rare cases of GBS (Yuki and Tagawa, 1998; Yuki et al., 2000) and Miller Fisher syndrome (Willison et al., 1994; Koga et al., 1999). In our current study, the LOSGD3 was used as an immunogen to induce neurodysfunction and concomitant serum anti-GD3 antibody activity in the rat. We previously demonstrated that the serum anti-GD3 antibody possesses neuromuscular junction (NMJ)-inhibitory activity (Usuki et al., 2005, 2006b). This model offers us an opportunity to test the concept of using an antiidiotype antibody for GD3 (BEC2) as a novel agent for treating dysfunction in an LOSGD3-induced animal model as a prototype for developing treatment of similar antiglycolipid-mediated neurological disorders, including GBS, Miller Fisher syndrome, and related immune-mediated neurological disorders.