Acute Graft Versus Host Disease Reduces Human Thymic T Cell Differentiation without Acting on Thymocyte Proliferation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2184-2184
Author(s):  
Emmanuel Clave ◽  
Corinne Douay ◽  
Maryvonnick Carmagnat ◽  
Marc Busson ◽  
Regis Peffault de Latour ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Absolute Number ◽  
T Cell Differentiation ◽  
Graft Versus Host ◽  
Thymic Output ◽  
Thymocyte Proliferation ◽  
Significant Difference

Abstract Thymic function is essential for an efficient long term T cell reconstitution after Hematopoietic Stem cell Transplantation (HSCT). We and others have shown that several factors and especially Acute Graft Versus Host Disease (aGVHD) could have an important impact on thymic output as measured by “signal joint T cell Receptor Excision Circles” (sjTREC) quantification. In order to go further in the understanding of aGVHD action on thymic output we quantified the sjTREC (generated just before the T cell Receptor (TCR) alpha chain recombination) but also others TRECs generated during the TCR beta chain recombination, named betaTREC: sj/beta TREC ratio being a marker of thymocyte proliferation. A group of 13 aGVHD Patients was selected first because of a long term follow-up (> 24 months) and compared to a control group of 8 patients that did not have aGVHD, matched for age (mean 29.8 and 28.9 years for aGVHD and non aGVHD patients respectively). Patients received, mainly for leukemia (17 out 21), a Bone Marrow (14) or Peripheral Blood (7) HSCT from a sibling genoidentical donor. TRECs (sj and beta) were quantified by multiplex real-time PCR with albumin gene as standard, using genomic DNA extracted from peripheral blood mononuclear cell samples obtained before HSCT and at 3, 6, 12 and 24 months after. In parallel, absolute number of CD3+ and naïve T cells was measured by flow cytometry using antibodies against CD3, CD4, CD8, CD45RA and CD62L. In our patients, the percentage and absolute number of naïve T cells, as defined by the CD45RA+, CD62L+ phenotype, were not different between the 2 groups showing again the inability of this parameter to measure the recent thymic emigrants in HSCT. Mean sjTREC /150000 cells decreased in both categories of patient 3 months after HSCT. Then, for non aGVHD patients, they started to rise up to reach near normal level at 12 months but not for aGVHD patients where they keeped decreasing until 6 months. At this last time point mean aGVHD patient sjTREC/150000 cells was significantly lower than for non aGVHD patients (255 versus 2402 respectively, p=0.031, Mann-Whitney). This was still true for the mean absolute number of sjTREC (1.44 versus 27.33/mL of blood, p=0.007). Mean betaTREC /150000 cells showed no decrease for control patients but the same pattern than sjTREC for aGVHD patients with also a significant difference at 6 months (55 versus 2302 betaTREC /150000 cells for aGVHD and non aGVHD patients respectively, p=0.010). Finally, there was no significant difference between the 2 groups for the sj/beta ratio. These data confirm that aGVHD patients have a lower thymic output in the first months after HSCT. We also show that the decrease in the thymic output could not be explained by a reduced thymocyte proliferation since the sj/beta TREC ratio is not different between the 2 groups. It is better explained by a decrease in the number of thymocyte precursors that start to differentiate and recombine their TCR beta chain (as measured by beta TRECs). Altogether this suggests that during aGVHD, the allogeneic reaction on the recipient thymic cells could either impair the thymus seeding by the T cell precursors or provoke an inhibition of the signals that trigger the T cell differentiation.

scholarly journals Plasticity of the Immune System in Children Following Treatment Interruption in HIV-1 Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Katrine Schou Sandgaard ◽  
Ben Margetts ◽  
Teresa Attenborough ◽  
Triantafylia Gkouleli ◽  
Stuart Adams ◽  
...  
Keyword(s):  
T Cell ◽  
Antiretroviral Therapy ◽  
T Cell Receptor ◽  
Treatment Interruption ◽  
Cell Receptor ◽  
Continuous Treatment ◽  
Thymic Output ◽  
Receptor Repertoire ◽  
Hiv 1

