Making dendritic cells that turn immune responses off

Replacement therapies for inherited protein deficiencies such as hemophilia or lysosomal storage disorders are plagued with antibody-mediated rejection of the therapeutic protein. This serious problem is well described in protein/enzyme replacement therapies and is likely to be a hurdle for gene therapies as well, especially when performed in subjects with severe mutations such as gene deletions, which are more likely to result in a lack of tolerance to the functional protein (Cao et al., 2009). Perhaps the most extensive clinical experience with confronting this problem comes from treatment of the X-linked bleeding disorder hemophilia A, caused by mutations in the gene for coagulation factor VIII (F.VIII). Approximately 30% of patients with severe hemophilia A form neutralizing antibodies ("inhibitors") during factor replacement therapy (which is based on intravenous infusion of plasma-derived or recombinant F.VIII). Above a certain titer, these antibodies render therapy ineffective, necessitating use of more complicated and even more expensive bypass reagents and increasing risks of morbidity and mortality. With a success rate of 60-80%, frequent high-dose F.VIII infusions eradicate the inhibitor over the course of months, and sometimes 1 to 2 years (Di Michele, 2011). No prophylactic protocols for prevention of the inhibitor response have been explored yet. In contrast, immune tolerance regimens are increasingly being performed early or even before the onset of enzyme replacement therapy (ERT) for the deadly infantile form of the lysosomal storage disorder Pompe disease, caused by mutations in acid alpha -glucosidase (Byrne et al., 2011). It is hoped that prevention of antibody formation increases the effectiveness of ERT and eliminates immunotoxicities. However, these protocols thus far rely on general immune suppression. Clearly, more refined antigen-specific approaches are desirable. Indeed, multiple avenues toward novel immune tolerance protocols for treatment of genetic diseases are being explored in preclinical studies. These include introduction of the antigen along with blockers of costimulation, transient blockade of T cell function, in vivo expansion of regulatory CD4 super(+) T cells (Tregs) with interleukin (IL)-2/IL-2 receptor complexes, deletion of effector T cells coupled with expansion of Tregs using the mTOR inhibitor rapamycin, mucosal antigen administration (such as oral tolerance), and transient manipulation of B cell function (Verma