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

Kubo, Kazuaki; Yamanaka, Katsuo; Kiyoi, Hitoshi; Fukutani, H; Ito, Masafumi; Hayakawa, Ritsuko; Ohno, Ryuzo; Naoe, Tomoki

doi:10.1182/blood.v87.7.3019.bloodjournal8773019

Cited by 31 publications

(17 citation statements)

References 43 publications

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“…While expanded tissue-derived clonotypes have been detected in peripheral blood by others (Michalek et al, 2003b;Michalek et al, 2003b;O'Keefe et al, 2004b) and correlated with the clinical course of GVHD, their antigenic specificities remained unclear, as is the case in this study. In addition, none of the clones identified in our study appeared to share any similarity in amino acid usage, as has been reported (Kubo et al, 1996). Our data also did not demonstrate preferential use of a single VB chain between different patients, as described by Liu et al (1996).…”

Section: Discussionsupporting

confidence: 69%

Efficient identification of T‐cell clones associated with graft‐versus‐host disease in target tissue allows for subsequent detection in peripheral blood

Beck¹,

Wlodarski²,

Gondek³

et al. 2005

Br J Haematol

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Summary Graft‐versus‐host disease (GVHD) causes severe morbidity and mortality in allogeneic haematopoietic stem cell transplantation (HSCT) because of destruction of recipient tissues by donor alloreactive T cells. We hypothesized that GVHD‐specific T‐cell clones are expanded within affected tissue of HSCT patients and can also be detected in blood at the time of active disease. A multiplex polymerase chain reaction (PCR) was used to amplify T‐cell receptor (TCR) variable beta (VB) chain rearrangements in skin biopsies from eight allogeneic HSCT patients. Molecular analysis of the complementarity‐determining region 3 (CDR3) of amplified products defined expanded, potentially disease‐associated ‘clonotypes’ and enabled the design of clonotype‐specific PCR assays. We detected immunodominant clones in seven of eight GVHD‐positive skin biopsies. In serial skin biopsies from the same patient, the identical clone was found in each biopsy. In a patient who underwent two successive HSCTs from different donors, distinct clones were identified for each engraftment. Using clonotypic PCR assays, individual tissue‐derived clones could be identified in peripheral blood samples obtained during active GVHD. We hypothesize that clonotypic sequences derived from target tissue can serve as markers for GVHD and may have utility in diagnosis and monitoring response to therapy, as well as enable future therapies targeted against pathogenic clones.

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Section: Discussionsupporting

confidence: 69%

Efficient identification of T‐cell clones associated with graft‐versus‐host disease in target tissue allows for subsequent detection in peripheral blood

Beck¹,

Wlodarski²,

Gondek³

et al. 2005

Br J Haematol

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“…Before transplant (A), a smear pattern was shown. After transplantation (B), several accumulating bands began to appear (see TCR Vb 4,5,16). Five days before the occurrence of AR, distinct bands increased for various Tcell families (C).…”

Section: Resultsmentioning

confidence: 99%

“…As for in-vivo studies, almost all research so far has been conducted on clinical allo-BMT cases [8,[14][15][16][17][18][19]. Gaschet et al proved that T-cell clones, which accumulated and proliferated in pathological lesions, such as the skin in GVHD, showed diversity and oligoclonality even targeted to the particularly mismatched HLA antigens [14].…”

Section: Discussionmentioning

confidence: 99%

“…Gaschet et al proved that T-cell clones, which accumulated and proliferated in pathological lesions, such as the skin in GVHD, showed diversity and oligoclonality even targeted to the particularly mismatched HLA antigens [14]. In contrast, Liu et al reported that the clones were biased to the Vb2 family in the presence of GVHD, both at the GVH site (skin) or in the peripheral blood [15], and Kubo et al found that some T-cell clones sharing TCR Vb gene segments and common CDR3 motifs recurrently emerged at the GVHD lesion (mucosal lesions) [16]. Those findings suggest that several T-cell clones are selected and play a role in immunological reactions, such as GVHD or tolerance.…”

