Increased Effector CD4+ T-Cells Early Post Hematopoietic Stem Cell Transplantation Using an Alemtuzumab-Based Reduced Intensity Conditioning Regimen Correlate with Subsequent Development of Graft Versus Host Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4999-4999
Author(s):  
Katie Matthews ◽  
ZiYi Lim ◽  
Laurence Pearce ◽  
Khalid Tobal ◽  
Alejandro Madrigal ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Cd4 T Cells ◽  
Subsequent Development ◽  
Effector T Cells ◽  
Cd4 T Cell ◽  
Hematopoietic Stem ◽  
Graft Versus Host

Abstract Lymphocyte depletion using the anti CD52 monoclonal antibody alemtuzumab reduces the incidence of graft versus host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), but some patients still develop this potentially life-threatening complication. We previously reported that patients achieving rapid full donor T cell chimerism after fludarabine, busulphan and alemtuzumab (FBC) conditioned allo-HSCT have a significantly increased risk of GvHD compared to patients with prolonged mixed donor chimerism beyond day 100 (Lim et al. Br. J. Haematology 2007). We performed a prospective study of 29 patients who received allo-HSCT with FBC conditioning (median age: 53 years; range: 34 – 69 presenting with AML or MDS) to examine the kinetics of lymphocyte reconstitution in relation to T-cell chimerism patterns and incidence of GvHD. Naïve, memory, effector and terminally differentiated CD4+ and CD8+ T-cells, activated T-cells (CD25+ HLA-DR+); putative regulatory CD4+ CD25high Foxp3+ T-cells, B-cells and NK cells were enumerated in whole peripheral blood of patients at days 30, 60, 90, 180, 270 and 360 after HSCT. Chimerism analysis of purified T-cells was performed by genetic profiling of polymorphic short tandem repeat loci. Ten patients developed GvHD (acute or chronic). Although alemtuzumab induced profound depletion of all T-cell subsets, significantly higher numbers of CD4+ effector (CD45RO+ CD27−) T-cells were detected at day 30 post transplant in patients who later developed GvHD (24 cells/μl; range: 1 – 84 cells/μl) compared to patients without GvHD (5 cells/μl; range: 1 – 40 cells/μl) (p = 0.026). In contrast, there were no significant differences in the numbers or rate of reconstitution of CD8+ T-cell sub-populations, NK cells or B-cells in patients that developed GvHD and those who did not at any time points. T-cells present at day 30 in patients that subsequently developed GvHD were 100% donor whereas the majority of patients that did not develop GvHD exhibited mixed donor and recipient T cell chimerism. Development of GvHD pathology was associated with expansion of these donor effector CD4+ T-cells (at day 60: 35 cells/μl; range: 9 – 154 cells/μl compared to 7 cells/μl; range: 1 – 56 cells/μl for patients without GvHD, p = 0.04). Absolute numbers of CD4+ CD25high Foxp3+ T-cells at day 30 were similar in both groups of patients (p = 0.8). However, of note, a significant deficit of these putative regulatory T-cells in the group that developed GvHD was apparent when numbers were considered relative to CD4+ effector T cells at day 30 (41 CD4+ effector T-cells; range: 28 – 51 /per regulatory CD4+ T cell for the GvHD group compared to 12 CD4+ effector T-cells; range: 2 – 33 /per regulatory CD4+ T-cell for patients without GvHD, p = 0.03). We speculate the higher numbers of effector CD4+ T-cells detected in patients at day 30 post HSCT are donor-derived mature T cells that alemtuzumab fails to deplete. In the solid organ transplant setting, alemtuzumab has been shown to be relatively sparing of effector memory CD4+ T-cells. Our correlation of donor-derived effector CD4+ T-cells with subsequent development of GvHD suggests they are alloreactive and that a deficit of T-regs relative to CD4+ effector T-cells early post HSCT contributes to GvHD.

