Correspondence

Chimerism and Tolerance in a Recipient of a Deceased-Donor Liver Transplant

N Engl J Med 2008; 358:2075May 8, 2008

Article

To the Editor:

Since the role of hepatotropic viruses in severe aplastic anemia is well established,1 we suggest that the presumptive viral infection in the patient described by Alexander et al. (Jan. 24 issue)2 affected liver and hematopoietic cells simultaneously. The lymphopenia was noted at the onset of the liver failure, which, in turn, could have resulted in partial myeloablation, providing bone marrow niches for stem-cell engraftment. Fortuitously for the recipient, the death of the liver donor involved a hypoxemic brain injury, which may have mobilized bone marrow stem cells, as seen in patients with acute myocardial infarction or stroke.3,4 However, the donor hematopoietic stem cells contained in the transplanted liver itself were probably very few as compared with the number of cells used routinely in hematopoietic-cell transplantation. Engraftment of so few stem cells would place much pressure on them to self-renew and give rise to more mature progenitor cells; it would thus perhaps be of interest to determine the telomere length of the donor hematopoietic cells, since the attrition of telomeres has been linked to late-onset graft failure.5

Troy Lund, M.D., Ph.D.
Jakub Tolar, M.D., Ph.D.
University of Minnesota, Minneapolis, MN 55455
tolar003@umn.edu

5 References

1. 1

   Brown KE, Tisdale J, Barrett AJ, Dunbar CE, Young NS. Hepatitis-associated aplastic anemia. N Engl J Med 1997;336:1059-1064
   Full Text | Web of Science | Medline

2. 2

   Alexander SI, Smith N, Hu M, et al. Chimerism and tolerance in a recipient of a deceased-donor liver transplant. N Engl J Med 2008;358:369-374
   Full Text | Web of Science | Medline

3. 3

   Dunac A, Frelin C, Popolo-Blondeau M, Chatel M, Mahagne MH, Philip PJ. Neurological and functional recovery in human stroke are associated with peripheral blood CD34+ cell mobilization. J Neurol 2007;254:327-332
   CrossRef | Web of Science | Medline

4. 4

   Paczkowska E, Larysz B, Rzeuski R, et al. Human hematopoietic stem/progenitor-enriched CD34(+) cells are mobilized into peripheral blood during stress related to ischemic stroke or acute myocardial infarction. Eur J Haematol 2005;75:461-467
   CrossRef | Web of Science | Medline

5. 5

   Awaya N, Baerlocher GM, Manley TJ, et al. Telomere shortening in hematopoietic stem cell transplantation: a potential mechanism for late graft failure? Biol Blood Marrow Transplant 2002;8:597-600
   CrossRef | Web of Science | Medline

Author/Editor Response

We agree with Lund and Tolar that the primary infection resulting in the recipient's liver failure may have also caused myeloablation, facilitating bone marrow stem-cell engraftment. This suggestion is supported by the patient's pretransplantation and post-transplantation lymphopenia and the early post-transplantation severe cytomegalovirus infection, which are consistent with a compromised immune system. We also agree that the telomeres of the engrafted cells may be shortened because of the extensive proliferation required for engraftment of a limited number of liver-derived stem cells. We have previously reported the effect of a limited number of T-cell precursors in a child with X-linked severe combined immunodeficiency treated with gene therapy; this child had reduced T-cell diversity because of a “bottleneck” in precursor numbers.1 In the case of our liver-transplant recipient, the young age of the donor may have been associated with a favorable initial telomere length in the engrafting stem cells, which may have, at least in part, offset the telomere shortening that accompanies proliferation.

Stephen I. Alexander, M.B., B.S.
Children's Hospital at Westmead, Sydney 2145, Australia

Roger R. Reddel, M.B., B.S., Ph.D.
Children's Medical Research Institute, Sydney 2145, Australia

Michael O. Stormon, M.B., B.S.
Children's Hospital at Westmead, Sydney 2145, Australia
michae6@chw.edu.au

1 References

1. 1

   Ginn SL, Curtin JA, Kramer B, et al. Treatment of an infant with X-linked severe combined immunodeficiency (SCID-X1) by gene therapy in Australia. Med J Aust 2005;182:458-463
   Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   S. Janes, P. Dhaliwal, K. Wood. (2009) Tolerance in renal transplantation: is mixed chimerism the missing link?. Nephrology Dialysis Transplantation 24:6, 1726-1729
   CrossRef