scholarly journals Direct evidence for new T-cell generation by patients after either T-cell–depleted or unmodified allogeneic hematopoietic stem cell transplantations

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2235-2242 ◽  
Author(s):  
Sharon R. Lewin ◽  
Glenn Heller ◽  
Linqi Zhang ◽  
Elaine Rodrigues ◽  
Eva Skulsky ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell ◽  
Opportunistic Infections ◽  
Cell Receptor ◽  
Hematopoietic Stem ◽  
Cell Immunity ◽  
The Difference ◽  
T Cell Phenotypes

Abstract Successful allogeneic hematopoietic stem cell transplantation (HSCT) requires reconstitution of normal T-cell immunity. Recipient thymic activity, biologic features of the allograft, and preparative regimens all contribute to immune reconstitution. We evaluated circulating T-cell phenotypes and T-cell receptor rearrangement excision circles (TRECs) in 331 blood samples from 158 patients who had undergone allogeneic HSCTs. All patients had received myeloablative conditioning regimens and were full donor chimeras in remission. Younger patients exhibited more rapid recovery and higher TRECs (P = .02). Recipients of T-cell–depleted allografts initially had lower TRECs than unmodified allograft recipients (P < .01), but the difference abated beyond 9 months. TREC level disparities did not achieve significance among adults with respect to type of allograft. Measurable, albeit low, TREC values correlated strongly with severe opportunistic infections (P < .01). This finding was most notable during the first 6 months after transplantation, when patients are at greatest risk but before cytofluorography can detect circulating CD45RA+ T cells. Low TRECs also correlated strongly with extensive chronic graft-versus-host disease (P < .01). Recipients of all ages of either unmodified or T-cell–depleted allografts therefore actively generate new T cells. This generation is most notable among adult recipients of T-cell–depleted allografts, most of whom had also received antithymocyte globulin for rejection prophylaxis. Low TREC values are significantly associated with morbidity and mortality after transplantation. T-cell neogenesis, appropriate to age but delayed in adult recipients of T-cell– depleted allografts, justifies interventions to hasten this process and to stimulate desirable cellular immune responses.

scholarly journals Direct evidence for new T-cell generation by patients after either T-cell–depleted or unmodified allogeneic hematopoietic stem cell transplantations

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2235-2242 ◽  
Author(s):  
Sharon R. Lewin ◽  
Glenn Heller ◽  
Linqi Zhang ◽  
Elaine Rodrigues ◽  
Eva Skulsky ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell ◽  
Opportunistic Infections ◽  
Cell Receptor ◽  
Hematopoietic Stem ◽  
Cell Immunity ◽  
The Difference ◽  
T Cell Phenotypes

Successful allogeneic hematopoietic stem cell transplantation (HSCT) requires reconstitution of normal T-cell immunity. Recipient thymic activity, biologic features of the allograft, and preparative regimens all contribute to immune reconstitution. We evaluated circulating T-cell phenotypes and T-cell receptor rearrangement excision circles (TRECs) in 331 blood samples from 158 patients who had undergone allogeneic HSCTs. All patients had received myeloablative conditioning regimens and were full donor chimeras in remission. Younger patients exhibited more rapid recovery and higher TRECs (P = .02). Recipients of T-cell–depleted allografts initially had lower TRECs than unmodified allograft recipients (P < .01), but the difference abated beyond 9 months. TREC level disparities did not achieve significance among adults with respect to type of allograft. Measurable, albeit low, TREC values correlated strongly with severe opportunistic infections (P < .01). This finding was most notable during the first 6 months after transplantation, when patients are at greatest risk but before cytofluorography can detect circulating CD45RA+ T cells. Low TRECs also correlated strongly with extensive chronic graft-versus-host disease (P < .01). Recipients of all ages of either unmodified or T-cell–depleted allografts therefore actively generate new T cells. This generation is most notable among adult recipients of T-cell–depleted allografts, most of whom had also received antithymocyte globulin for rejection prophylaxis. Low TREC values are significantly associated with morbidity and mortality after transplantation. T-cell neogenesis, appropriate to age but delayed in adult recipients of T-cell– depleted allografts, justifies interventions to hasten this process and to stimulate desirable cellular immune responses.