Increased Functional T Cell Defects in Patients with low CD4 Counts after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4588-4588
Author(s):  
Udo Holtick ◽  
Lukas P. Frenzel ◽  
Shimabukuro-Vornhagen Alexander ◽  
Sebastian Theurich ◽  
Julia Claasen ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Hematopoietic Stem ◽  
Cd4 Counts ◽  
Graft Vs Host Disease

Background The recovery of the host immune system after allogeneic hematopoietic stem cell transplantation is pivotal to prevent infections, relapse and secondary malignancies. In particular, numerical CD4 T-cell reconstitution is delayed and CD4-helper cell function considered impaired as consequence of the transplant procedure and concommitant immunosuppressive medication. From HIV/AIDS patients it is known that numerical and functional CD4 defects increase the risk of opportunistic infections. Therefore, even in the absence of immunosuppressants and graft-vs-host disease, anti-infective prophylaxis is usually given for at least six months. We hypothesized that the numerical CD4 defect in patients may be reflected by immunosuppressive RNA fingerprints previously established for certain immuno-inhibitory molecules and tested whether the functional CD4 capacity was different according to the CD4 cell number. Methods RNA was separated from CD4 T-cells of 10 patients with CD4 counts >500/µl, 10 patients with CD4 counts <200/µl and four healthy controls. All patients had to be off immunosuppression and without any clinical signs of graft-vs-host disease. Transcriptional activity was assessed with regard to previously defined fingerprints motives for CTLA-4, IL-10, PD-1, TGF-β and PGE-2. CD4 T-cells from all groups were further tested for their proliferative capacity and cytokine production. Results Hierarchical clustering segregated the three groups. Applying the immunosuppressive fingerprints, patients with CD4 T-cells >500/µl were demonstrated to be under the influence of PGE2, whereas patients with CD4 T-cells <200/µl were demonstrated to be under the influence of PGE2 and CTLA-4. In normal controls, no association was found. The proliferative capacity of patient CD4 T-cells upon CD3-CD28-bead stimulation was not significantly different from healthy controls. The production of IL-2 by stimulated CD4 T-cells was significantly downregulated in patients with CD4 T-cells <200/µl, while there was no difference in IFN-ƴ and TNF-α secretion. Conclusion The severity of the CD4 numerical defect reflects the state of immunosuppression as demonstrated by RNA immuno-inhibitory fingerprint motives. This partially translates into functional differences as measured by decreased IL-2 secretion. In addition to time after transplant, CD4 T-cell numbers should be considered for the decision to stop or maintain anti-microbial prophylaxis in patients after allogeneic stem cell transplantation. (UH, LPF and CW, JMC contributed equally to this work.) Disclosures: No relevant conflicts of interest to declare.

Increased Proliferation of FoxP3 Regulatory T Cells after Allogeneic Hematopoietic Stem Cell Transplantation Is Counterbalanced by Increased Susceptibility to Apoptosis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 720-720
Author(s):  
Ken-ichi Matsuoka ◽  
Corey Cutler ◽  
John Koreth ◽  
Joseph H Antin ◽  
Robert J Soiffer ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Ki 67 ◽  
Hematopoietic Stem ◽  
Healthy Donors

