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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
N Engl J Med. Author manuscript; available in PMC 2012 April 23.
Published in final edited form as:
PMCID: PMC3334358
NIHMSID: NIHMS369644

Induced Immune Tolerance for Kidney Transplantation

TO THE EDITOR

Recipients of kidney transplants require the lifelong use of immunosuppressive drugs to prevent graft rejection, but immunosuppressive medications are associated with cumulative side effects, including increased risks of heart disease, infection, cancer, and diabetes.1 Despite maintenance immunosuppression, chronic rejection results in gradual long-term graft loss.1 Eliminating the lifelong need for immunosuppressive medications that result in freedom from rejection remains an elusive and important goal.

The induction of immune tolerance achieved this goal in pilot clinical studies based on pre-clinical models of combined organ and hematopoietic-cell transplantation.25 In the current proof-of-concept study, 12 patients who received HLA-matched kidney transplants received a donor-cell infusion of highly enriched CD34+ hematopoietic progenitor cells mixed with CD3+ T cells, and a conditioning regimen of total lymphoid irradiation and anti–T-cell antibodies according to a protocol described in detail in a previous case report of the successful induction of tolerance.5

Patients received a conditioning regimen of 10 doses of total lymphoid irradiation (80 to 120 cGy) targeted to the lymph nodes, spleen, and thymus, and 5 doses of rabbit antithymocyte globulin during the first 10 days after kidney transplantation. The duration of hospitalization for transplantation surgery was 4 to 7 days, and no patients were hospitalized again for viral or opportunistic infections. Donor CD34+ selected cells (5×106 to 16×106 per kilogram of body weight) and a defined dose of T cells (1×106 to 10×106 per kilogram) were injected intravenously on day 11 in the outpatient infusion center. All patients received mycophenolate mofetil (2 g per day after cell infusion) for 1 month and cyclosporine starting at day 0 for at least 6 months. Cyclosporine was discontinued 6 to 17 months after transplantation as long as chimerism persisted for at least 6 months according to short-tandem-repeat analysis of DNA from blood granulocytes and lymphocytes5 and there was no evidence of graft-versus-host disease, clinical rejection, or rejection on microscopical assessment of surveillance biopsy specimens at the time of withdrawal.

In eight patients, antirejection drugs were discontinued, and patients were observed thereafter for at least 12 to 36 months (mean, 25) without subsequent rejection episodes (Table 1). There was no evidence of chronic rejection or graft injury according to subsequent creatinine clearances (57 to 107 ml per minute per 1.73 m2 of body-surface area), proteinuria (<250 mg of protein per 24 hours), and histopathological scoring of tubular atrophy, fibrosis, and injury on repeat surveillance biopsies 6 to 18 months after discontinuation. Four of the patients were tested for the mixed leukocyte reaction, and all showed a specific unresponsiveness pattern to donor cells similar to that reported previously.5 Patient 1, who discontinued antirejection drugs for 3 years, died suddenly while exercising, 4 months after a myocardial infarction. Four patients continued to receive immunosuppressive drugs because of the recurrence of focal segmental glomerulosclerosis in one (Patient 2) and rejection episodes during the tapering of cyclosporine in the others (Table 1). Rejection episodes were reversed with standard medications, serum creatinine levels returned to baseline, and maintenance immunosuppressive agents were resumed without evidence of graft dysfunction or chronic rejection thereafter.

Table 1
Patient Characteristics and Outcomes.

In conclusion, the majority of patients were able to discontinue antirejection medications, and all patients had excellent graft function at the last observation point. We are applying the protocol to patients who were mismatched for one HLA haplotype on the basis of the safety profile of the current study.

Acknowledgments

Supported by grants (P01 HL075462 and R01 AI1085024) from the National Institutes of Health.

Footnotes

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

References

1. Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med. 2002;346:580–90. [PubMed]
2. Strober S, Spitzer TR, Lowsky R, Sykes M. Translational studies in hematopoietic cell transplantation: treatment of hematologic malignancies as a stepping stone to tolerance induction. Semin Immunol. 2011 Jun 24; (Epub ahead of print) [PMC free article] [PubMed]
3. Fudaba Y, Spitzer TR, Shaffer J, et al. Myeloma responses and tolerance following combined kidney and nonmyeloablative marrow transplantation: in vivo and in vitro analyses. Am J Transplant. 2006;6:2121–33. [PubMed]
4. Kawai T, Cosimi AB, Spitzer TR, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med. 2008;358:353–61. [PMC free article] [PubMed]
5. Scandling JD, Busque S, Dejbakhsh-Jones S, et al. Tolerance and chimerism after renal and hematopoietic-cell transplantation. N Engl J Med. 2008;358:362–8. [PubMed]