Berkeley Sickle Mice Demonstrate CD8- and NK1.1-Dependent Increased Rejection of Allogeneic Hematopoietic Stem Cell Transplants.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2332-2332
Author(s):  
Leslie Kean ◽  
Kelly Hamby ◽  
Jennifer Perry ◽  
Christian Larsen ◽  
David Archerq
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Sickle Cell Disease ◽  
Hematopoietic Stem Cell ◽  
Sickle Cell ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Cell Immunity ◽  
Increased Risk

Abstract While hematopoietic stem cell transplantation (HSCT) represents the only curative therapy for sickle cell disease, sickle patients undergoing HSCT face many complications, including an increased risk of graft rejection compared to non-sickle patients. We have used the Berkeley sickle mouse model to study the potential mechanisms underlying this increased risk of rejection. Using a CD28/CD40 costimulation-blockade-based non-myeloablative HSCT regimen, we transplanted Berkeley sickle mice with fully allogeneic SJL bone marrow. While the vast majority (&gt;85%, n=25) of control C57BL/6 animals became stably chimeric and immunologically donor-tolerant with this transplant regimen, sickle mice were much more prone to reject the transplant (~20% graft acceptance, n=25). Both CD8+ cells and NK1.1+ cells were found to contribute to this rejection, as depletion of either of these cell populations led to a marked increase in the percent of engrafted mice (&gt;85% graft acceptance, n=15–25), while depletion of CD4+ cells led to the opposite effect, with 0% (n=25) animals engrafted in this depletion cohort. The increased propensity of HSCT rejection in the Berkeley sickle mice may, in part, be explained by the presence of increased numbers of donor-reactive T cells (5–10-fold compared to C57BL/6 controls) in naïve sickle mice, despite their lack of exposure to donor antigens, and their housing in a Specific-Pathogen-Free environment. We speculate that these increased numbers of anti-donor T cells may occur as a result of heightened inflammation in the context of active sickle cell disease, which could lead to increased expansion and persistence of a T cell repertoire containing anti-donor heterologous T cell immunity. This heterologous immunity may have a profound effect on the success of HSCT for sickle cell disease, especially when non-myeloablative regimens are employed.

scholarly journals Genetic T-cell receptor diversity at 1 year following allogeneic hematopoietic stem cell transplantation

Leukemia ◽  
2019 ◽  
Vol 34 (5) ◽  
pp. 1422-1432 ◽  
Author(s):  
Stéphane Buhler ◽  
Florence Bettens ◽  
Carole Dantin ◽  
Sylvie Ferrari-Lacraz ◽  
Marc Ansari ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Hematopoietic Stem

Prediction of T-cell reconstitution by assessment of T-cell receptor excision circle before allogeneic hematopoietic stem cell transplantation in pediatric patients

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 886-893 ◽  
Author(s):  
Xiaohua Chen ◽  
Raymond Barfield ◽  
Ely Benaim ◽  
Wing Leung ◽  
James Knowles ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Hematopoietic Stem ◽  
Thymic Function ◽  
T Cell Reconstitution