It is intriguing that, unlike adults with HIV-1, children with HIV-1 reach a greater CD4+ T cell recovery following planned treatment cessation. The reasons for the better outcomes in children remain unknown but may be related to increased thymic output and diversity of T cell receptor repertoires. HIV-1 infected children from the PENTA 11 trial tolerated planned treatment interruption without adverse long-term clinical, virological, or immunological consequences, once antiretroviral therapy was re-introduced. This contrasts to treatment interruption trials of HIV-1 infected adults, who had rapid changes in T cells and slow recovery when antiretroviral therapy was restarted. How children can develop such effective immune responses to planned treatment interruption may be critical for future studies. PENTA 11 was a randomized, phase II trial of planned treatment interruptions in HIV-1-infected children (ISRCTN 36694210). In this sub-study, eight patients in long-term follow-up were chosen with CD4+ count>500/ml, viral load <50c/ml at baseline: four patients on treatment interruption and four on continuous treatment. Together with measurements of thymic output, we used high-throughput next generation sequencing and bioinformatics to systematically organize memory CD8+ and naïve CD4+ T cell receptors according to diversity, clonal expansions, sequence sharing, antigen specificity, and T cell receptor similarities following treatment interruption compared to continuous treatment. We observed an increase in thymic output following treatment interruption compared to continuous treatment. This was accompanied by an increase in T cell receptor clonal expansions, increased T cell receptor sharing, and higher sequence similarities between patients, suggesting a more focused T cell receptor repertoire. The low numbers of patients included is a limitation and the data should be interpreted with caution. Nonetheless, the high levels of thymic output and the high diversity of the T cell receptor repertoire in children may be sufficient to reconstitute the T cell immune repertoire and reverse the impact of interruption of antiretroviral therapy. Importantly, the effective T cell receptor repertoires following treatment interruption may inform novel therapeutic strategies in children infected with HIV-1.

scholarly journals Thymic output, T-cell diversity, and T-cell function in long-term human SCID chimeras

Blood ◽  
2009 ◽  
Vol 114 (7) ◽  
pp. 1445-1453 ◽  
Author(s):  
Marcella Sarzotti-Kelsoe ◽  
Chan M. Win ◽  
Roberta E. Parrott ◽  
Myriah Cooney ◽  
Barry K. Moser ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Function ◽  
Nk Cell ◽  
Severe Combined Immunodeficiency ◽  
Cell Receptor ◽  
Term Survival ◽  
Thymic Output ◽  
T Cell Function

Abstract Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B, and sometimes NK-cell function. Nonablative human leukocyte antigen–identical or rigorously T cell–depleted haploidentical parental bone marrow transplantation (BMT) results in thymus-dependent genetically donor T-cell development in the recipients, leading to long-term survival. We reported previously that normal T-cell numbers, function, and repertoire developed by 3 to 4 months after transplantation in SCID patients, and the repertoire remained highly diverse for the first 10 years after BMT. The T-cell receptor diversity positively correlated with T-cell receptor excision circle levels, a reflection of thymic output. However, the fate of thymic function in SCID patients beyond 10 to 12 years after BMT remained to be determined. In this greater than 25-year follow-up study of 128 patients with 11 different molecular types of SCID after nonconditioned BMT, we provide evidence that T-cell function, thymic output, and T-cell clonal diversity are maintained long-term.

