ITS 2012 Report – Translational approaches to tolerance induction

by Maria Dalby – Patients receiving kidney transplants from human leukocyte antigen (HLA)-matched donors can be induced to develop tolerance to the graft and thereby avoid lifelong immunosuppressive treatment. At Stanford University, the transplant team have developed a protocol for tolerance induction involving total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) conditioning which induces immune tolerance by promoting the development of chimerism. Professor John Scandling, who has been responsible for translating the protocol from animal models to clinical practice, presented a summary of the development and experience over the past 10 years.

In transplant medicine, tolerance is defined as a state of unresponsiveness of the recipient’s immune system to donor-specific antigens which, if achieved successfully, will reduce or ideally eliminate the need for immunosuppressive medication. Given the often debilitating side effect profile of most effective and widely used immunosuppressants, tolerance induction has become the ‘holy grail’ of transplantation with intense research efforts and resources going into developing protocols that are both safe and efficient.

Professor Scandling and his team based their work on data from studies on mice that had undergone combined organ and haematopoietic cell transplantation, which showed that tolerance conveyed by persistent mixed chimerism (that is, coexistence of donor and recipient cells within an individual), could be achieved with a combination of TLI and ATG. In the course of 10 years, a total of 25 patients at the Palo Alto centre, 14 men and 11 women aged between 22 and 61 years, have undergone HLA-mismatched (n=7) and matched (n=18) renal transplantation with kidneys from living donors and received post-transplant conditioning with 10 doses of TLI and 5 doses of ATG. Under the protocol, the conditioning treatment was followed by infusions of donor-derived CD34+ haematopoietic progenitor cells and T cells. Patients who were shown to have developed transient chimerism (in the first 6 HLA-mismatched patients) or stable chimerism for at least six months (in the 18 HLA-matched and the final HLA-mismatched patient), and who showed no sign of graft rejection or graft versus host disease could have their anti-rejection medication withdrawn after a minimum of six months.

When Professor Scandling made his last observation prior to leaving for the conference, all patients maintained excellent graft function, up to 11 years post-transplantation. The first six HLA-mismatched donors were transplanted between 2000 and 2003; of these, two were able to stop their anti-rejection medication after developing transient chimerism, but had to resume treatment following acute rejection episodes at 3.5 and 5.5 months post-transplant, respectively – once back on immunosuppressants, graft function returned to baseline. Of the 18 HLA-matched patients who were transplanted during 2005-2012, three developed acute rejection that could be easily reversed, and one patient developed immediately recurrent focal segmental glomerulosclerosis that went into long-term remission. All four of these patients remain on anti-rejection therapy. Of 11 HLA-matched patients who have been able to stop their immunosuppressive therapy, three patients have been observed for five months and eight patients for between two and four years, with no signs of rejection. At the time of Professor Scandling’s presentation, patients number 16 and 17 had developed stable chimerism and were in the process of stopping their immunosuppressive medication, and patient number 18 had only been recently transplanted. The seventh HLA-mismatched patient was transplanted in 2010, and remains on immunosuppression having so far developed only transient chimerism. Based on these findings, Professor Scandling and the team will continue to enroll patients in the HLA-matched protocol, and modify the HLA-mismatched protocol to enhance its ability to induce stable chimerism and long-term tolerance.

John D Scandling, Stanford University, Palo Alto, USA