Reuters Health Information (2008-01-23): Kidney transplants with stem cells remain functional without immunosuppression
Kidney transplants with stem cells remain functional without immunosuppression
Last Updated: 2008-01-23 17:00:24 -0400 (Reuters Health)
NEW YORK (Reuters Health) - Renal function can be maintained for years without immunosuppressive therapy following the combination of kidney and hematopoietic stem cell transplantation from living related donors, according to two articles in The New England Journal of Medicine for January 24.
Authors of a third article in the Journal report similar potential for full immune tolerance in liver transplant recipients.
The three research teams agree with the author of an accompanying editorial that immune tolerance induced by persistent mixed lymphohematopoietic chimerism allowed cessation of immunosuppressive therapy without altering organ function in their patients.
In one report, Dr. Samuel Strober and associates at Stanford University School of Medicine in California describe outcomes for a 47-year-old man with end-stage renal disease transplanted with an HLA-matched kidney from his brother.
Following a conditioning regimen of total lymphoid irradiation and antithymocyte globulin, the patient received donor peripheral mononuclear cells enriched with hematopoietic progenitor cells.
Persistent mixed chimerism in B cells, natural killer cells, granulocytes and T cells developed during the first month after transplantation and persisted until the last analysis. Cyclosporine was discontinued after 6 months, and "the patient remains in good health 34 months after transplantation," Dr. Strober and his associates report, with no episodes of rejection or graft-versus-host disease.
Four patients who received combined bone marrow and kidney transplants following a nonmyeloablative preparative regimen also retained renal function during follow-up of 1.2 to 4.6 years after withdrawal of immunosuppressive therapy, according to authors of the second paper.
Dr. David H. Sachs, from Harvard Medical School in Boston, and associates report that donors in all four cases were HLA single-haplotype mismatched living relatives. Immunosuppressants were discontinued 9 to 14 months after transplantation. Despite the achievement of only transient multilineage blood-cell chimerism, "they have retained the graft and maintained stable renal function for 2.0 to 5.3 years after the transplantation."
The third report involves a 9-year-old girl in Australia who received a fully HLA-mismatched, sex-mismatched liver allograft and developed severe hemolysis due to host-versus-graft disease, which resolved after withdrawal of immunosuppressive therapy. Liver function normalized, Dr. Michael O. Stormon at the University of Sydney and his associates report, and she "remains well 5 years after transplantation."
At 9 months it was discovered that her blood type had changed from group O, RhD-negative, to that of the donor -- group O, RhD-positive. Dr. Stormon's group suggests that this change reflects "the development of chimerism by engraftment of the recipient marrow from passenger hematopoietic stem cells within the transplanted liver."
The chimerism, in turn, may have resulted from the immune-modifying effects of lymphopenia and CMV infection in the host and increased stem cell population in the transplanted liver related to the young age of the 12-year-old donor.
Dr. Thomas E. Starzl, from the University of Pittsburgh, states in an editorial that "the explanation that links the three articles begins with the description of blood-cell chimerism in freemartin cattle," which led to "the demonstration of the induction of immunologic tolerance in chimeric neonatal mice.'
However, current transplant protocols in which large doses of immunosuppressants are administered following transplantation preclude the development of immune tolerance and independence from immunosuppressive therapy.
Dr. Starzl suggests that, by suppressing the recipient's immune system prior to transplantation, and using the least possible amount of immunosuppressive medication afterward, "perhaps it will be possible to systematically achieve stable organ engraftment with very low dependence on long-term treatment."
N Engl J Med 2008;358:353-374,407-411.