Drug-free kidney transplants could one day be an option even for people without immune-matched donors, according to a pair of papers published today.
In January, I wrote a news feature about an experimental protocol to help recipients of kidney transplants avoid having to take immunosuppressive drug therapy for life. The approach, investigated for more than a decade by doctors in Massachusetts and California, involves giving bone marrow or just a subset of marrow-derived stem cells from the same people who donate the kidneys in an effort to induce tolerance to the foreign organ.
In one of the two papers published today, the same California team reports in the American Journal of Transplantation that 11 of 16 people who underwent the procedure since 2005 with tissue-matched siblings as donors achieved long-term normal kidney function and successfully weaned off their immunosupressants, and a twelfth study subject is now in the process of tapering the drug regimen. In unpublished results, the Massachusetts group has achieved similar success in seven of ten people who were only half matches with their donors. Both groups, however, have not always seen levels of donor immune cells sustained over the long haul—and this means that the risk of organ rejection can return.
But other research groups that have incorporated the drug cyclophosphamide, a chemotherapy medication used to treat lymphoma, have seen more lasting effects. For example, the second paper published today from a team led by Suzanne Ildstad, director of the University of Louisville’s Institute for Cellular Therapeutics in Kentucky, and Joseph Leventhal, a kidney transplant surgeon at the Northwestern Memorial Hospital in Chicago, describes a way to boost the level of donor immune cells in the recipient for the long term—so much that it completely takes over the recipients’ native bone marrow.
Traditionally, this wholesale replacement of a person’s immune system often leads to graft versus host disease (GvHD), in which the donor cells start attacking the recipient’s healthy organs. But five of eight subjects in the new study maintained normal kidney function for at least seven months off of immunosuppression, with no signs of this debilitating and sometimes deadly complication. The results were published in Science Translational Medicine.
Notably, four of the five individuals who remain off immunosuppressive drugs received kidneys and marrow from donors who were completely unrelated to them. “We’ve shown that this tolerance induction strategy can work in mismatched donor-recipient pairs,” says Leventhal.
The chemotherapy and radiation protocol involving cyclophosphamide—which is thought to help prevent both graft rejection and GvHD—was largely developed by Ephraim Fuchs, a bone marrow transplant expert at the Johns Hopkins Kimmel Cancer Centre in Baltimore, Maryland. Fuchs himself has unpublished results from a trial of 11 people who received partially mismatched bone marrow to treat sickle cell disease, eight of whom show no signs of GvHD.
But Leventhal and Ildstad went the extra step of manipulating the blood stem cells to eliminate any GvHD-producing cells while retaining a set of specialized bone marrow-derived cells dubbed ‘facilitating cells’. Ildstad and the company she founded, Regenerex, consider the cell preparation technique proprietary, so a full description of the facilitating cells themselves has not been revealed. As such, researchers remain uncertain whether the cyclophosphamide in the conditioning regimen or the facilitating cells themselves is responsible for the authors’ latest results.
“What role her facilitating cells have in all this remains enigmatic,” says Rainer Storb, head of the Transplantation Biology Program at the Fred Hutchinson Cancer Research Center in Seattle. “Nobody knows.”
Image: Matt Huynh