Medical News: Kidney and Liver Transplant Rejection Purged by Chimerism - in Surgery, Transplantation from MedPage Today
Kidney and Liver Transplant Rejection Purged by Chimerism
By John Gever, Staff Writer, MedPage Today
Published: January 24, 2008
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine. Earn CME/CE credit
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BOSTON, Jan. 23 -- Six organ-transplant recipients have remained healthy for up to five years without anti-rejection drugs, said researchers in the U.S. and Australia whose strategy was chimerism.
In essence, the recipients' immune systems were re-engineered to treat the donor organs -- five kidneys and one liver -- as their own, according to three reports in the Jan. 24 issue of the New England Journal of Medicine.
All but one of the transplants involved HLA-mismatched donations. Action Points
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Explain that the studies found that anti-rejection drugs could be withdrawn successfully in some kidney and liver transplant patients.
Point out that most of the cases involved carefully selected patients not representative of most transplant candidates.
Point out the techniques remain experimental and need to be confirmed in larger numbers of patients.
The idea is to chimerize the organ donor's immune system with the recipient. A successfully chimerized immune system recognizes both the donor organ as well as the recipient's native tissues as self. Thus, there is no need for antirejection therapy and also no danger of graft-versus-host disease.
These are not the first human instances of allograft tolerance, as dozens of cases have been reported before. But the new results show how chimerism and tolerance might be applied to a broad population of transplant recipients.
David Sachs, M.D., at Massachusetts General Hospital, and colleagues reported that four of five kidney transplant patients have been stable for 2.0 to 5.3 years without antirejection therapy.
At Stanford in California, John Scandling, M.D., and colleagues said one patient had gone more than 28 months without antirejection drugs or signs of GvHD. The researchers have tried the same approach in six additional patients, three with less successful results and the other three only just recently.
And clinicians at the University of Sydney in Australia, led by Stephen I. Alexander, M.B., B.S., described a remarkable case of graft tolerance in a young liver transplant recipient.
Both U.S. groups sought to induce chimerism by infusing donor hematopoietic cells along with the organ transplant.
Dr. Sachs and colleagues certainly had the largest number of successes, even more noteworthy because the cases involved HLA-mismatched donors.
Prior to transplant, the recipients received a myeloablative regimen including cyclophosphamide, the MEDI507 anti-CD2 monoclonal antibody drug, cyclosporine A, and thymic irradiation. The last two patients also received rituximab (Rituxan) to deplete B cells.
The patients then received kidneys and intravenous infusions of bone marrow from parents or siblings mismatched by one HLA haplotype. Oral cyclosporine A at 8 to 12 mg daily began with transplant but was tapered and then discontinued over several months.
After transplant, both donor- and native-type leukocytes were found in the patients' blood. But by day 21, this mixed chimerism had disappeared, the researchers said.
In an interview, Dr. Sachs said this period of transient chimerism reflects a normal selection process in the thymus by which immune cells that target self-proteins are eliminated. In their study, as they hoped, not only anti-self reactions were eliminated, but anti-donor reactions as well.
In an accompanying editorial, Thomas Starzl, M.D., the University of Pittsburgh liver transplant pioneer, questioned the disappearance of chimerism in these patients. He pointed out that Dr. Sachs and colleagues had looked for recipient-lineage cells only in blood, not in other tissues.
Dr. Starzl said he believed that a few recipient cells continued to survive. The coexistence of donor and recipient immune cells is critical to successful tolerance, he said.
All the Boston patients showed capillary leak syndrome, a sign of rejection, and one patient developed acute humoral rejection with irreversible loss of renal function. The others were treated with corticosteroids and had cyclosporine withdrawn on schedule, with rejection symptoms eventually disappearing and kidney function remaining normal.
"Stable graft function after planned, complete withdrawal of immunosuppressive drugs is feasible in recipients of HLA-mismatched grafts," the Boston team wrote.
The Stanford team's approach was similar except that the recipient underwent no conditioning prior to the transplant day.
In an interview, Dr. Scandling said the lack of pre-transplant conditioning was important because it means the technique should be adaptable to cadaver transplants, making it more broadly applicable.