Abstract CD4+FoxP3+ Regulatory T cells (Treg) play a critical role in the maintenance of tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). We previously demonstrated that patients with active chronic graft-versus-host disease (cGVHD) have a reduced frequency of Treg. However, the mechanisms responsible for inadequate Treg reconstitution in patients with cGVHD have not been characterized. We therefore examined phenotypic and functional characteristics of Treg in 16 patients 2–41 months (median 10 months) post-HSCT to elucidate these mechanisms. Treg were compared to conventional CD4+FoxP3-T cells (Tcon) within individual patient samples and to healthy donors. All patients received TBI-based myeloablative conditioning, peripheral blood stem cells from HLA-matched donors (12 MRD; 4 URD) and acute GVHD prophylaxis (11 tacrolimus and sirolimus; 5 tacrolimus and methotrexate). At the time of analysis, 9 patients had no chronic GVHD, 5 had active chronic GVHD (1 limited disease; 4 extensive disease) and 2 had inactive chronic GVHD. Total CD4 counts were relatively low after HSCT compared to healthy donors (median CD4 273/ul vs 756/ul). After HSCT, patient Treg exhibited a predominant CD45RA(−)CCR7(−) effector/memory phenotype. Expression of CD31 on CD45RA+ Tcon and Treg was used to identify cells within these subsets that were recent thymic emigrants (RTE). In patient samples, 16.5% of Tcon and 2.8% of Treg expressed CD31+CD45RA+. In healthy donors, 22.9% of Tcon and 5.4% of Treg were CD31+CD45RA+. The lower fraction of RTE within the Treg population after transplant suggests that Treg primarily reconstitute through peripheral proliferation rather than through thymic generation. The proliferative capacity of both Tcon and Treg was examined by evaluating expression of Ki-67 in these subsets. After transplant, Ki-67 expression was significantly higher in Treg (5.2%) than in Tcon (1.5%) (p<0.001). This was significantly higher in both populations compared to healthy donors where 2.5% of Treg (p<0.05) and 0.2% of Tcon (p<0.01) expressed Ki-67. In both patients and healthy donors, Ki-67 expression was found almost entirely in cells that were CD45RA-indicating that proliferation was primarily occurring within the memory subsets of Tcon and Treg. Increased expression of Ki-67 on Treg was associated with low CD4 T cell counts (p<0.001), but not with time after HSCT (p=0.21) and chronic GVHD status (p=0.35). Treg Ki-67 expression after HSCT showed a strong positive correlation with CD95 (FAS) expression (p<0.01), but this association was not present in Tcon post-HSCT or in Treg from healthy donors. To determine whether increased expression of CD95 results in apoptosis of Treg, we purified 4 different CD4+ T cell subsets by cell sorting (CD45RA+ Tcon, CD45RA− Tcon, CD45RA+ Treg and CD45RA− Treg) from healthy donors and HSCT patients. Purified cells were cultured with or without agonistic FAS antibody (anti-FAS) and apoptosis was measured using Annexin-V staining. Anti-FAS rapidly induced apoptosis of CD45RA− memory-like Treg from HSCT patients while all other Treg and Tcon subsets were relatively resistant to apoptosis. In summary, these results indicate that Treg reconstitution post-HSCT is characterized by high levels of peripheral proliferation, which appear to be driven primarily by persistent CD4 T lymphopenia. However, post-HSCT Treg are also highly sensitive to FAS-mediated apoptosis. This process does not affect the survival of other CD4 T cell subsets. In the absence of thymic generation of Treg from hematopoietic precursors, this dynamic process results in a relative deficiency of Treg post-HSCT. Our findings provide important information for developing strategies aimed at monitoring and modulating Treg to promote immune tolerance following HSCT.

Reconstitution of Regulatory T Cells Involves in the Development of Acute Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2204-2204
Author(s):  
Shuhei Karakawa ◽  
Kazuhiro Nakamura ◽  
Keiichi Hara ◽  
Yoko Mizoguchi ◽  
Mizuka Miki ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Acute Gvhd ◽  
The Other ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Self Tolerance

