Taming the ABO barrier in transplantation.

Donor shortage remains the single most important factor limiting the success of transplantation medicine. In face of this unrelenting pressure, otherwise prohibitive immunological barriers are increasingly accepted, such as ABO incompatibility of a kidney from an available living donor. Treatment protocols for such situations involve varying combinations of B-cell depletion, removal of isohemagglutinins through plasmapheresis/immunoadsorption, and augmented immunosuppression. Outcome in terms of patient and graft survival is excellent both in pediatric and adult recipients. The rate of graft loss in the first weeks after transplant is increased, however, in ABO-incompatible transplants, and concerns regarding the long-term infection risk persist. Moreover, indirect signs of antibody deposition are commonly found on graft biopsies even though their clinical significance remains unclear. Also, treatment protocols need to start before the transplant, making them unsuitable for the deceased donor setting and thus restricting their use. Although ABO compatibility is less important in hematopoietic stem cell transplantation, clinical outcome is nevertheless inferior in recipients of an ABO-incompatible graft. Thus, therapies better controlling ABO-antibody production could improve outcome in ABO-incompatible organ and stem cell transplantation. In this issue of Blood, Tazawa et al find that iNKT cells regulate the production of antibodies against the blood group A antigen. Previously, the authors had established that in mice B cells (of the B-1a type) exist with surface IgM receptors for group A antigen, that natural anti-A antibodies are present, and that anti-A antibody levels are further increased on immunization. They now demonstrate that 2 strains of mice deficient in iNKT cells (CD1d and Ja18 mice) fail to develop increased anti-A levels on immunization with blood group A red blood cells. In the reverse experiment, activation of iNKT cells with a-galactosyl ceramide boosts anti-A levels. Importantly, the authors then manage to block the induced anti-A antibody production by administering an anti-CD1d monoclonal antibody (mAb) at the time of immunization. They conclude that CD1d-restricted iNKT cells are required to induce anti-A antibody production, presumably through interacting with CD1d expressed on B cells. To dissect the mechanism of how iNKT cells stimulate anti-A production, the authors measured cytokine serum levels and found a transient elevation of interleukin (IL) iNKT cells stimulate B cells to produce antibodies against ABO blood group antigens through a mechanism involving the interaction of invariant T-cell receptor–CD1d and the production of IL5. Anti-CD1d mAb blocks antibody production against blood group A antigen, potentially revealing a novel therapeutic strategy for ABO-incompatible transplant recipients, preventing rejection episodes mediated by antibodies against the widely expressed ABO blood group antigens. Professional illustration by Alice Y. Chen.