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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 proportion of the top 10 CDR3 sequences and diversity between non-GVHD and GVHD patients. In all patients, the proportion of top 10 CDR3 of TCRA (a) and TCRB (b) of non-GVHD (n=10) were compared with that of GVHD patients (n=11). In the non-relapsed group, the proportion of top 10 CDR3 of TCRA (c) and TCRB (d) of GVHD patients (n=6) were compared with that of non-GVHD patients (n=7). In the relapsed group, the proportion of top 10 CDR3 of TCRA (e) and TCRB (f) of GVHD (n=5) were compared with that of non-GVHD (n=3). In the non-relapsed group, the diversity of TCRA (g) and TCRB (h) of non-GVHD patients (n=7) were compared with that of GVHD patients (n=6). In the relapsed patients, the diversity of TCRA (i) and TCRB (j) of GVHD (n=5) were compared with that of non-GVHD (n=3) patients.
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fig3: Comparison of the proportion of the top 10 CDR3 sequences and diversity between non-GVHD and GVHD patients. In all patients, the proportion of top 10 CDR3 of TCRA (a) and TCRB (b) of non-GVHD (n=10) were compared with that of GVHD patients (n=11). In the non-relapsed group, the proportion of top 10 CDR3 of TCRA (c) and TCRB (d) of GVHD patients (n=6) were compared with that of non-GVHD patients (n=7). In the relapsed group, the proportion of top 10 CDR3 of TCRA (e) and TCRB (f) of GVHD (n=5) were compared with that of non-GVHD (n=3). In the non-relapsed group, the diversity of TCRA (g) and TCRB (h) of non-GVHD patients (n=7) were compared with that of GVHD patients (n=6). In the relapsed patients, the diversity of TCRA (i) and TCRB (j) of GVHD (n=5) were compared with that of non-GVHD (n=3) patients.

Mentions: To examine whether enrichment of certain T-cells may be involved in the development of GVHD, we analyzed changes over time from baseline and sequentially through the development of acute GVHD. On the basis of their V(D)J combination and defined CDR3 sequences (by insertion and deletion of the nucleotides at the rearranged junction), we sorted independent cDNA sequences according to their number of appearance in the sequence reads from the most to least abundant. We demonstrated the 10 most abundant CDR3 sequences at the time point closest to the date when each patient was diagnosed with acute GVHD. We observed that certain T-cell clones were expanded in each of the GVHD patients and were very low at any other time points. We then compared the combined proportion of top ten CDR3 sequences at the time point closest to acute GVHD diagnosis and multiple time points of non-GVHD patients after HSCT. We found significantly stronger enrichment of the ten most abundant T-cell clones of TCRB in GVHD patients than those with non-GVHD patients (P=0.0029). On the other hand we only observed a very modest tendency in the difference in TCRA (P=0.18) (Figures 3a 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 proportion of the top 10 CDR3 sequences and diversity between non-GVHD and GVHD patients. In all patients, the proportion of top 10 CDR3 of TCRA (a) and TCRB (b) of non-GVHD (n=10) were compared with that of GVHD patients (n=11). In the non-relapsed group, the proportion of top 10 CDR3 of TCRA (c) and TCRB (d) of GVHD patients (n=6) were compared with that of non-GVHD patients (n=7). In the relapsed group, the proportion of top 10 CDR3 of TCRA (e) and TCRB (f) of GVHD (n=5) were compared with that of non-GVHD (n=3). In the non-relapsed group, the diversity of TCRA (g) and TCRB (h) of non-GVHD patients (n=7) were compared with that of GVHD patients (n=6). In the relapsed patients, the diversity of TCRA (i) and TCRB (j) of GVHD (n=5) were compared with that of non-GVHD (n=3) patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Comparison of the proportion of the top 10 CDR3 sequences and diversity between non-GVHD and GVHD patients. In all patients, the proportion of top 10 CDR3 of TCRA (a) and TCRB (b) of non-GVHD (n=10) were compared with that of GVHD patients (n=11). In the non-relapsed group, the proportion of top 10 CDR3 of TCRA (c) and TCRB (d) of GVHD patients (n=6) were compared with that of non-GVHD patients (n=7). In the relapsed group, the proportion of top 10 CDR3 of TCRA (e) and TCRB (f) of GVHD (n=5) were compared with that of non-GVHD (n=3). In the non-relapsed group, the diversity of TCRA (g) and TCRB (h) of non-GVHD patients (n=7) were compared with that of GVHD patients (n=6). In the relapsed patients, the diversity of TCRA (i) and TCRB (j) of GVHD (n=5) were compared with that of non-GVHD (n=3) patients.
Mentions: To examine whether enrichment of certain T-cells may be involved in the development of GVHD, we analyzed changes over time from baseline and sequentially through the development of acute GVHD. On the basis of their V(D)J combination and defined CDR3 sequences (by insertion and deletion of the nucleotides at the rearranged junction), we sorted independent cDNA sequences according to their number of appearance in the sequence reads from the most to least abundant. We demonstrated the 10 most abundant CDR3 sequences at the time point closest to the date when each patient was diagnosed with acute GVHD. We observed that certain T-cell clones were expanded in each of the GVHD patients and were very low at any other time points. We then compared the combined proportion of top ten CDR3 sequences at the time point closest to acute GVHD diagnosis and multiple time points of non-GVHD patients after HSCT. We found significantly stronger enrichment of the ten most abundant T-cell clones of TCRB in GVHD patients than those with non-GVHD patients (P=0.0029). On the other hand we only observed a very modest tendency in the difference in TCRA (P=0.18) (Figures 3a 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