The Molecular Characteristics of T-Cell Immune Reconstitution in Leukemia Patients after Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5141-5141
Author(s):  
Yuewen Fu ◽  
De Pei Wu ◽  
Aining Sun ◽  
Yufeng Feng ◽  
Weirong Chang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Amino Acid ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Marrow Transplantation ◽  
Immune Reconstitution ◽  
Cmv Infection ◽  
Amino Acid Motif ◽  
Hematopoietic Stem

Abstract The clinical and experimental results indicated that the T cell immune reconstitution was slow after hematopoietic stem cell transplantation. This study was To analyze the molecular characteristics of T lymphocytic clones during immune reconstitution in leukemia patients after allogeneic hematopoietic stem cell transplantation(Allo-HCST)by investigating complementarity determining region (CDR3) repertoires of T cell receptor β chain variable region (TCRVB) and made it possible to understand the relationship between the express of TCRVB and immune reconstitution. Reverse transcriptase-polymerase chain reaction(RT-PCR) amplified 24 subfamily genes of TCRVB from peripheral blood lymphocytes (PBLs) of twenty-four patients with leukemia underwent three kinds of Allo-HSCT(haploidentical bone marrow transplantation, matched sibling bone marrow transplantation and matched-unrelated PBSCT), five normal donors as control. The PCR products were further analyzed by genescane to evaluate the clonality of VB subfamily. The monoclonal bands which associated with GVHD and CMV infection were obtained through denaturation polyacrylamide gel electrophoresis and sequenced. Compared the sequences of TCRVB CDR3 gene repertoire with other sequences associated with GVHD or CMV infection which had been reported. +2~+19months after transplantation, for nine patients among them which underwent haploidentical bone marrow transplantation, there were 6~14 VB subfamilies expressed with 33% 15 VB subfamilies expressed, which 45%of them were polyclones. In the 5 patients of matched-unrelated PBSCT, there were 10~15 VB families expressed, with 45% the polyclone expression. For ten patients underwent matched sibling bone marrow transplantation, 10~16 VB subfamilies expressed and more than 48% were polyclones. Monoclones and oligoclones existed in 24 VB subfamilies, no common monoclone VB subfamilies expressed. According to the usage of VB family and polyclonal expression, Immune reconstitution in patients which underwent haploidentical BMT was later than that of other two groups (p<0.05), there were no different between other two groups (p>0.05). After Allo-HSCT, two patients detected TCRVB in +2m and +3m and found that it has tendency of adding to use VB subfamilies and increasing to express CDR3 polymorphism. Using biology-information tool, compared 23 TCRVB CDR3 molecules which related to GVHD and CMV infection and found that, different cases in the same VB subfamilies may share similarity in amino acid motif, while in different VB subfamilies none of clones appeared to share the same amino acid motif. In 1.5 years after AHSCT, the usage of TCRVB subfamilies still restricted. T-cell immune reconstitution in patients which underwent haploidentical BMT was later than that of other two groups. TCRVB CDR3 molecules which related to GVHD and CMV infection showed that different cases in the same VB subfamilies may share similarity in amino acid motif, while in different VB subfamilies none of clones appeared to share the same amino acid motif.

The Molecular Characteristics of T-Cell Receptor Repertoire of Clonal Expansion of T Lymphocytes in Leukemia Patients after Haploidentical Bone Marrow Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5145-5145
Author(s):  
YueWen Fu ◽  
De Pei Wu ◽  
YuFeng Feng ◽  
WeiRong Chang ◽  
ZiLin Zhu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Amino Acid ◽  
T Cell ◽  
Marrow Transplantation ◽  
Immune Reconstitution ◽  
Stable Condition ◽  
Molecular Characteristics ◽  
Gene Repertoire ◽  
Amino Acid Motif