T-cell receptor pharmacodynamics associated with survival and response to tremelimumab (T) in combination with durvalumab (D) in patients (pts) with unresectable hepatocellular carcinoma (uHCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4087-4087
Author(s):  
Patricia McCoon ◽  
Young S Lee ◽  
Robin Kate Kelley ◽  
Violeta Beleva Guthrie ◽  
Song Wu ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Single Agent ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Combination Regimen ◽  
Cell Counts ◽  
Significant Difference ◽  
Dose Dependent ◽  
Cell Clonal Expansion

4087 Background: Study 22, a phase 2 clinical study (NCT02519348) evaluating T (anti-CTLA-4) and D (anti-PD-L1) as monotherapies and in combination indicated the best efficacy-safety profile with a novel combination regimen containing a single, priming dose of T (T300+D). Additionally, an expansion of proliferative CD8+ lymphocytes at Day 15 was observed with T300+D that was associated with improved response. Here, an exploratory molecular analysis of peripheral blood T cell receptors is presented. Methods: Immune-checkpoint inhibitor-naïve pts were randomized to 1 of 2 T+D combinations: T300+D (T 300 mg [1 dose] + D 1500 mg, then D every 4 weeks [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 doses], then D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W [7 doses] then Q12W). DNA was isolated from PAXgene-preserved whole blood collected at baseline and on Day 29 during the first cycle of Q4W dosing, and then underwent CDR3 sequencing of T-cell receptor β using the immunoSEQ Assay (Adaptive Biotechnologies, Seattle, WA). Associations with objective response rate (ORR) and overall survival (OS) were evaluated. Results: The number of evaluable pts, samples, and overall ORR and OS are provided (Table). Immunosequencing analysis did not reveal significant differences in baseline T-cell clonality across arms. Increased T-cell clonal expansion at Day 29 appeared to be T dose dependent (Table), with no significant difference in the median expansion between the D and T75+D arms. Across all arms, responders had a larger median number of expanded T-cell clones on Day 29 than nonresponders (77.5 vs 40), and this greater expansion trended with longer OS (Table). Further evaluation by arm demonstrated an increase in T-cell clonal expansion in responders vs nonresponders in the T300+D arm. Pts with T-cell expansion above the median in the T300+D and T75+D arms also exhibited longer OS. Both newly expanded and total expanded clones on Day 29 vs Day 1 were associated with improved OS. Conclusions: The observed T dose-dependent increase in T-cell clonal expansion trended with improved ORR and longer OS, with the greatest overall benefit seen with T300+D vs T75+D, D and T. This is consistent with the previously reported observation that T300+D led to the highest median proliferating CD8+ T-cell counts and radiographic response. Further work is needed to differentiate the relative contributions of CD4 and CD8 clonal expansion to increased efficacy. T300+D and D are being evaluated in the phase 3 HIMALAYA study (NCT03298451) in uHCC vs sorafenib. Funding: AstraZeneca. Clinical trial information: NCT02519348. [Table: see text]

scholarly journals Different T-cell receptor repertoires between lesions and peripheral blood in acute graft-versus-host disease after allogeneic bone marrow transplantation

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 3019-3026 ◽  
Author(s):  
K Kubo ◽  
K Yamanaka ◽  
H Kiyoi ◽  
H Fukutani ◽  
M Ito ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
T Cell Receptor ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cell Receptor ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Acute Graft

From the viewpoint of T-cell receptor (TCR) repertoire, we studied the role of T cells in acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT) from an HLA-identical sibling. By means of inverse polymerase chain reaction method and DNA sequencing, we analyzed TCR-alpha and -beta transcripts from GVHD lesions and peripheral blood (PB) in a patient with typical GVHD together with PB from donor. At the initial onset of GVHD, V alpha-7 and -19 subfamilies were oligoclonally expanded in the PB compared with those in the oral mucosal lesions. At the second onset, V alpha-2, and V beta-6 subfamilies were more frequently detected in the cutaneous lesion than in the PB. Some TCR transcripts were recurrently found either in the mucosal or cutaneous lesions (or in both) and not in the PB. Furthermore, some of recurrent TCR transcripts in the lesions shared V gene segments and common motifs of complementarity determining region-3. These findings suggested that T cells infiltrating the GVHD lesions recognized a limited kind of antigens presented by patient's tissues with GVHD, and that T-cell repertoire in the GVHD lesions was different from that in the PB.

