A distinct evolution of the T-cell repertoire categorizes treatment refractory gastrointestinal acute graft-versus-host disease

Meyer, Everett; Hsu, Andro; Liliental, Joanna; Löhr, Andrea; Florek, Mareike; Zehnder, James L.; Strober, S; Lavori, Philip W.; Miklos, David B.; Johnson, D. S.; Negrin, Robert S.

doi:10.1182/blood-2013-03-489757

Cited by 59 publications

(64 citation statements)

References 19 publications

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“…Novel in our study was the analysis of the TCR-a chain repertoire with the simultaneous typing of TCR-a and TCR-b by single-cell sequencing, and a semi-functional characterization of cells by their gene expression. Previous studies have focused on TCR-b and few studies have included whole TCR-b repertoire analysis using NGS [5][6][7]30]. A recent study found marked expansion of CMVspecific TCR-b clones together with a contraction of effector memory CD8…”

Section: Discussionmentioning

confidence: 99%

Abundant cytomegalovirus (CMV) reactive clonotypes in the CD8+ T cell receptor alpha repertoire following allogeneic transplantation

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Eugster²,

Heidenreich

et al. 2016

Clinical and Experimental Immunology

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SummaryAllogeneic stem cell transplantation is potentially curative, but associated with post-transplantation complications, including cytomegalovirus (CMV) infections. An effective immune response requires T cells recognizing CMV epitopes via their T cell receptors (TCRs). Little is known about the TCR repertoire, in particular the TCR-a repertoire and its clinical relevance in patients following stem cell transplantation. Using next-generation sequencing we examined the TCR-a repertoire of CD8 T cells and half of the total CD8 1 T cell repertoire was dominated by few CMV-reactive clonotypes. Some TCR-a clonotypes were shared between patients. Gene expression of the circulating CMV-specific CD8 1 T cells was consistent with chronically activated effector memory T cells. The CD8 1 T cell response to CMV reactivation resulted in an expansion of a few TCR-a clonotypes to dominate the CD8 1 repertoires. These results warrant further larger studies to define the ability of oligoclonally expanded T cell clones to achieve an effective anti-viral T cell response in this setting.

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Section: Discussionmentioning

confidence: 99%

Abundant cytomegalovirus (CMV) reactive clonotypes in the CD8+ T cell receptor alpha repertoire following allogeneic transplantation

Link

Eugster²,

Heidenreich

et al. 2016

Clinical and Experimental Immunology

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“…A number of studies have focused on GVHD and anti-cytomegalovirus responses to date, demonstrating the clinical utility of these types of analyses. 4,5 For example, using TCR HTS clonal populations of T cells were found in patients who developed clinically significant GVHD in gastrointestinal biopsies and identified a population of patients responsive to corticosteroids in which these infiltrating clones receded compared with those patients who had steroid refractory GVHD in which the representative clones expanded dramatically in the peripheral blood of these patients such that up to 10%-20% of all T cells were of this particular TCR sequence. A similar analysis could be performed for GVT responses once available assays can be developed to assess how similar or different are the populations responsible for these diverse biological reactions.…”

Section: Analysis Of Gvhd and Gvl Responsesmentioning

confidence: 99%

Graft-versus-host disease versus graft-versus-leukemia

Negrin

2015

Hematology

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Graft-versus-host disease (GVHD) is a significant clinical problem after allogenic hematopoietic cell transplantation (HCT) associated with substantial morbidity and mortality that limits the potential utility of transplantation. Associated with GVHD is the well-recognized phenomenon of the graft-versus-leukemia (GVL) effect that results in reduced risk of disease relapse. GVL effects have been observed after treatment for a broad range of hematological malignancies. Both GVHD and GVL are the results of T cell-effector functions that frames a major question in the field of how linked are these two phenomena. A major goal of basic science and translational research has been to develop strategies to reduce the risk of GVHD while maintaining or enhancing GVL. In this review, a number of different strategies developed from preclinical animal models will be explored with a focus on those approaches that have been extended to the clinic in an attempt to achieve this goal. Needless to say, there is no proven strategy; however, with the use of modern technology and clinical translation, there has been substantial progress toward this goal of reducing the risks of GVHD while promoting and enhancing GVL responses. Learning Objectives• To understand the biology of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) responses in preclinical models • To learn about current and future strategies of suppressing GVHD while maintaining or enhancing GVL responses in the treatment of patients undergoing allogenic hematopoietic cell transplantation Allogenic hematopoietic cell transplantation (HCT) is an established therapy for a broad range of hematological malignancies, bone marrow failure states, and genetic diseases. After transplantation, donor-derived T cells provide many functions, such as enhancement of engraftment, protection from opportunistic infections, and, in the setting of malignancies, rejection of the underlying disease. However, these same T cells also result in graft-versus-host disease (GVHD) that can range from a mild skin rash to a life-threatening and in some instances life-ending complication (Figure 1). GVHD and the risk of opportunistic infections have limited the potential utility of allogenic HCT that could also be an effective therapy for the treatment of patients with severe autoimmune disorders, induction of organ transplantation tolerance, and perhaps other clinical settings if these problems could be addressed effectively. It has been recognized for several decades that a major benefit of allogenic HCT has been the graft-versus-leukemia (GVL) effect that is a result of donor T cells capable of recognizing residual tumor cells and rejecting these cells, resulting in dramatically reduced risk of relapse. The GVL concept was developed from many lines of evidence, including the increased risk of relapse after syngenic transplantation, the finding that T-cell depletion resulted in reduced risk of GVHD but also increased relapse rates, a decreased relapse rate associated with chronic GVHD, an...

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“…23,32 With the development of next generation sequencing, an increasingly detailed analysis of T-cell and B-cell diversity is emerging. 22,[32][33][34] We recently reported on the TCR diversity in allogeneic HSCT and found significantly higher diversity in CD4 ϩ T cells than CD8 ϩ T cells, demonstrating the need to study subsets separately. 33 Furthermore, we showed that the most rapid recovery in TCR diversity was seen in cord blood recipients, followed by conventional grafts and T-cell depleted grafts.…”

Section: Monitoring Of Post-transplant Immune Reconstitutionmentioning

confidence: 99%

Immune reconstitution following stem cell transplantation

2015

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A distinct evolution of the T-cell repertoire categorizes treatment refractory gastrointestinal acute graft-versus-host disease

Abstract: Key Points T-cell clones identified in the GI tract of patients with steroid-refractory acute GI GVHD expand in the blood with disease progression. The T-cell repertoire in the GI tract of steroid-refractory patients at the time of diagnosis is more similar than for responsive patients.

Cited by 59 publications

References 19 publications

Abundant cytomegalovirus (CMV) reactive clonotypes in the CD8+ T cell receptor alpha repertoire following allogeneic transplantation

Abundant cytomegalovirus (CMV) reactive clonotypes in the CD8+ T cell receptor alpha repertoire following allogeneic transplantation

Graft-versus-host disease versus graft-versus-leukemia

Immune reconstitution following stem cell transplantation

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