Abstract The extent and rapidity with which T cells are regenerated from graft-derived precursor cells directly influences the incidence of infection and the T-cell–based graft-versus-tumor effect. Measurement of T-cell receptor excision circles (TRECs) in peripheral blood is a means of quantifying recent thymic T-cell production and has been used after transplantation in many studies to estimate thymus-dependent T-cell reconstitution. We hypothesized that the quality of thymic function before transplantation affects thymus-dependent T-cell reconstitution after transplantation. We used real-time polymerase chain reaction (PCR) to quantify signal-joint TRECs (sjTRECs) before and after transplantation. T-cell reconstitution was evaluated by T-cell receptor β (TCRβ) CDR3 size spectratyping. We tested 77 healthy sibling donors and 244 samples from 26 pediatric recipients of allogeneic hematopoietic stem cell transplantation (AHSCT). Blood from the healthy donors contained 1200 to 155 000 sjTREC copies/mL blood. Patients who had greater than 1200 copies/mL blood before transplantation showed early recovery of sjTREC numbers and TCRβ repertoire diversity. In contrast, patients who had fewer than 1200 copies/mL blood before transplantation demonstrated significantly slower restoration of thymus-dependent T cells. We conclude that the rate of reconstitution of thymus-dependent T cells is dependent on the competence of thymic function in the recipients before transplantation. Therefore, pretransplantation measurement of sjTREC may provide an important tool for predicting thymus-dependent T-cell reconstitution after transplantation.

The Molecular Characteristics in CDR3 of TCR Vα and Vβ Genes Associated with cGVHD in Patients after Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3247-3247
Author(s):  
Xiuli Wu ◽  
Yangqiu Li ◽  
Kanger Zhu ◽  
Xin Du ◽  
Shaohua Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
T Cell Immunity ◽  
Molecular Characteristics ◽  
Hematopoietic Stem ◽  
T Cell Clones ◽  
New Name ◽  
Cell Immunity ◽  
Cell Clones

Abstract Successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) requires reconstitution of normal T-cell immunity. Chronic graft-versus-host disease (cGVHD) is one of the major complications following allo-HSCT. The poor reconstitution of T-cell immunity (including the reconstitution of recent thymic output function and T-cell receptor (TCR) repertoire) was associated with cGVHD. In the previous study, we found that cGVHD predicted low TCR rearrangement excision circles (TRECs) levels and slow naïve T-cell recovery. Because GVHD displayed as clonal proliferation of special T-cells clones, which was triggered by donor T cells to recognize the host’s allogene antigen, in the present study we analyzed the TCR Vα and Vβ repertoire and cloanlity in patients with cGVHD, in order to find the special T-cell clones associated with cGVHD and evaluate the molecular characteristics of the CDR3 of TCR Vα and Vβ repertoire of GVHD-associated T-cell clones. Peripheral blood mononuclear cells (PBMNCs) were obtained from 5 leukemia patients with cGVHD after allo-HSCT. The expression and cloanlity analysis of TCR Vα and Vβ repertoire were detected by RT-PCR and genescan technique. Six donors served as controls. Almost all of TCR Vα and Vβ repertoire with polyclonal pattern were identified in normal controls. However, the skew expression pattern of TCR Vα and Vβ repertoire could be detected in patients with cGVHD even more than 4 year after allo-HSCT. Among 29 Vα and 24 Vβ subfamilies, there were only 4∼12 Vα and 4∼11 Vβ subfamilies expressed in patients with cGVHD. Oligoclonal or monoclonal expanded T cells were identified in TCR Vα 2, 3, 6, 10, 12, 14, 15, 25, 26 and TCR Vβ 1, 3, 7∼9, 13, 17, 19, 20 subfamilies respectively. The CDR3 sequences were further analyzed and all the sequences were blasted by internet (http://www.ncbi.nlm.nih.gov) and confirmed that it belonged to specific TCR Vα or Vβ gene rearrangement. The lengths of CDR3 were ranged from 12 to 15 amino acids. The molecular characteristics of the CDR3 of TCR Vα and Vβ genes rearrangement were TCRVα 3 (new name: Vα 17*01)-N-Jα 48*01-Cα (motif: CATEVDFGNEKLIF), TCRVα 2 (new name: Vα 12–2*01)-N-Jα 20*01-Cα (motif: CAVNLNDYKLIF), TCRVβ 1 (new name: Vβ 9*01)-N-Dβ 2*01-N-Jβ 2–1*01-Cβ 2 (motif: CASSDPPETYNEQFF), TCRVβ 7 (new name: Vβ 4–3*01)-N-Dβ 1*01-Jβ 1–1*01-Cβ 1 (motif: CASSHESGNTEAFF). Some TCR subfamily genes shared similarity in CDR3 amino acid motif. The role of specific sequences of CDR3 of TCR Vα and Vβ repertoire and T-cell clones will be confirmed in vivo by animal models.