Abstract Graft-versus-host disease (GVHD) is a significant complication in hematopoietic stem cell transplantation (SCT). On the other hand, graft-versus-tumor (GVT) effect has been known to be concerned with the prevention of relapses in various hematological or non-hematological malignant disorders. The regulation of GVHD without suppressing GVT effect is a pivotal role in the success of hematopoietic SCT. Recently CD4+CD25+regulatory T cells have been recognized to regulate the maintenance of self-tolerance, and associate with several autoimmune diseases. In transplant immunity, CD4+CD25+regulatory T cells have been reported to regulate GVHD without suppressing GVT effect in several animal studies. Natural killer T (NKT) like cells also have been recognized to associated with the maintenance of self-tolerance by inducing CD4+CD25+regulatory T cells through the production of IL-2. In this study, we examined the roles of CD4+CD25+regulatory T cells and NKT like cells in cases underwent hematopoietic SCT. Blood samples from patients underwent SCT in our institution during past 3 years (7 months through 26 years of age, n =19) were obtained every two weeks until day 90 after SCT. Primary disorders of patients were non-malignant hematological disease such as aplastic anemia (n=3), chronic granulomatous disease (n=8) and malignant disease such as leukemia (n=5), and solid tumors (n=3). Pre-conditioning regimens used in this study were myeloablative regimens in 10 cases and reduced intensity regimens in 9 cases, respectively. The frequencies of CD4+CD25+regulatory T cells were assessed by the expression of CD4 and CD25, and those of NKT like cells were assessed by the expression of CD3, CD16, and CD56 using flow cytometry. The mRNA expression of FOXP3 in purified CD4+CD25+regulatory T cells were determined by quantitative real-time PCR method. In 13 patients who had none or Grade 1 acute GVHD, the frequency of CD4+CD25+regulatory T cells in CD4+ T cells was increased up to 25–90% at early period after SCT and normalized below 20% after day 45 post SCT. On the other hand, four of 6 patients who had acute GVHD (more than Grade 2) showed that the frequency of CD4+CD25+regulatory T cells in CD4+ T cells persisted below 20%. In other one patient, the development of acute GVHD (Grade 2) was associated with decreasing the frequency of CD4+CD25+regulatory T cells (30 to 10%) and the recovery of GVHD was found with increasing CD4+CD25+regulatory T cells (10 to 30%). The mean frequency of CD4+CD25+regulatory T cells in CD4+ T cells on day 15 after SCT was 44% in patients without GVHD and 21% in patients with GVHD (p=0.07). No difference in the expressions of FOXP3 mRNA in purified CD4+CD25+regulatory T cells was noted between patients with GVHD and those without GVHD. The reconstitution pattern of CD3+CD16+CD56+ NKT like cells after SCT was not associated with the development of GVHD. These results suggest that the development of acute GVHD may be strongly associated with the reconstitution of donor derived CD4+CD25+regulatory T cells in CD4+ T cells. The measurement of CD4+CD25+regulatory T cells in CD4+ T cells might lead to the early diagnosis and the prevention of acute GVHD. (Future studies will be needed to examine the association between the frequency of regulatory T cells and GVT effect.)

IL-12hi Rapamycin-Conditioned Dendritic Cells Mediate IFN-γ-Dependent Apoptosis of Alloreactive CD4+ T Cells and Limit Graft-Versus-Host Diseas

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4110-4110
Author(s):  
Elizabeth O. Stenger ◽  
Brian R. Rosborough ◽  
Lisa Mathews ◽  
Huihui Ma ◽  
Markus Mapara ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Cell Apoptosis ◽  
Cd4 T Cells ◽  
Annexin V ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
T Cell Apoptosis ◽  
Ifn Γ

