Tolerance induction: a job for B cells?

Comment on Lei and Scott, page 4865

B cells transduced with dominant factor VIII epitopes suppress the production of inhibitory antibodies

Inducing antigen-specific unresponsiveness into fully immunocompetent hosts has been a long quest for immunologists. Numerous potential applications in fields such as autoimmunity, allergy, and transplantation come immediately to mind. The recent emergence of methods by which immune cells can be handled in vitro to express transgenes could be a way to end that quest.

Up to now, most work has been carried out with immature dendritic cells, but B cells offer a valuable alternative, given their capacity to induce tolerance by cognate interaction with T cells.^1,2  Properly manipulated B cells can survive for long periods of time after transfer to the host and have the potential to locate in germinal centers for close encounter with specific T cells.

Until recently, research in the field has been hampered by the difficulties of obtaining efficient transduction of B cells with full expression of T-cell epitopes into major histocompatibility complex (MHC) class II complexes.³  In this issue of Blood, Lei and Scott used an alternative strategy, in which the transgene is linked to the immunoglobulin heavy chain. In the past, the authors have reported on the efficacy of such constructs in a number of models of autoimmune diseases, including uveitis,⁴  multiple sclerosis,⁵  and diabetes.⁶  Their report in this issue deals with the vexing problem of inhibitory antibodies elicited by factor VIII (fVIII) replacement therapy in patients with hemophilia A. Thus, fVIII^-/- mice that underwent transplantation with B cells containing major B-cell epitopes of fVIII linked to an immunoglobulin G (IgG) heavy chain backbone produce virtually no inhibitor upon subsequent administration of fVIII according to a protocol mimicking fVIII administration in patients and known to elicit inhibitors in all mice. Moreover, transfer of such transduced B cells suppressed an ongoing inhibitor response. These observations were unexpected, as B cells tolerize naive but not primed T cells. The expansion of regulatory T cells may provide a potential explanation for this paradox.

These fascinating results raise a number of issues. First, the precise mechanism of action is not elucidated. Further phenotypic characterization of the putative regulatory CD4⁺CD25⁺ T cells is needed, as are transfer experiments. Second, the effect of the immunoglobulin heavy chain added to the construct remains unclear, particularly in terms of the mechanism by which the T-cell epitopes are loaded onto MHC class II molecules. Third, there is the question of whether a single injection of transduced B cells would be all that is required for long-term suppression of antibodies in patients exposed on a regular basis to the fVIII antigen.

Applying this type of approach to patients might not be too distant. Human B cells can be transduced efficiently, but methods to expand B cells in vitro would be required, since the number of cells presently used might exceed what could be obtained from a peripheral vein. Alternative strategies for transduction will also be required, as a substitute for retroviruses.

Clearly, the findings of Lei and Scott open new possibilities not only for innovative the rapeutic strategies, but for improving our understanding of the mechanisms by which anti-fVIII immuneresponses are kept under control. ▪