On the other hand, the group's cases have involved fully HLA-matched donations -- from a live brother in the successful case reported in the NEJM.
Dr. Scandling described the approach as just one step toward the ultimate goal. Success with HLA-matched donors will pave the way toward testing with mismatched donations, he suggested.
"We'll know more in about six months," he said, when the later patients included in the protocol can be evaluated.
Unlike the Boston group's result in which donor-lineage immune cells predominated after transplant, Dr. Scandling and colleagues found about equal division between donor- and recipient-type immune cells in their successful case.
For both groups, the results capped a long and carefully planned research program.
The Boston and Stanford teams had spent years testing different approaches, first in animals and then in selected human patients.
That's not what happened with Dr. Alexander's group in Australia. They were hoping to save a nine-year-old girl in a desperate crisis.
They had performed what was intended as a conventional liver transplant on the girl, using an HLA-mismatched, cadaver male donor organ and followed by standard immunosuppression.
Ten months later, the girl developed life-threatening hemolytic anemia. It apparently arose as her initially RhD-negative blood subgroup switched to the donor's RhD-positive subgroup. Antibodies to the resulting RhD-positive red blood cells were prompting the hemolytic crisis.
Lab studies suggested that although donor-type hematopoietic cells had largely taken over in her marrow, some residual B cells of the girl's own type persisted and were mounting the antibody attack.
Dr. Alexander and colleagues considered two options for saving the girl. One was to deplete all the girl's antibody-producing B cells with rituximab, including those of the donor's type as well as her own, which would leave her vulnerable to infection.
The other option was to withdraw immunosuppressant therapy altogether, allowing the donor-type hematopoietic cells to completely crowd out the girl's residual B cells. That would end the anti-RhD-positive immune attack.
They chose the second option and it succeeded. The hemolytic anemia resolved and, 17 months after the transplant, Dr. Alexander and colleagues determined that the girl had achieved complete hematopoietic chimerism. Her peripheral blood reflected the donor's HLA typing with repeat studies, although some donor-reactive T-cell populations remained five years after transplant.
Four years after immunosuppressive treatment ended, the researchers said the girl remains healthy, fully tolerant of the liver allograft without immunosuppressant therapy. There were no signs of graft-versus-host disease.
One side effect of her ordeal was that wiping out her original B cells also erased her immunity to mumps, measles, and rubella. Dr. Alexander and colleagues said that normal antibody responses to these pathogens were restored after a standard round of vaccinations.
The researchers said that other factors besides their decision to stop antirejection treatment could have contributed to the outcome. Both the initial period of immunosuppression and an active cytomegalovirus infection that appeared shortly after transplant may have played roles, they said.
In his editorial, Dr. Starzl suggested additional work is needed before tolerance can be induced routinely.
"Perhaps it will be possible to systematically achieve stable organ engraftment with very low dependence on -- or in some cases complete freedom from -- long-term treatment," Dr. Starzl wrote. "To do so will require just the right dose and timing of immunosuppressive therapy with or without the aid of adjunct hematopoietic stem cells."
The Boston group's work was supported by the Immune Tolerance Network, a collaborative clinical research project supported by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Juvenile Diabetes Research Foundation.
The Stanford group's work was supported by the National Heart, Lung, and Blood Institute.
The Australian group was supported by the Juvenile Diabetes Research Foundation.
The Boston group reported no potential conflicts of interest.
Dr. Scandling reported receiving lecture fees from Astellas and research support from Astellas, Novartis, and Roche. Another co-author received research support from Astellas, Isotechnika, Pfizer, and Novartis.
The Australian researchers reported no potential conflicts of interest.
Dr. Starzl reported no potential conflicts of interest.
Primary source: New England Journal of Medicine
Source reference:
Kawai T, et al "HLA-mismatched renal transplantation without maintenance immunosuppression" N Engl J Med 2008; 358: 353-61.
Additional source: New England Journal of Medicine
Source reference:
Scandling J, et al "Tolerance and chimerism after renal and hematopoietic-cell transplantation" N Engl J Med 2008; 358: 362-68.
Additional source: New England Journal of Medicine
Source reference:
Starzl T, "Immunosuppressive therapy and tolerance of organ allografts" N Engl J Med 2008; 358: 407-10.
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