Editorial was successful with the administration of methotrexate within the first 24 h of ERT. Since there was an increase in peritoneal B1 B cells within the first 24 h of ERT administration, it is believed that the reduction of this B1 B-cell response may be part of the complex mechanism of action of methotrexate-induced immune tolerance [12]. Methotrexate also targets rapidly dividing B and T cells, which reduces overall antibody production. Tissuespecific adeno-associated virus vector-mediated gene therapy has also been investigated in the murine Pompe model and appears to induce immune tolerance to rhGAA due to the upregulation of regulatory T cells [13]. A monoclonal nondepleting anti-CD4 antibody has previously been used to suppress the immune response to equine IgG in nonhuman primates [14], prompting its consideration for use in Pompe disease. This antibody appears to block T-cell activation and prevent T-cell help to antigenactivated B cells, while upregulating regulatory T cells. The utility of this anti-CD4 antibody in counteracting the immune response to ERT is currently being explored in the murine Pompe model with early success [15].

In addition to these studies in the murine Pompe model, the clinical setting of IPD has served as an excellent model for the understanding of the impact of antibody responses to thera peutic protein and demonstrating the potential clinical applications of immunomodulation to optimize therapeutic efficacy. Various combinations of rituximab (anti-CD20 monoclonal antibody), plasmapheresis, intravenous immunoglobulin (IVIg), cyclophosphamide, methotrexate and increased-dose ERT have been used to try to prevent the development of or eliminate anti bodies against ERT in the IPD setting [16–19]. Of these, the combination of rituximab and methotrexate±intravenous γ globulin has been able to successfully tolerize IPD patients to rhGAA in the naive or early ERT setting [16, 17]. Although the exact mechanism by which this immunomodulatory regimen counteracts the immune response has not been elucidated, a basic understanding may be developed based on the proposed mechanisms of the individual agents. While methotrexate targets both B and T cells, rituximab targets CD20-positive B cells, which are responsible for the initiation and propagation of an immune response. IVIg downregulates antibody responses by binding to inhibitory FcR and also protects against infectious agents in immune suppressed conditions. It is believed that the suppression of B-and T-cell populations responsible for antibody formation, with simultaneous upregulation of regulatory T cells, is important for the success of this immunomodulatory regimen in diminishing the immune response to rhGAA.