Immune reconstitution after double umbilical cord blood stem cell transplantation: comparison with unrelated peripheral blood stem cell transplantation

Abstract

Double umbilical cord blood (DUCB) transplantation is an accepted transplantation strategy for patients without suitable human leukocyte antigen (HLA) matched donors. However, DUCB transplantation is associated with increased morbidity and mortality because of slow recovery of immunity and a high risk of infection. To define the differences in immune reconstitution between DUCB transplantation and HLA matched unrelated donor (MUD) transplantation, we performed a detailed, prospective analysis of immune reconstitution in 42 DUCB recipients and 102 filgrastim-mobilized unrelated peripheral blood stem cell recipients. Reconstitution of CD3 T cells was significantly delayed in the DUCB cohort compared with the MUD cohort for 1 to 6 months posttransplantation (P < .001), including naive (CD45RO-) and memory (CD45RO+) CD4 T cells, regulatory (CD4CD25) T cells, and CD8 T cells. In contrast, CD19 B cells recovered more rapidly in the DUCB cohort and numbers remained significantly greater from 3 to 24 months after transplantation (P = .001). CD56CD16 natural killer (NK) cells also recovered more rapidly in DUCB recipients and remained significantly greater from 1 to 24 months after transplantation. B cell activating factor (BAFF) levels were higher in the DUCB cohort at 1 month (P < .001), were similar in both cohorts at 3 and 6 months, and were lower in the DUCB cohort at 12 months (P = .002). BAFF/CD19 B cell ratios were lower in the DUCB cohort at 3 (P = .045), 6 (P = .02), and 12 months (P = .002) after transplantation. DUCB recipients had more infections within the first 100 days after transplantation (P < .001), and there was less chronic graft-versus-host disease (P < .001), but there were no differences in cumulative incidence of relapse, nonrelapse death, progression-free survival, or overall survival between the 2 groups. These results suggest that increased risk of infections is specifically associated with delayed reconstitution of all major T cell subsets, but the increased risk is limited to the first 3 months after DUCB transplantation. There is no increased risk of relapse, suggesting that graft-versus-leukemia activity is maintained. Early reconstitution of B cells and NK cells may, in part, account for these findings.

Figure 1. Reconstitution of CD3, CD4, and CD8 T cells after stem cell transplantation

Median absolute CD3 (A), CD4 (B), and CD8 (C) T cells/μL at 1, 2, 3, 6, 9, 12, 18, and 24 months after DUCB (blue lines) and MUD (pink lines) transplantation. The sample sizes at each time point are 26 vs 81, 27 vs 88, 33 vs 77, 35 vs 65, 20 vs 54, 31 vs 52, 11 vs 34, and 14 vs 23, for DUCB and MUD cohorts respectively. The range of absolute CD3, CD4, and CD8 T cell counts in our normal healthy control cohort is represented in gray. * indicates differences that are statistically significant (p<0.05).

Figure 2. Reconstitution of CD19 and CD20 B cells after stem cell transplantation

Median absolute CD19 B cells/μL (A), and CD56CD16 NK cells/μL (B) at 1, 2, 3, 6, 9, 12, 18, and 24 months after DUCB (blue lines) and MUD (pink lines) transplantation. The sample sizes at each time point are 27 vs 80, 27 vs 88, 33 vs 77, 35 vs 64, 20 vs 54, 31 vs 53, 11 vs 34, and 14 vs 23, for DUCB and MUD cohorts respectively. The range of absolute CD19 B cell and CD56CD16 NK cell counts in our normal healthy control cohort is represented in gray. * indicates differences that are statistically significant (p<0.05).

Figure 3. Reconstitution of T cell subsets after stem cell transplantation

Median absolute CD4CD45RO− naive (A), CD4CD45RO+ memory (B), and CD4CD25 regulatory (C) T cells/μL, and CD3CD56 cells/μL at 1, 2, 3, 6, 9, 12, 18, and 24 months after DUCB (blue lines) and MUD (pink lines) transplantation. The sample sizes at each time point are 21 vs 79, 20 vs 88, 22 vs 77, 24 vs 64, 3 vs 53, 17 vs 52, 3 vs 34, and 6 vs 23, for DUCB and MUD cohorts respectively. The range of absolute naïve, memory, and regulatory T cells and CD3CD56 cells in our normal healthy control cohort is represented in gray. * indicates differences that are statistically significant (p<0.05).

Figure 4. Reconstitution of myeloid and plasmacytoid dendritic cells after stem cell transplantation

Absolute and median absolute CD11c myeloid (A) and CD123 plasmacytoid (B) dendritic cells/μL at 6 and 12 months after DUCB (blue diamonds) and MUD (pink circles) transplantation. The sample sizes at each time point are 6 vs 31, and 9 vs 26 for DUCB and MUD cohorts, respectively. * indicates differences that are statistically significant (p<0.05).

Figure 5. Immunoglobulin levels after stem cell transplantation

Median serum IgG levels in mg/dL at one month intervals after transplantation from one month to one year after DUCB (blue line) and MUD (pink line) transplantation. The sample sizes at each one month time point are 50 vs 113, 44 vs 106, 32 vs 87, 44 vs 61, 36 vs 75, 36 vs 60, 34 vs 55, 27 vs 56, 22 vs 53, 18 vs 52, 23 vs 53, and 14 vs 49 for DUCB and MUD cohorts, respectively. The range of normal IgG levels is represented in gray.

Figure 6. Levels of BAFF, and BAFF/CD19 B cells after stem cell transplantation

Median levels of BAFF in ng/mL (A), and BAFF/CD19 B cells (B) at 1, 3, 6, and 12 months after DUCB (blue lines) and MUD (pink lines) transplantation. The sample sizes at each time point are 22 vs 77, 30 vs 71, 21 vs 59, and 25 vs 37 for DUCB and MUD cohorts, respectively. The range of normal BAFF and BAFF/CD19 B cell ratios are represented in gray [24]. *indicates differences that are statistically significant (p<0.05).