When he was a medical trainee, UCLA Health nephrologist Erik Lum, MD, was part of a team at Stanford University exploring how to create “tolerance” in kidney-transplant patients — a process that encourages the body to welcome the new organ without the necessity for a lifelong regimen of anti-rejection drugs.
Now, Dr. Lum is among the leaders of a multidisciplinary team making transplant tolerance a reality at UCLA Health. Two kidney transplants have been performed thus far under the advanced protocol, making UCLA Health one of only five medical centers in the world capable of the groundbreaking approach hailed as “the Holy Grail” of transplantation.
“It requires a lot of interplay between different divisions,” Dr. Lum says. “To me, it really demonstrates the strength of a place like UCLA. You can’t do this just anywhere. It’s a huge collaboration.”
The protocol, made possible by funding provided by the OneLegacy Foundation, brings together a broad range of specialties, including nephrology, urology, hematology, radiation oncology and others, for a series of treatments that prime the transplant recipient’s body to accept the new organ.
With traditional transplants, the body recognizes the new organ as a foreign invader, prompting the immune system to attack. A regimen of immunosuppressive anti-rejection drugs tamps down this natural response. The drugs, which themselves carry potentially significant risks, remain necessary throughout the patient’s life because the body continues to see the organ as foreign.
Teaching the body to tolerate transplanted organs
The tolerance approach calls for blending the donor’s and recipient’s immune systems through an infusion of the organ donor’s stem cells shortly after the organ transplant. Called “mixed chimerism,” this blending prompts the recipient’s body to recognize, rather than reject, the new organ.
“If you have introduced both the donor’s stem cells and kidney, then the recipient’s immune system recognizes that kidney as self,” says Jeffrey Veale, MD, who specializes in renal transplantation and was instrumental in developing the new tolerance protocol at UCLA Health.
The science that led to the development of the organ-transplant tolerance approach has been evolving for decades.
"The recipient's immune system recognizes that kidney as self."
Jeffrey Veale, MD
Solid-organ transplants have been successfully performed since the 1950s, but they always have required powerful medications to prevent the recipient from rejecting the new organ. In addition to being expensive, these immunosuppressive drugs carry with them a number of serious potential complications, including increased risk of cancer, infection, diabetes, hypertension and heart disease, and they must be carefully managed throughout the patient’s life.
Because these powerful medicines are filtered through the kidneys — including the very kidney that has been transplanted — they eventually overwhelm and overtax the new organ. A goal of the tolerance approach is to extend the survival of the transplanted kidney.
Eliminating the need for anti-rejection medication
Incorporating an infusion of stem cells from the donor’s blood as part of the organ-transplant process works to prevent the recipient’s body from rejecting the kidney without the need for immunosuppressive drugs. The immune systems of the host and donor live side by side.
“Stem-cell transplants and solid-organ transplants are usually conducted very independently of each other,” says bone-marrow transplant specialist Neil Kogut, MD, who worked closely with Dr. Veale to develop UCLA Health’s transplant-tolerance protocol.
“These are very separate worlds that the doctors and researchers in these fields occupy,” Dr. Kogut says. “This protocol is a unique opportunity to bring stem-cell transplantation and solid-organ transplantation together to try to achieve something very positive for transplant recipients. It is a unique synergy of these two fields.”
Radiation therapy also plays a role
Creating tolerance in an organ recipient also requires radiation treatment to prime the recipient’s immune system to accept the donor’s stem cells. Called “total lymphoid irradiation,” the approach was once employed to treat Hodgkin’s disease, but it now is used primarily to minimize the need for post-transplant immunosuppressive drugs, says radiation oncologist Ann Raldow, MD, MPH, another member of UCLA Health’s transplant-tolerance team.
Patients receive the treatment shortly after their transplant surgery to help prevent graft-versus-host disease, Dr. Raldow explains. “The patients come in before their transplant and we develop a radiation-therapy plan that is specific to their anatomy,” taking special care to avoid exposing the newly transplanted kidney to radiation, she says.
UCLA’s new protocol is based on a procedure successfully performed at Stanford, where kidney-transplant recipients have survived without immunosuppressive drugs for 15 years.
Taking the science further
While tolerance has been achieved in transplants with well-matched sibling donor-recipient pairs, UCLA Health physicians, in collaboration with OneLegacy, intend to expand the protocol to include deceased donors, the source for most of the organs transplanted in the U.S. Deceased donors accounted for more than 77% of the 22,800 kidney transplants performed nationally in 2020.
If that goal is achieved, “it will have a huge impact,” Dr. Kogut says. Extending tolerance transplants to include deceased donors would allow for other kinds of transplants — from solid organs to composite-tissue allografts for hands and faces — to be done without the necessity for lifelong immunosuppression-drug regimens.
“It opens up a whole new world,” says Dr. Veale.