scholarly journals T-cell subpopulations identified by monoclonal antibodies after human marrow transplantation. I. Helper-inducer and cytotoxic-suppressor subsets

Blood ◽  
1982 ◽  
Vol 59 (6) ◽  
pp. 1292-1298 ◽  
Author(s):  
K Atkinson ◽  
JA Hansen ◽  
R Storb ◽  
S Goehle ◽  
G Goldstein ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Absolute Number ◽  
Cell Sorter ◽  
Graft Versus Host ◽  
Significant Difference ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Abstract Peripheral blood helper-inducer and cytotoxic-suppressor T-cell subpopulations in patients receiving marrow transplants for the treatment of acute leukemia or severe aplastic anemia were quantitated on the fluorescence-activated cell sorter (FACS) using the monoclonal antibodies OKT4 and OKT8, respectively. The relative (percent) and absolute number of OKT4+ cells were severely and persistently depleted for up to 2.7 yr posttransplant. In contrast, the percent and absolute number of OKT8+ cells began to recover within the first 60 days of transplant and subsequently remained at normal or high levels for periods of up to 7.3 yr. There was no significant difference in percent or absolute numbers of OKT8+ cells for patients with or without acute graft-versus-host disease (GVHD). The reversal of the normal OKT4:OKT8 ratio (2:1) occurred regardless of whether the recipient was given an allogeneic, syngeneic, or autologous transplant and regardless of whether or not acute or chronic GVHD developed. The reversed ratio was due in the first 3 mo posttransplant to low numbers of OKT4+ cells and later to a combination of low numbers of OKT4+ and high numbers of OKT8+ cells. Normalization and then an increase in the number of OKT8+ cells correlated with increasing time posttransplant and not with resolution of acute GVHD.

scholarly journals Molecular analysis of T-cell receptor repertoire in bone marrow transplant recipients: evidence for oligoclonal T-cell expansion in graft-versus-host disease lesions

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 3032-3044 ◽  
Author(s):  
X Liu ◽  
V Chesnokova ◽  
SJ Forman ◽  
DJ Diamond
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Cell Receptor ◽  
Graft Versus Host Disease ◽  
Cell Receptor ◽  
Supporting Evidence ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Beta 2

We have analyzed the T-cell receptor (TCR) V beta repertoire using polymerase chain reaction (PCR) in a cohort of eight patients receiving allogeneic bone marrow transplantation (BMT) from related and unrelated donors at the City of Hope. Results of PCR studies from graft-versus- host disease (GVHD) skin lesions show a bias in the usage of TCR V beta families, whereas examination of peripheral blood (PB) withdrawn at the same time did not reveal a similar phenomenon. In one such family, TCR V beta 2 is predominantly expressed in 7 of 7 biopsy specimens examined. V beta 2 TCR expression from these patients was analyzed more extensively using a combination of individual TCR gene cloning, followed by sequence analysis. We found evidence of oligoclonal expansion of single V beta 2-bearing TCRs in GVHD lesions, and in the PB of some patients after diagnosis of GVHD. In contrast, GVHD-negative biopsy samples showed no evidence for clonotypic TCR amplification. Sequence-specific TCR CDR3 region probes were derived from analysis of the predominant expressed TCR in GVHD lesions, and used to probe Southern blots of amplified V beta 2 TCR mRNA from PB and tissue from BMT recipients and their respective donors. In most cases the probes are highly specific in detecting TCR expression from GVHD lesions alone, although in several instances expression could be detected in PB after GVHD diagnosis. These data provide supporting evidence for the hypothesis that acute GVHD is associated with expansion of T-cell clones expressing antigen-specific TCRs that may contribute to the disease pathology.

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