Clearance of CMV viremia and survival after double umbilical cord blood transplantation in adults depends on reconstitution of thymopoiesis.
Umbilical cord blood grafts are increasingly used as sources of hematopoietic stem cells in adults. Data regarding the outcome of this approach in adults are consistent with delayed and insufficient immune reconstitution resulting in high infection-related morbidity and mortality. Using cytomegalovirus (CMV)-specific immunity as a paradigm, we evaluated the status, mechanism, and clinical implications of immune reconstitution in adults with hematologic malignancies undergoing unrelated double unit cord blood transplantation. Our data indicate that CD8(+) T cells capable of secreting interferon-gamma (IFN-gamma) in a CMV-specific enzyme-linked immunosorbent spot (ELISpot) assay are detectable at 8 weeks after transplantation, before reconstitution of thymopoiesis, but fail to clear CMV viremia. Clearance of CMV viremia occurs later and depends on the recovery of CD4(+)CD45RA(+) T cells, reconstitution of thymopoiesis, and attainment of T-cell receptor rearrangement excision circle (TREC) levels of 2000 or more copies/mug DNA. In addition, overall survival was significantly higher in patients who displayed thymic regeneration and attainment of TREC levels of 2000 or more copies/mug DNA (P = .005). These results indicate that reconstitution of thymopoiesis is critical for long-term clinical outcome in adult recipients of umbilical cord blood transplant. The trial was prospectively registered at http://www.clinicaltrials.gov (NCT00133367).
Brown
Julia A
JA
Department of Medicine, Division of Hematology/Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Stevenson
Kristen
K
Kim
Haesook T
HT
Cutler
Corey
C
Ballen
Karen
K
McDonough
Sean
S
Reynolds
Carol
C
Herrera
Maria
M
Liney
Deborah
D
Ho
Vincent
V
Kao
Grace
G
Armand
Philippe
P
Koreth
John
J
Alyea
Edwin
E
McAfee
Steve
S
Attar
Eyal
E
Dey
Bimalangshu
B
Spitzer
Thomas
T
Soiffer
Robert
R
Ritz
Jerome
J
Antin
Joseph H
JH
Boussiotis
Vassiliki A
VA
D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D036101:Cord Blood Stem Cell Transplantation; D003587:Cytomegalovirus / Q000472:pathogenicity*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D005260:Female; D005312:Fetal Blood; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology*; D014766:Viremia / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D055815:Young Adult
D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma