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Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients.

Yew PY, Alachkar H, Yamaguchi R, Kiyotani K, Fang H, Yap KL, Liu HT, Wickrema A, Artz A, van Besien K, Imoto S, Miyano S, Bishop MR, Stock W, Nakamura Y - Bone Marrow Transplant. (2015)

Bottom Line: Using this approach, our study demonstrates that higher percentage of cord-blood cells at 30 days after transplant was correlated with higher diversity of TCR repertoire, implicating the role of cord-chimerism in enhancing immune recovery.Importantly, we found that GVHD and relapse, exclusive of each other, were correlated with lower TCR repertoire diversity and expansion of certain T-cell clones.Our results highlight novel insights into the balance between GVHD and GVL effect, suggesting that higher diversity early after transplant possibly implies lower risks of both GVHD and relapse following the HSCT transplantation.

View Article: PubMed Central - PubMed

Affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, USA.

ABSTRACT
Allogeneic hematopoietic stem cell transplantation (HSCT) is one of curative treatment options for patients with hematologic malignancies. Although GVHD mediated by the donor's T lymphocytes remains the most challenging toxicity of allo-HSCT, graft-versus-leukemia (GVL) effect targeting leukemic cells, has an important role in affecting the overall outcome of patients with AML. Here we comprehensively characterized the TCR repertoire in patients who underwent matched donor or haplo-cord HSCT using next-generation sequencing approach. Our study defines the functional kinetics of each TCRA and TCRB clone, and changes in T-cell diversity (with identification of CDR3 sequences) and the extent of clonal expansion of certain T-cells. Using this approach, our study demonstrates that higher percentage of cord-blood cells at 30 days after transplant was correlated with higher diversity of TCR repertoire, implicating the role of cord-chimerism in enhancing immune recovery. Importantly, we found that GVHD and relapse, exclusive of each other, were correlated with lower TCR repertoire diversity and expansion of certain T-cell clones. Our results highlight novel insights into the balance between GVHD and GVL effect, suggesting that higher diversity early after transplant possibly implies lower risks of both GVHD and relapse following the HSCT transplantation.

No MeSH data available.


Related in: MedlinePlus

Reconstruction of TCR repertoires observed in the haplo-cord transplant patients at day 100. (a) Distribution of patients according to the median of percentage of cord-derived cells at day 30 or day 100 after haplo-cord transplant (n=9). The diversity of TCRA (b) and TCRB (c) of patients with >6% (n=4) cord-derived cells at day 30 were compared with that of patients with ⩽6% cord-derived cells (n=5). The diversity of TCRA (d) and TCRB (e) of MD patients were compared with that of haplo-cord patients.
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fig2: Reconstruction of TCR repertoires observed in the haplo-cord transplant patients at day 100. (a) Distribution of patients according to the median of percentage of cord-derived cells at day 30 or day 100 after haplo-cord transplant (n=9). The diversity of TCRA (b) and TCRB (c) of patients with >6% (n=4) cord-derived cells at day 30 were compared with that of patients with ⩽6% cord-derived cells (n=5). The diversity of TCRA (d) and TCRB (e) of MD patients were compared with that of haplo-cord patients.

Mentions: We assessed the TCR diversity by calculating the inverse Simpson's diversity index (1/Ds) (Supplementary Table S1). As expected, the diversity for TCRA and TCRB was significantly lower in samples obtained after transplant in comparison with pre-transplant samples (P=0.0054 and 0.015 for TCRA and TCRB, respectively) (Figures 1a and b). In order to investigate a correlation between the source of donor cells in the haplo-cord transplanted patients and TCR repertoire reconstruction after transplantation, we correlated the diversity of TCRs with the proportion of cord cells in patient's blood at different time points. Patients were dichotomized into two groups according to the median percentage of cord-derived cells at day 30 (⩽6% vs >6%) after haplo-cord transplantation (Figure 2a), and compared the diversity at day 100 between the two groups. We found that TCRA and TCRB of patients in the >6% group at day 30 were significantly more diverse at day 100 than those of ⩽6% group (TCRA; 116.1±17.25 vs 23.87±9.84 and TCRB; 89.59±15.49 vs 21.84±10.51) (P=0.0017 and P=0.0072 for TCRA and TCRB, respectively) (Figures 2b and c). The same correlation was observed when we examined the diversity on day 100 and percentage of cord-derived cells on day 100 post transplant (data not shown).


Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients.

Yew PY, Alachkar H, Yamaguchi R, Kiyotani K, Fang H, Yap KL, Liu HT, Wickrema A, Artz A, van Besien K, Imoto S, Miyano S, Bishop MR, Stock W, Nakamura Y - Bone Marrow Transplant. (2015)

Reconstruction of TCR repertoires observed in the haplo-cord transplant patients at day 100. (a) Distribution of patients according to the median of percentage of cord-derived cells at day 30 or day 100 after haplo-cord transplant (n=9). The diversity of TCRA (b) and TCRB (c) of patients with >6% (n=4) cord-derived cells at day 30 were compared with that of patients with ⩽6% cord-derived cells (n=5). The diversity of TCRA (d) and TCRB (e) of MD patients were compared with that of haplo-cord patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4559843&req=5

fig2: Reconstruction of TCR repertoires observed in the haplo-cord transplant patients at day 100. (a) Distribution of patients according to the median of percentage of cord-derived cells at day 30 or day 100 after haplo-cord transplant (n=9). The diversity of TCRA (b) and TCRB (c) of patients with >6% (n=4) cord-derived cells at day 30 were compared with that of patients with ⩽6% cord-derived cells (n=5). The diversity of TCRA (d) and TCRB (e) of MD patients were compared with that of haplo-cord patients.
Mentions: We assessed the TCR diversity by calculating the inverse Simpson's diversity index (1/Ds) (Supplementary Table S1). As expected, the diversity for TCRA and TCRB was significantly lower in samples obtained after transplant in comparison with pre-transplant samples (P=0.0054 and 0.015 for TCRA and TCRB, respectively) (Figures 1a and b). In order to investigate a correlation between the source of donor cells in the haplo-cord transplanted patients and TCR repertoire reconstruction after transplantation, we correlated the diversity of TCRs with the proportion of cord cells in patient's blood at different time points. Patients were dichotomized into two groups according to the median percentage of cord-derived cells at day 30 (⩽6% vs >6%) after haplo-cord transplantation (Figure 2a), and compared the diversity at day 100 between the two groups. We found that TCRA and TCRB of patients in the >6% group at day 30 were significantly more diverse at day 100 than those of ⩽6% group (TCRA; 116.1±17.25 vs 23.87±9.84 and TCRB; 89.59±15.49 vs 21.84±10.51) (P=0.0017 and P=0.0072 for TCRA and TCRB, respectively) (Figures 2b and c). The same correlation was observed when we examined the diversity on day 100 and percentage of cord-derived cells on day 100 post transplant (data not shown).

Bottom Line: Using this approach, our study demonstrates that higher percentage of cord-blood cells at 30 days after transplant was correlated with higher diversity of TCR repertoire, implicating the role of cord-chimerism in enhancing immune recovery.Importantly, we found that GVHD and relapse, exclusive of each other, were correlated with lower TCR repertoire diversity and expansion of certain T-cell clones.Our results highlight novel insights into the balance between GVHD and GVL effect, suggesting that higher diversity early after transplant possibly implies lower risks of both GVHD and relapse following the HSCT transplantation.

View Article: PubMed Central - PubMed

Affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, USA.

ABSTRACT
Allogeneic hematopoietic stem cell transplantation (HSCT) is one of curative treatment options for patients with hematologic malignancies. Although GVHD mediated by the donor's T lymphocytes remains the most challenging toxicity of allo-HSCT, graft-versus-leukemia (GVL) effect targeting leukemic cells, has an important role in affecting the overall outcome of patients with AML. Here we comprehensively characterized the TCR repertoire in patients who underwent matched donor or haplo-cord HSCT using next-generation sequencing approach. Our study defines the functional kinetics of each TCRA and TCRB clone, and changes in T-cell diversity (with identification of CDR3 sequences) and the extent of clonal expansion of certain T-cells. Using this approach, our study demonstrates that higher percentage of cord-blood cells at 30 days after transplant was correlated with higher diversity of TCR repertoire, implicating the role of cord-chimerism in enhancing immune recovery. Importantly, we found that GVHD and relapse, exclusive of each other, were correlated with lower TCR repertoire diversity and expansion of certain T-cell clones. Our results highlight novel insights into the balance between GVHD and GVL effect, suggesting that higher diversity early after transplant possibly implies lower risks of both GVHD and relapse following the HSCT transplantation.

No MeSH data available.


Related in: MedlinePlus