TRANSPLANTATION MEDICINE

Mismatched Kidney Transplant Succeeds Without Immunosuppression

Donor Bone Marrow, T Cell Depletion Induce Tolerance to Organ Graft

For the first time, a medical team reports stable kidney function after deliberately withdrawing antirejection drugs from patients. Transplanted kidneys from close but immune-mismatched relatives have survived in four of the five people in the study for two to five years, says the team from Massachusetts General Hospital in the Jan. 24 New England Journal of Medicine.

Copyright 2006 Joshua Touster

Transplanting organs without immunosuppressive drugs may be possible, based on studies in mice, monkeys, pigs, and people by a team of bench scientists that attend clinical rounds and clinicians who visit the labs. Pictured here are team members (clockwise from left) David Sachs, Tatsuo Kawai, Thomas Spitzer, Megan Sykes, Dicken Ko, Benedict Cosimi, Jennifer Searl (the first study patient), and Nina Tolkoff-Rubin.

It is too soon to know if this protocol means the end of lifelong drugs and their life-shortening side effects for these four people, but the results mark a hopeful milestone in a long quest to induce tolerance to transplanted tissue.

“Every transplant physician has a few patients off drugs—in the liver, it’s as high as 20 percent,” said Mohamed Sayegh, director of the Transplantation Research Center at Brigham and Women’s Hospital and Children’s Hospital Boston, who was not involved in the study. “But we don’t know what is going on with them. This is the first time a procedure was done intentionally to transplant patients to get them off drugs, based on well-done mouse and monkey studies. This is a positive and important first step toward wider clinical applicability.” Sayegh is the Warren Grupe–John P. Merrill professor of transplantation medicine at HMS and BWH.

The enthusiasm of the team and other transplant specialists is tempered by stories of kidney rejection among the few accidental and experimental cases of people who stopped taking antirejection drugs. Caution also arises because the underlying mechanism in the four people may be different from the mechanism originally identified in mouse studies.

“This is just the beginning,” said transplant surgeon and first author Tatsuo Kawai, HMS assistant professor of surgery at Massachusetts General Hospital. “There are a lot of things we don’t know. We have to do more in terms of clarifying the mechanisms of tolerance induction, having more patient experience, and establishing the long-term safety of this protocol.”

Raising Tolerance
To pass muster with doctors, patients, and insurance companies, the experimental protocol must be at least as good as the method that now saves the lives of many people with malfunctioning kidneys or other organs—at least for a while. Most patients and their new organs survive at least one year and usually five years. Some transplanted organs, such as kidneys, can survive for decades, but nearly 40 percent of them from living donors, and many more from deceased donors will fail by 10 years. The failure rate has not budged noticeably for a decade.

The price for hanging onto new organs is constant immunosuppression. Few people have genetically identical donors, so most recipients must take the drugs for the rest of their lives. Without the drugs, the body attacks the transplanted organs, but the drugs themselves take a toll by promoting infections and cancer.

“Ten years used to be a long time after a transplant,” said Benedict Cosimi, the Claude E. Welch professor of surgery at HMS and MGH and co-principal investigator of the study. “Now, we anticipate patients will need to go on for 40 years. They will need multiple transplants, and we don’t have the kidneys to give them.”

Tolerance offers the prospect of longer and higher-quality lives free from the complications of antirejection drugs, said David Sachs, the Paul S. Russell/Warner Lambert professor of surgery, director of the MGH Transplantation Biology Research Center, and co-principal investigator of the study. Sachs and his colleagues envision healthier grafts at lower risk of acute and chronic damage or rejection, lower costs due to savings in part on immunosuppressive drugs, more available organs if any advances can be translated to xenotransplantation, and other applications, such as in autoimmune diseases.

Tricking and Training
The experimental protocol trades a lifetime of immunosuppressive drugs for a complicated and potentially dangerous procedure up front. In a traditional kidney transplant, a patient can be in and out of the hospital in five days, said renal specialist and co-author Nina Tolkoff-Rubin, an HMS professor of medicine at MGH. In this procedure, the preconditioning alone takes five days and may cause nausea, fatigue, and temporary hair loss. After the transplant, the patient spends at least two weeks in a sterile room while the bone marrow and immune cells grow back.

The protocol aims to mix the recipient’s and donor’s bone marrow long enough to trick the immune system into tolerating the donor organ forever. In preparation for the combined kidney and bone marrow transplant, the medical team uses chemotherapy to partially destroy the patient’s bone marrow, an antibody targeted to mature T cells, and radiation of the thymus. This makes room for the donor’s bone marrow, which is infused immediately after the kidney transplant. The circulating antibody keeps working to deplete donor T cells.

The strategy worked in the first two patients, but the preconditioning now includes an antibody to deplete the B cells, because B cell antibodies caused the third patient to develop early rejection and organ failure. He received another kidney in a conventional transplant. In the modified protocol, the final two patients in the study were weaned off immunosuppressive drugs within several months with no rejection so far.

Lab studies confirmed that donor marrow engrafted and produced a full lineage of blood and immune cells for less than a month, before all evidence of donor cells vanished. Yet recipients showed systemic tolerance to donor but not third party cells in laboratory studies.

It seems to work, but maybe not exactly as research predicted. In the well-studied mice, the researchers understand that permanent chimerism sends bone marrow progeny to the thymus, where maturing T cells are educated to tolerate their genetic kin.

“We call this central tolerance,” said co-author Megan Sykes, the Harold and Ellen Danser professor of surgery at HMS and MGH. “I don’t think that’s what’s going on in our patients. There is some evidence that regulatory cells might be involved. Comparisons with patients who received similar hematopoietic cell transplants without the kidney indicate that the tolerance we see in vitro requires the kidney transplant.”

Animal studies of kidneys and other solid organs seem to suggest that tolerance depends in part on the kidney being in place during the transient chimerism. In an accompanying commentary, Pittsburgh transplant surgeon Thomas Starzl hypothesizes that an undetectable sustained state of microchimerism explains the tolerance, but the MGH team has found no evidence of that.

Five people in need of kidney transplants underwent an experimental procedure that included withdrawing immunosuppressive drugs. Jennifer Searl, the first patient, had a transplanted kidney that was failing and painful viral warts on her face and legs. The warts disappeared after immunosuppression stopped in March 2003, and now she is training for a marathon. Her lab tests plotted above show stable creatinine, a measure of kidney function, as the immunosuppressive drug is lowered a year after the procedure. Another test shows her cytotoxic T cells becoming unresponsive to donor cells (right; arrow indicates complete end of immunosuppressive drugs.)

From a patient care perspective, Kawai feels more comfortable with the transient macrochimerism because of the lower risk for graft-versus-host disease. He remains concerned about capillary leak, a syndrome that occurred about one week after the transplant in each patient, likely a result of cytokines released during rejection of the donor bone marrow, which resulted in transient renal insufficiency.

The National Institutes of Health has agreed in principle to fund a second clinical trial, probably involving 20 people and likely including two other sites in the Immune Tolerance Network (www.immunetolerance.org), the authors said. The next series of transplants could begin as early as this year. Interested physicians and patients may contact Tolkoff-Rubin, ntolkoffrubin@partners.org, or Sandra deBronkart, clinical research coordinator, sdebronkart@partners.org. For more information, see massgeneral.org/transplant/kidney/research/index.htm.

—Carol Cruzan Morton

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