Failure to Recover Thymopoiesis After Allogeneic Hematopoietic Stem Cell Transplantation Predicts for High Incidence of Opportunistic Infections and Non-Relapse Mortality

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 832-832
Author(s):  
Evert-Jan Wils ◽  
Bronno van der Holt ◽  
Annoek E.C. Broers ◽  
Sandra J. Posthumus-van Sluijs ◽  
Jan W. Gratama ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
T Cell Receptor ◽  
Opportunistic Infections ◽  
Cell Receptor ◽  
Risk Status ◽  
Hematopoietic Stem ◽  
Donor Type ◽  
Severe Infections

Abstract Abstract 832 Recovery of thymopoiesis after allogeneic hematopoietic stem cell transplantation (alloSCT) is considered pivotal for full immune competence. Failure to recover thymopoiesis after alloSCT is suggested by the absence of newly developed T-cells that contain signal joint T-cell Receptor Excision Circles (sjTREC), which are produced during T-cell receptor rearrangement. Higher age, reduced pre-transplant thymic function, and graft versus host disease have all been associated with impaired thymic recovery after alloSCT. However, it is still unclear to what extent insufficient thymic recovery itself predicts for subsequent opportunistic infections and non-relapse mortality (NRM). A detailed, prospective survey of all post-engraftment infectious complications, NRM, overall survival (OS), and lymphocyte subsets and thymic recovery during long-term follow-up after alloSCT was performed in 83 high-risk recipients of T cell depleted related or unrelated donor grafts after myeloablative conditioning. A cumulative incidence of common toxicity criteria (CTC) grade 3 and 4 severe infections at 12 months after alloSCT was 66% with a median number of 1.6 severe infectious episodes per patient. The rate of severe post-engraftment infections was 0.64 per 100 patient days during the first year and 0.16 in the second year. After a median follow-up of 118 months, OS was 52%, as determined by a NRM of 25% and relapse mortality of 23%. Outcome was significantly predicted for by the European Group for Blood and Marrow Transplantation (EBMT)-risk score (Gratwohl et al, Cancer, 2009), based on age, gender, risk-status, donor-type and time to SCT (p=0.01). Lymphocyte recovery was slow with median CD4+ T cells exceeding 200/ul by 12 months post alloSCT. At that time, median sjTREC content measured 5.629/ml, which was significantly lower than the median sjTREC content in stem cell donors (19.044/ml, p=0.001). The recovery rate of overall lymphocyte counts as well as T cell subsets did not consistently predict for opportunistic infections and NRM. Patients without thymic recovery at 2, 6, 9, or 12 months were at 3- to 9-fold higher risk for severe infections, which remained significant following multivariable analysis (hazard ratio (HR)-6 months: 0.30 (95%CI 0.09–1.02, p=0.04), HR-12 months: 0.11 (0.01-0.93 p=0.02)). Impaired thymic recovery also translated into a higher risk for NRM (HR-6 months: 0.06 (0.01-0.47 p=0.008), HR-12 months: 0.00 (0.00-1.42 p=0.0005)) and outweighed pre-transplant risk factors including age, donor-type, risk-status when evaluated individually or collectively as the EBMT risk score. Impaired thymic recovery at 6 months was also predictive for lower OS (HR; 0.35 (0.12-1.00 p=0.05)). In conclusion, these results indicate that patients, who fail to recover thymopoiesis after alloSCT are at very high risk for severe infections and adverse clinical outcome, independent of other pre-transplant risk factors and despite intensive monitoring and prophylactic antimicrobial measures. These results indicate that monitoring thymopoiesis after alloSCT may be applied more routinely and strategies to reduce NRM should be directed at thymic regeneration. Disclosures: No relevant conflicts of interest to declare.

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