Abstract The clinical and experimental results indicated that the T cell immune reconstitution was slow after haploidentical hematopoietic stem cell transplantation and existed high rate of GVHD and infection. This study was to analyze the molecular characteristics of T cell clones during immune reconstitution in leukemia patients after haploidentical bone marrow transplantation (H-BMT). Reverse transcriptase-polymerase chain reaction (RT-PCR) amplified 24 subfamily genes of TCRVB from peripheral blood lymphocytes of nine leukemia patients underwent H-BMT, five normal donors as control. The PCR products were further analyzed by genescane to evaluate the clonality of VB subfamily and characteristics of CDR3 and usage rate in VB subfamily. The monoclonal bands which associated with GVHD obtained and sequenced. Compared the sequences of TCRVB CDR3 gene repertoire with other sequences associated with GVHD had been reported before. In +10~+19m, the usage of TCRVB subfamilies still restricted. It can detected that some VB subfamilies were missing, others expanded in monoclonal or oligoclonal. 4 patients in stable condition showed that 9~14 VB subfamilies expressed and more than 50 percent were polyclone. In other 5 patients which have GVHD or CMV-pp65(+), the usage of TCRVB decreased obviously(p<0.05), the express of CDR3 were monoclonal or oligoclonal, only 30 percent were polyclonal. No common monoclone VB subfamilies expressed. After treatment and GVHD controled, the usage of VB subfamilies was increased and CDR3 polymorphism increased in 2 patients. Analyzed the sequences associated with GVHD and found that none of the clones appeared to share any similarity in amino acid motif. In +10~+19m, the usage of TCRVB subfamilies still skewing. In stable condition, there were 9~14 VB subfamilies expressed and dominated by polyclones, in active condition, the express of VB subfamilies decreased and dominated by monoclones or oligoclones. A group of CDR3 molecules related to GVHD showed no common amino acid motif.

scholarly journals Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion

Blood ◽  
2008 ◽  
Vol 111 (12) ◽  
pp. 5745-5754 ◽  
Author(s):  
Denise A. Carbonaro ◽  
Xiangyang Jin ◽  
Daniel Cotoi ◽  
Tiejuan Mi ◽  
Xiao-Jin Yu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Immune Reconstitution ◽  
Myeloid Cells ◽  
Normal Donor ◽  
Dependent Manner ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Donor Cells

Abstract Adenosine deaminase (ADA)–deficient severe combined immune deficiency (SCID) may be treated by allogeneic hematopoietic stem cell transplantation without prior cytoreductive conditioning, although the mechanism of immune reconstitution is unclear. We studied this process in a murine gene knockout model of ADA-deficient SCID. Newborn ADA-deficient pups received transplants of intravenous infusion of normal congenic bone marrow, without prior cytoreductive conditioning, which resulted in long-term survival, multisystem correction, and nearly normal lymphocyte numbers and mitogenic proliferative responses. Only 1% to 3% of lymphocytes and myeloid cells were of donor origin without a selective expansion of donor-derived lymphocytes; immune reconstitution was by endogenous, host-derived ADA-deficient lymphocytes. Preconditioning of neonates with 100 to 400 cGy of total body irradiation before normal donor marrow transplant increased the levels of engrafted donor cells in a radiation dose–dependent manner, but the chimerism levels were similar for lymphoid and myeloid cells. The absence of selective reconstitution by donor T lymphocytes in the ADA-deficient mice indicates that restoration of immune function occurred by rescue of endogenous ADA-deficient lymphocytes through cross-correction from the engrafted ADA-replete donor cells. Thus, ADA-deficient SCID is unique in its responses to nonmyeloablative bone marrow transplantation, which has implications for clinical bone marrow transplantation or gene therapy.

Comparison of Immune Reconstitution After Unrelated and Related T-Cell–Depleted Bone Marrow Transplantation: Effect of Patient Age and Donor Leukocyte Infusions

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 467-480 ◽  
Author(s):  
T.N. Small ◽  
E.B. Papadopoulos ◽  
F. Boulad ◽  
P. Black ◽  
H. Castro-Malaspina ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Immune Reconstitution ◽  
Opportunistic Infections ◽  
Cd8 T Cell ◽  
Cell Populations ◽  
Increased Risk ◽  
Life Threatening

Unrelated bone marrow transplantation (BMT) is often complicated by fatal opportunistic infections. To evaluate features unique to immune reconstitution after unrelated BMT, the lymphoid phenotype, in vitro function, and life-threatening opportunistic infections after unrelated and related T-cell–depleted (TCD) BMT were analyzed longitudinally and compared. The effects of posttransplant donor leukocyte infusions to treat or prevent cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infections on immune reconstitution were also analyzed. This study demonstrates that adult recipients of TCD unrelated BMTs experience prolonged and profound deficiencies of CD3+, CD4+, and CD8+ T-cell populations when compared with pediatric recipients of unrelated BMT and adults after related BMT (P < .01), that these adults have a significantly increased risk of life-threatening opportunistic infections, and that the rate of recovery of CD4 T cells correlates with the risk of developing these infections. Recovery of normal numbers of CD3+, CD8+, and CD4+ T-cell populations is similar in children after related or unrelated BMT. This study also demonstrates that adoptive immunotherapy with small numbers of unirradiated donor leukocytes can be associated with rapid restoration of CD3+, CD4+, and CD8+T-cell numbers, antigen-specific T-cell responses, and resolution of CMV- and EBV-associated disease after unrelated TCD BMT.

