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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

Comparison of the TCR diversity between relapse and non-relapse patients. In all patients, the diversity of TCRA (a) and TCRB (b) of relapsed patients (n=7) were compared with that of non-relapsed patients (n=13). In non-GVHD patients, the diversity of TCRA (c) and TCRB (d) of non-relapsed patients (n=7) were compared with that of relapsed patients (n=3). In GVHD patients, the diversity of TCRA (e) and TCRB (f) of relapsed patients were compared with that of non-relapse patients.
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fig4: Comparison of the TCR diversity between relapse and non-relapse patients. In all patients, the diversity of TCRA (a) and TCRB (b) of relapsed patients (n=7) were compared with that of non-relapsed patients (n=13). In non-GVHD patients, the diversity of TCRA (c) and TCRB (d) of non-relapsed patients (n=7) were compared with that of relapsed patients (n=3). In GVHD patients, the diversity of TCRA (e) and TCRB (f) of relapsed patients were compared with that of non-relapse patients.

Mentions: In order to assess the TCR repertoire in HSCT patients with higher likelihood to have the GVL effect, we examined the correlation of the diversity index of TCR repertoire of samples collected at day 50, 75–100 or 1 year with relapse status. The TCR diversity in relapsed patients was not significantly different from that of non-relapsed patients (P=0.82 and 0.70, for TCRA and TCRB, respectively, Figures 4a and b). However, in the non-GVHD group, we found that the diversity index was significantly higher in non-relapsed patients compared to that in relapsed patients (85.73±16.59 vs 10.95±4.06 for TCRA; 85.69±14.77 vs 13.25±3.84 for TCRB; P=0.042 for TCRA and 0.029 for TCRB; Figures 4c and d). Consistently, the proportions of the 10 most abundant clones for both TCRA and TCRB were significantly higher in the relapsed patients of the non-GVHD group than in the non-relapsed patients (P=0.015 and 0.017 for TCRA and TCRB, respectively; Supplementary Figures 4a and b).


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)

Comparison of the TCR diversity between relapse and non-relapse patients. In all patients, the diversity of TCRA (a) and TCRB (b) of relapsed patients (n=7) were compared with that of non-relapsed patients (n=13). In non-GVHD patients, the diversity of TCRA (c) and TCRB (d) of non-relapsed patients (n=7) were compared with that of relapsed patients (n=3). In GVHD patients, the diversity of TCRA (e) and TCRB (f) of relapsed patients were compared with that of non-relapse patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Comparison of the TCR diversity between relapse and non-relapse patients. In all patients, the diversity of TCRA (a) and TCRB (b) of relapsed patients (n=7) were compared with that of non-relapsed patients (n=13). In non-GVHD patients, the diversity of TCRA (c) and TCRB (d) of non-relapsed patients (n=7) were compared with that of relapsed patients (n=3). In GVHD patients, the diversity of TCRA (e) and TCRB (f) of relapsed patients were compared with that of non-relapse patients.
Mentions: In order to assess the TCR repertoire in HSCT patients with higher likelihood to have the GVL effect, we examined the correlation of the diversity index of TCR repertoire of samples collected at day 50, 75–100 or 1 year with relapse status. The TCR diversity in relapsed patients was not significantly different from that of non-relapsed patients (P=0.82 and 0.70, for TCRA and TCRB, respectively, Figures 4a and b). However, in the non-GVHD group, we found that the diversity index was significantly higher in non-relapsed patients compared to that in relapsed patients (85.73±16.59 vs 10.95±4.06 for TCRA; 85.69±14.77 vs 13.25±3.84 for TCRB; P=0.042 for TCRA and 0.029 for TCRB; Figures 4c and d). Consistently, the proportions of the 10 most abundant clones for both TCRA and TCRB were significantly higher in the relapsed patients of the non-GVHD group than in the non-relapsed patients (P=0.015 and 0.017 for TCRA and TCRB, respectively; Supplementary Figures 4a and b).

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