Abstract Abstract 4110 Introduction: Rapamycin (RAPA) inhibits the serine/threonine kinase mammalian Target of Rapamycin to profoundly modulate immune cell function. Dendritic cells (DC) exposed to RAPA (RAPA-DC) exhibit tolerogenic properties, including promotion of experimental cardiac allograft survival. RAPA-DC enrich for CD4+FoxP3+ regulatory T cells and induce alloreactive T cell apoptosis and anergy. Yet, paradoxically, RAPA-DC secrete increased IL-12, which is central for the generation of IFN-γ+CD4+ T helper type 1 cells. IFN-γ can be pro-apoptotic, and IL-12-driven IFN-γ inhibits graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. We hypothesized that IL-12hi RAPA-DC, unlike control (CTR)-DC, would be effective in the prevention of GVHD by supporting IFN-γ-mediated apoptosis of alloreactive T cells. Methods: DC were generated from C57BL/6 (H2-b) or B6.129S7-Ifngr1tm1Agt/J (IFN-γ-R−/− [H2-b]) bone marrow (BM) in 7 day (d) culture in the absence (CTR-DC) or presence of RAPA (RAPA-DC). CTR- and RAPA-DC cultures remained either untreated or were stimulated via TLR4 with LPS (100 ng/ml) for an additional 18 hours. Washed and CD11c+ purified DC from these groups were then used as stimulators of allogeneic CD4+ T cells (BALB/c [H2-d] or CByJ.129S7(B6)-Ifngr1tm1Agt/J [IFN-γ-R−/− {H2-d}]) in 5 d mixed leukocyte reaction (MLR) with or without anti-IFN-γ antibody. T cell apoptosis was quantified using an Annexin V Apoptosis Detection kit. The capacity of DC to prevent GVHD was assessed in irradiated BALB/c mice reconstituted with 5×106 T cell-depleted B6 BM on d0. Recipient mice received 1×106 CD11c+ BALB/c DC (CTR-, RAPA-, or LPS-exposed DC) on d0 and 1×106 B6 T cells on d1. Mice were monitored daily, and moribund mice or those with >20% weight loss were euthanized. Results: Compared to CTR-DC, especially when LPS-stimulated, RAPA-DC induced increased apoptosis (Annexin V+7-AAD+) of alloreactive CD4+ T cells in MLR (13.9±1.6% versus 7.1±0.2%; +LPS: 30.6±3.4% versus 14.7±3.6%; both p<0.05). Neutralization of IFN-γ in co-cultures containing LPS-stimulated RAPA-DC decreased levels of apoptosis to those of LPS-exposed CTR-DC (18.5±1.3% versus 14.7±3.6%; NS). IFN-γ-R−/− CD4+ T cells exposed to LPS-stimulated IL-12hi RAPA-DC exhibited decreased apoptosis when compared to wild-type CD4+ T cells (WT 15.7±3.6% versus IFN-γ-R−/− 4.9±1.1%; p<0.05) (Figure 1). There was no difference in the extent of apoptosis of alloreactive CD4+ T cells induced by IFN-γ-R−/− RAPA-DC compared to WT RAPA-DC (10.6±7.6% versus 12.4±7.6% respectively; +LPS: 30.1±16.3% versus 27.3±12.0%; both p=NS) (Figure 2). The addition of anti-IFN-γ mAb to LPS-stimulated IFN-γ-R−/− RAPA-DC significantly decreased levels of CD4+ T cell apoptosis comparable to LPS-stimulated WT CTR-DC (18.0±10.3% versus 22.0±6.3%, p<0.05). Depletion of IFN-γ did not impact on the Treg-enriching capacity (CD4hiFoxP3+/CD4hiFoxP3−) of RAPA-DC (24.2±0.4% versus 29.2±6.2% with anti-IFN-γ mAb; p=NS). Further, whereas CTR-DC and LPS-exposed CTR-DC did not prolong survival, IL-12hi RAPA-DC significantly prolonged survival from GVHD (median survival in days: GVHD, 17.5 d; RAPA-DC, 27 d, p=NS compared to GVHD; RAPA-DC + LPS, 35 d, p<0.01; syngeneic control, >50 d, p<0.01) (Figure 3). In contrast, CTR-DC had comparable GVHD mortality (21 d, p=NS). Conclusions: Increased apoptosis induced by LPS-stimulated IL-12hi RAPA-DC is mediated directly on CD4+ allogeneic T cells via IFN-γ and not through actions on DC. Thus, increased IL-12 may support IFN-γ-mediated activation-induced cell death while sparing regulatory T cells and may underlie the capacity of LPS-exposed RAPA-DC to prevent GVHD. IL-12hi human RAPA-DC, generated with the aid of endotoxin-free, synthetic TLR4 agonists, may offer a means to harness the demonstrated capacity of both IL-12 and tolerogenic DC to prevent GVHD following hematopoietic stem cell transplant. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Predicting Immune Pathology after Hematopoietic Stem Cell Transplant with Transcriptomics: Naïve CD4 T Cell Expansion at Day 100 Predicts Patients with De Novo Chronic Gvhd

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 38-39
Author(s):  
Ben Watkins ◽  
James Kaminski ◽  
Muna Qayed ◽  
Kayla Betz ◽  
Yvonne Suessmuth ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Cd4 T Cells ◽  
Research Funding ◽  
De Novo ◽  
Cd4 T Cell ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Stem