Section: Discussionmentioning

confidence: 99%

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T‐Cell Clonal Change after Allo‐Kidney Transplantation in Humans

et al. 1998

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Whether T cells circulating peripherally express changes at a clonal level after renal transplantation is uncertain. To clarify this issue, we analyzed T-cell clonality of peripheral blood lymphocytes (PBLs) in 12 renal transplant recipients by a novel polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method that can discriminate T-cell clones with different T-cell receptor (TCR) Vb motifs. The PCR-SSCP study showed that after transplantation, only a few distinct T-cell clonotypes accumulated in the absence of clinical episodes, irrespective of the compatibility of HLA antigens. In contrast, various T-cell clones appeared in cases of acute rejection (AR) and infection. These subsided immediately after the AR was resolved; however, they remained long after the resolution of the infection. In a case of AR followed by an infectious episode, distinct T-cell clones appeared concomitantly with each episode. Several of them disappeared or remained thereafter. In one case, significant numbers of accumulating bands were observed by in-vitro stimulation by mixed lymphocyte reaction (MLR); several were identical to those found in vivo. However, some of those that did not appear in vitro were apparent in vivo. In conclusion, the appearance of Tcell clonotypes at a peripheral level indicates the existence of immunologically activated T-cell clones, which were significantly affected by immunosuppressive therapy. It was also determined that the T-cell immune system is much more complicated in vivo than in vitro.

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“…7,13,14 This has been evident when assessing tissue infiltrating T cells in cases of aGVHD, 15,16 which often are distinct from patient to patient, and may or may not correlate with the T cells in circulation. 8,16,17 However, other studies have suggested that acute GVHD may lead to a more diverse T cell phenotype, 6 ultimately suggestive of study and transplant type dependency of the observations. Aside from GVHD, other factors, such as cytomegalovirus (CMV) reactivation or serostatus, have also been associated with immune recovery and T cell receptor clonality post-transplant.…”

Section: Introductionmentioning

confidence: 99%

T Cell Repertoire Evolution After Allogeneic Bone Marrow Transplantation: An Organizational Perspective

Meier

Fawaz

Abdeen

et al. 2018

Preprint

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281 words; Manuscript 7895 words; Figures 6; Tables 2; Supplementary figures 7; Supplementary table 1. Abstract High throughput sequencing (HTS) of human T cell receptors has revealed a high level of complexity in the T cell repertoire. In an attempt to correlate T cell reconstitution with clinical outcomes several measures of T cell repertoire complexity have emerged. However, the associations identified are of a broadly statistical nature, not allowing precise modeling of outcomes based on T cell repertoire development in clinical contexts such as following bone marrow transplantation (BMT). Previous work demonstrated that there is an inherent, mathematically definable order observed in the T cell population that is conserved in a diverse group of donors, and which is perturbed in recipients following BMT. Herein, we use a public database of human leukocyte antigen matched related-donor and recipient T cell receptor (TCR) b sequences to further develop this methodology. TCR b sequencing from unsorted T cells and sorted T cell subsets isolated from peripheral blood samples from BMT donors and recipients show remarkable conservation and symmetry of VJ segment usage in the clonal frequencies, linked to the organization of the gene segments along the TCR locus. This TCR b VJ segment translational symmetry is preserved post-transplant, and even in cases of acute GVHD (aGVHD), suggesting that GVHD occurrence represents a polyclonal donor T cell response to recipient antiges. We also observe that the complexity of the repertoire is significantly diminished after BMT and is not restored even years out posttransplant. The results here provide a new method of quantifying and characterizing post-transplant T cell repertoire reconstitution by further analyzing the mathematical rules governing TCR usage in the context of BMT. This approach may allow for a new means to correlate clinical outcomes with the evolving T cell repertoire post-transplant.

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

Cited by 31 publications

References 43 publications

Efficient identification of T‐cell clones associated with graft‐versus‐host disease in target tissue allows for subsequent detection in peripheral blood

Efficient identification of T‐cell clones associated with graft‐versus‐host disease in target tissue allows for subsequent detection in peripheral blood

T‐Cell Clonal Change after Allo‐Kidney Transplantation in Humans

T Cell Repertoire Evolution After Allogeneic Bone Marrow Transplantation: An Organizational Perspective

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