T-Cell Immune Reconstitution in Pediatric Leukemia Patients After Allogeneic Bone Marrow Transplantation With T-Cell–Depleted or Unmanipulated Grafts: Evaluation of Overall and Antigen-Specific T-Cell Repertoires

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 4358-4369 ◽  
Author(s):  
Barbara C. Godthelp ◽  
Maarten J.D. van Tol ◽  
Jaak M. Vossen ◽  
Peter J. van den Elsen
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Immune Reconstitution ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cell Selection ◽  
Allogeneic Bone ◽  
T Cell Selection

To evaluate the role of T-cell selection in the thymus and/or periphery in T-cell immune reconstitution after allogeneic bone marrow transplantation (allo-BMT), we have analyzed the overall and antigen-specific T-cell repertoires in pediatric allo-BMT recipients treated for leukemia. We observed a lack of overall T-cell receptor (TCR) diversity in the repopulating T cells at 3 months after allo-BMT, as was deduced from complementarity determining region 3 (CDR3) size distribution patterns displaying reduced complexity. This was noted particularly in recipients of a T-cell–depleted (TCD) graft and, to a lesser extent, also in recipients of unmanipulated grafts. At 1 year after allo-BMT, normalization was observed of TCR CDR3 size complexity in almost all recipients. Analysis of the antigen-specific T-cell repertoire at 1 year after BMT showed that the T cells responding to tetanus toxoid (TT) differed in TCR gene segment usage and in amino acid composition of the CDR3 region when comparing the recipient with the donor. Moreover, the TT-specific TCR repertoire was found to be stable within a given allo-BMT recipient, because TT-specific T cells with completely identical TCRs were found at 3 consecutive years after transplantation. These observations suggest an important role for T-cell selection processes in the complete restoration of the T-cell immune repertoire in children after allo-BMT.

IL-7 increases both thymic-dependent and thymic-independent T-cell regeneration after bone marrow transplantation

Blood ◽  
2001 ◽  
Vol 97 (5) ◽  
pp. 1491-1497 ◽  
Author(s):  
Crystal L. Mackall ◽  
Terry J. Fry ◽  
Cathy Bare ◽  
Paul Morgan ◽  
Anne Galbraith ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Cell Expansion ◽  
Immune Reconstitution ◽  
Cell Regeneration ◽  
T Cell Expansion ◽  
Peripheral Expansion

Thymic-dependent differentiation of bone marrow (BM)-derived progenitors and thymic-independent antigen-driven peripheral expansion of mature T cells represent the 2 primary pathways for T-cell regeneration. These pathways are interregulated such that peripheral T-cell expansion is increased in thymectomized versus thymus-bearing hosts after bone marrow transplantation (BMT). This study shows that this interregulation is due to competition between progeny of these 2 pathways because depletion of thymic progeny leads to increased peripheral expansion in thymus-bearing hosts. To test the hypothesis that competition for growth factors modulates the magnitude of antigen-driven peripheral expansion during immune reconstitution in vivo, a variety of T-cell active cytokines were administered after BMT. Of the cytokines (interleukins) tested (IL-3, IL-12, IL-6, IL-2, and IL-7), IL-2 modestly increased peripheral expansion in the face of increasing numbers of thymic emigrants, whereas IL-7 potently accomplished this. This report also demonstrates that the beneficial effect of IL-7 on immune reconstitution is related to both increases in thymopoiesis as well as a direct increase in the magnitude of antigen-driven peripheral expansion. Therefore, the administration of exogenous IL-7, and to a lesser extent IL-2, abrogates the down-regulation in antigen-driven peripheral expansion that occurs in thymus-bearing hosts after BMT. These results suggest that one mechanism by which T-cell–depleted hosts may support antigen-driven T-cell expansion in vivo is via an increased availability of T-cell–active cytokines to support clonal expansion.