Background: Chronic graft-versus-host disease (CGVHD) is the leading cause of long-term morbidity and mortality following hematopoietic stem cell transplant (HCT) and occurs in over 50% of patients undergoing unrelated donor HCT. Despite its frequency, the mechanisms driving this disease remain incompletely understood, making its prevention and successful treatment challenging. To address this issue, we have undertaken a transcriptomic analysis of T cell reconstitution after unrelated donor HCT, to dissect mechanisms driving CGVHD. Methods: The patients studied were enrolled on a Phase 2, randomized, placebo-controlled trial of abatacept for GVHD prevention in patients receiving 8/8 unrelated-donor HCT for hematologic malignancies (NCT01743131). All immune analyses in the current study were performed on patients randomized to standard GVHD prophylaxis with calcineurin inhibition + methotrexate alone (placebo cohort, n =69), and thus provide insights into the drivers of CGVHD during standard unrelated donor HCT. On Day +100, CD4+ T cells were purified from the peripheral blood of these patients, and then analyzed by RNASeq. To determine the transcriptomic drivers of CGVHD without the confounder of significant prior acute GVHD (AGVHD) or exposure to steroids, we focused on profiling the CD4+ transcriptome of de novo CGVHD (CGVHD which develops in the absence of prior grade II-IV AGVHD, n = 7) and compared these patients to those who were 'operationally tolerant' and never developed either grade II-IV AGVHD or any CGVHD (n= 4). Gene expression from the resulting transcriptomes was quantified using kallisto. Differentially expressed (DE) genes were identified using DESeq2 (threshold for DE, adjusted (for multiple testing) p &lt;0.05). Gene Set Enrichment Analysis (GSEA) was also performed, with genes ranked by Log2FC/std_error (Log2FC), and gene signatures with an adjusted p &lt;0.05 considered significantly enriched. Results: DE analysis identified 101 genes that were significantly upregulated in CD4+ T cells from de novo CGVHD group and 54 genes that were significantly upregulated in the 'operationally tolerant' group (Figure 1A). GSEA identified that the mostly highly enriched signatures in patients with de novo CGVHD encompassed naïve CD4+ transcriptional programing (Figure 1B-C), in agreement with flow cytometric analysis, which also demonstrated expansion of CD4+ naïve T cells at Day +100 in patients developing de novo CGVHD compared to those demonstrating operational tolerance (Figure 1D). Importantly, the naïve CD4+ T cell signatures that were identified were distinct from those defining CD4+ stem cell memory T cells (which did not enrich in the de novo CGVHD cohort). In contrast, the gene signature of the operationally tolerant patients were enriched for regulatory gene sets (Figure 1C), consistent with a large body of evidence demonstrating that Treg expansion can be protective against CGVHD. Discussion: This study represents, to our knowledge, the first interrogation of the transcriptomic features of patients developing de novo CGVHD versus those operationally tolerant patients who develop neither significant AGVHD nor CGVHD after HCT. These patients may represent a particularly effective cohort in which to study immunologic drivers of CGVHD, given their freedom from prior treatment with corticosteroids, which can confound downstream transcriptomic analyses. Our data provide compelling evidence for a prominent naïve CD4+ T cell signature in patients who develop moderate-to-severe CGVHD despite their lack of antecedent AGVHD. These results are provocative, as they implicate a cell subset that is often considered more quiescent (naïve T cells) as associated with patients who develop immune pathology associated with CGVHD. These results suggest that naïve CD4+ T cells may represent a potent reservoir for alloreactivity, that, once activated, can cause significant disease. This would be in agreement with the implications of previously reported trials of naïve T cell depletion, which resulted in significant control of CGVHD. These results suggest that strategies to restrain naïve T cell pathogenic activation after Day +100 may improve CGVHD outcomes, and that the CD4+ T cell transcriptomic signature at this timepoint could be developed into a robust immunologic biomarker for the risk of developing CGVHD versus operational tolerance after HCT. Figure 1 Disclosures Watkins: Bristol Myers Squib: Honoraria. Qayed:Novartis: Consultancy; Mesoblast: Consultancy. Blazar:Tmunity: Other: Co-founder; KidsFirst Fund: Research Funding; BlueRock Therapeutics: Research Funding; Childrens' Cancer Research Fund: Research Funding; BlueRock Therapeuetic: Consultancy; Magenta Therapeutics: Consultancy; Fate Therapeutics Inc.: Research Funding. Horan:Bristol Myers Squib: Honoraria, Research Funding. Langston:Kadmon Corporation: Research Funding; Astellas Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Bristol Myers Squib: Research Funding; Chimerix: Research Funding; Takeda: Research Funding. Kean:fortyseven: Consultancy; regeneron: Research Funding; hifibio: Consultancy; kymab: Consultancy; Bristol Meyers Squibb: Research Funding; gilead: Research Funding; novartis: Consultancy; bluebird bio: Research Funding; magenta: Research Funding.

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.

Sign in / Sign up

Export Citation Format

Share Document