Page 1842 - Hematology_ Basic Principles and Practice ( PDFDrive )

1638 Part X Transplantation

that an immune mechanism accounts for unit dominance. Studies nondominant unit were present in the PB 28 days after transplanta-
in nonobese diabetic severe combined immunodeficient interleukin-2 tion in 9 of 10 DCBT recipients engrafting with single units regard-
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receptor gamma null (NOD/SCID/IL-2R-γ ) mice demonstrated less of the conditioning regimen. Interestingly, the three patients who
that despite each unit engrafting alone, coinfusion of mononuclear had persistent mixed chimerism also did not develop an alloreactive
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cells as a double-unit graft was associated with predominance of one CD8 T-cell response.
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CB unit. 54,55 Further, unit dominance could be mitigated (and Clinical data from Avery et al have demonstrated a role of
engraftment of both units achieved) with either lineage depletion of HLA-match in unit dominance. Interestingly, in this analysis of 84
the units or cotransplantation of third-party BM-derived mesenchy- DCBT recipients, the dominant units were not necessarily better
mal stromal cells and mixed chimerism could be generated by HLA-matched to the recipient compared with the nondominant unit
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CD34 cell selection. 54,55 It was also shown that the unit dominance of a double-unit pair (Fig. 107.4). However, the unit–unit HLA
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was T-cell–mediated and involved both CD4 and CD8 cells. match influenced the length of time the ultimately nonengrafting
Furthermore, it can be hypothesized that the failure of sustained unit was able to be detected. Specifically, recipients of double-unit
engraftment of ex vivo expanded CB units in clinical trials of grafts in whom the unit–unit HLA match was 7/10 or greater HLA-
DCBT in which one of two units is expanded is not attributable to allele matched were significantly more likely to have initial coengraft-
failure to expand or maintain sufficient progenitors in the manipu- ment and transient persistence of the ultimately nonengrafting unit
lated unit but because the expanded unit is T-cell depleted and with one patient having sustained engraftment of both units long
therefore cannot compete with a T-cell replete unmanipulated term. By contrast, recipients of units highly mismatched (<6/10) to
unit. 56 each other were more likely to have engraftment with only a single
Graft-versus-graft interactions also play a role in determining unit unit. This is likely because of an enhanced unit-versus-unit immune
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dominance. This is suggested from NOD/SCID/IL2R-γ murine response, whereas closely HLA-matched units are more likely to be
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study showing that DCBT using CD34 cells was associated with loss relatively tolerant of each other, and in this setting, at least transient
−
of both unit dominance, and addition of CD34 cells from only one coengraftment is possible.
of the two units restored unit dominance, with engraftment being Taken together, these findings suggest that unit dominance likely
−
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mediated by the origin of the CD34 cells. Moreover, Brunstein et involves a complex interplay of hematopoietic potential as suggested
+
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al evaluated the safety of ex vivo expanded regulatory T cells (Tregs) by the role of CD34 cell viability as well as immune factors that
in DBCT recipients and found an increased prevalence of coengraft- are likely T-cell–mediated because no role for natural killer (NK)
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ment of both units (dual donor chimerism), suggesting that graft- cells has been identified to date. Future studies need to elucidate
versus-graft interactions could be ameliorated by suppressing T-cell the specific cell population mediating the graft-versus-graft effect in
responses. the setting of the transplantation of two units with adequate
Additional evidence in favor of an immune basis for unit engraftment potential. This will enhance our CB unit selection
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dominance comes from the study by Gutman et al, who identified process for infusion and for novel graft manipulation techniques
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CD8 T cells derived from the dominant unit that recognized the elaborated later.
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15

Units, n 10

5

0
1/10 2/10 3/10 4/10 5/10 6/10 7/10 8/10 9/10 10/10
10 Allele unit-recipient match
Dominant unit, engrafting patients (n = 79)
Nondominant unit, engrafting patients (n = 79)
Dominant unit, graft failure patients (n = 5)
Nondominant unit, graft failure patients (n = 5)
Fig. 107.4 INFLUENCE OF HIGH RESOLUTION UNIT-RECIPIENT HUMAN LEUKOCYTE
ANTIGEN MATCH ON SUSTAINED DONOR ENGRAFTMENT AFTER DOUBLE-UNIT D BLOOD
TRANSPLANTATION (n = 84). The engrafting units were not better matched to the recipient. (From Avery
S, Shi W, Lubin M, et al: Influence of infused cell dose and HLA match on engraftment after double-unit cord blood
allografts. Blood 117:3277, 2011.)