scholarly journals Detection of Cells with Low Side Scatter and Dimmer CD45 Expression after Allogeneic Hematopoietic Stem Cell Transplantation Predicts Good Survival

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3207-3207
Author(s):  
Yoshimitsu Shimomura ◽  
Hayato Maruoka ◽  
Yotaro Ochi ◽  
Yusuke Koba ◽  
Yuichiro Ono ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Bone Marrow Transplantation ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Marrow Transplantation ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

Abstract <Introduction> Hematogones are lymphoblast-like cells that increase transiently in the bone marrow and have a characteristic profile of normal B cell precursors co-expressing CD10 and CD19. A cluster of hematogones is often found in the region of low side scatter and dimmer CD45 expression (SSC low CD45 dim), which also includes lymphoid and myeloid precursors, basophils, and partial components of natural killer cells. However, in steady state healthy adult bone marrow, SSC low CD45 dim populations are hardly detectable. In the bone marrow of patients recovering from chemotherapy or bone marrow transplantation, SSC low CD45 dim populations occasionally appear, with the majority of the population consisting of hematogones, especially in patients in complete remission (CR). Studies have shown that increased hematogones in patients with high-risk hematological malignancies after allogeneic hematopoietic stem cell transplantation (HSCT) improved survival. The specific detection of hematogones is difficult because multicolor flow cytometry is necessary to exclude myeloid/lymphoid blasts in active leukemia patients. However, after allogeneic HSCT in patients with leukemia and confirmed CR or malignant lymphoma without bone marrow invasion, hematogones can be easily detected as cells with SSC low CD45 dim populations. <Patients and methods> This retrospective case analysis included 88 patients treated with allogeneic HSCT at our hospitals from October 2010 to November 2014. The cases included acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in CR at the time of allogeneic HSCT, chemo-naïve or azacitidine-treated myelodysplastic syndrome (MDS) and malignant lymphoma (ML) or adult T cell leukemia/lymphoma (ATL) with marrow CR or without bone marrow invasion. We excluded 8 patients without engraftment. The remaining 80 patients underwent bone marrow aspiration around 28 days after HSCT and were confirmed to be in CR. Bone marrow cells were stained with APC-Cy7-conjugated CD45 and analyzed using FACSCanto. Patients were defined as being simply detected hematogones (SHG)-positive if 0.6%, which is the median proportion of SSC low CD45 dim cells in this study, or more of total nuclear cells were SSC low CD45 dim; the others were defined as SHG-negative. <Results> The median follow-up of survivors of our cohort was 773 (81-1593) days. Primary diagnoses were AML (n=36), ALL (n=21), MDS (n=8), and ML or ATL (n=15). They were treated with bone marrow transplantation (n=51), peripheral blood stem cell transplantation (n=6), and cord blood transplantation (n=23). Among them, 40 were SHG-positive and 40 were SHG-negative. Overall survivals (OS) at 2 years was 94.8% and 58.2% (p<0.001), event free survival (EFS) at 2 years was 94.9% and 46.5% (p<0.001). Cumulative incidence of relapse at 2 years was 5.1% and 34.0% (p<0.001), and cumulative incidence of treatment related mortality (TRM) at 2 years was 0% and 20.6% (p=0.0059) in SHG-positive and SHG-negative groups, respectively. Cumulative incidence of acute graft-versus-host disease (aGVHD) at day 100 was 68.3% and 65.5% (p=0.31) and for severe aGVHD (grade II-IV) was 31.8% and 36.3% (p=0.87) in SHG-positive and SHG-negative groups, respectively. Age ≥50 years, sex, hematopoietic cell transplant-comorbidity index over 2, disease risk index (DRI), myeloablative conditioning regimen and donor source were entered into multivariate analysis, which identified SHG-positive and a low or intermediate DRI as independently associated with a good prognosis. <Conclusion> Thus, the presence of SHG at day 28 predicts improved OS and EFS, and a lower incidence of relapse and TRM. This population of cells is easily detectable, providing useful information for outcome predictions. Patients without SSC low CD45 dim populations should be carefully observed after allogeneic HSCT. Disclosures No relevant conflicts of interest to declare.

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