Different Qualitative and Quantitative Regulation of Vβ TCR Transcripts During Early Acute Allograft Rejection and Tolerance Induction

Guillet, Marina; Brouard, Sophie; Gagne, Katia; Sébille, Fabien; Cuturi, Maria‐Cristina; Delsuc, Marc-André; Soulillou, Jean‐Paul

doi:10.4049/jimmunol.168.10.5088

Cited by 39 publications

(33 citation statements)

References 44 publications

(64 reference statements)

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“…The TCR repertoire was analyzed using TcLandscape technology (TcLand Expression, Nantes, France), which has been described and validated elsewhere (27,40). Samples were selected on the basis of comparable synovial histologic features and a high semiquantitative score for infiltrating T cells.…”

Section: Methodsmentioning

confidence: 99%

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Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

Cantaert¹,

Brouard²,

Thurlings³

et al. 2009

Arthritis & Rheumatism

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Objective. The association of HLA-DRB1 alleles with anti-citrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA) suggests the potential involvement of T lymphocytes in ACPA-seropositive disease. The purpose of this study was to investigate this hypothesis by systematic histologic and molecular analyses of synovial T cells in ACPA؉ versus ACPA-RA patients.Methods. Synovial biopsy samples were obtained from 158 RA patients. Inflammation was determined histologically and immunohistochemically. RNA was extracted from peripheral blood mononuclear cells and synovial tissues obtained from 11 ACPA؉ RA patients, 7 ACPA-RA patients, and 10 spondylarthritis (SpA) patients (arthritis controls). T lymphocyte clonality was studied by combined quantitative and qualitative T cell receptor CDR3 length distribution (LD) analysis and direct sequencing analysis.Results. ACPA؉ and ACPA-RA patients were similar at both the clinical and histologic levels. At the molecular level, however, patients with ACPA؉ synovitis displayed a marked elevation of qualitative CDR3 LD alterations as compared with those with ACPA-synovitis and with the SpA controls. These differences in CDR3 LD were not observed in the peripheral blood, indicating a selective recruitment and/or local expansion of T cells in the synovial compartment. The CDR3 LD alterations reflected true monoclonal or oligoclonal expansions, as confirmed by direct sequencing of the T cell receptor. The CDR3 LD alterations in RA synovium did not correlate with B cell clonal expansions but were inversely associated with synovial lymphoid neogenesis.Conclusion. The T cell repertoire is specifically restricted in RA patients with ACPA؉ synovitis. Whereas the origin and role of these clonal alterations remain to be determined, our data suggest the preferential involvement of T lymphocytes in ACPAseropositive RA.

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Section: Methodsmentioning

confidence: 99%

“…Analysis of CDR3 length distribution was performed using Immunoscope software (27,(40)(41)(42) (Figure 1). One drawback of classic spectratyping is that a low number of transcripts for a given V ␤ family increases the chance of false-positive deviation from Gaussian distribution.…”

Section: Methodsmentioning

confidence: 99%

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

Cantaert¹,

Brouard²,

Thurlings³

et al. 2009

Arthritis & Rheumatism

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“…This suggests a perturbation in the T cell repertoire that potentially could be measured. TcLandscape is one method for characterizing changes in the TCR repertoire (63). Briefly, this assay uses quantitative PCR, gel electrophoresis, and DNA sequencing to determine the proportion of T cells that use each of the V␤ chains and to determine the CDR3 length distributions of each V␤ gene product.…”

Section: Characterization Of the Tcr Repertoirementioning

confidence: 99%

How Can We Measure Immunologic Tolerance in Humans?

Najafian

Albin²,

Newell³

2006

Journal of the American Society of Nephrology

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Prevention and treatment of allograft rejection in organ transplant recipients relies primarily on non-antigen-specific immunosuppression, with all its associated potential hazards and costs. Currently, the status of the recipient immune response is measured by monitoring pharmacologic drug levels and clinical/pathologic evaluation of graft function. Development of reliable assays that can measure accurately the status of the immune response not only would help clinicians customize the prescription of immunosuppressive drugs in individual patients but also may allow their complete withdrawal in some patients with immunologic tolerance. Furthermore, these assays would facilitate the safe evaluation of novel tolerogenic regimens. Achieving this goal has proved to be very difficult because it requires both a more in-depth understanding of complex mechanisms of tolerance and also identification of transplant patients with acquired tolerance to an allograft that can be studied. This review discusses the current understanding of tolerance mechanisms and outlines the unique and specific challenges in development of tolerance/monitoring assays in the field of transplantation. In addition, several of the most promising candidate assays are discussed in detail.

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“…There is strong evidence suggesting an important role of clonal deletion in the induction and maintenance of transplantation tolerance after intra-thymic antigen injection in animal models (1,2,11). In studies of animals with tolerated allografts (8,12), T-cell infiltration in the transplanted organ was comparable to that observed during allograft rejection; however, T cells of tolerated allografts were characterized by a highly altered TCR repertoire. These studies suggest a suppressed immune state as the major determinant of transplantation tolerance and provide a possible explanation for the down-regulation of activated T cells in tolerant animals.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of T-Cell Receptor Repertoires in Patients with Long-Term Renal Allograft Survival

Álvarez

Opelz

Giraldo

et al. 2005

American Journal of Transplantation

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The mechanisms underlying long-term acceptance of kidney allografts in humans under minimal or no maintenance immunosuppression are poorly understood. We analyzed the T-cell receptor (TCR) repertoires in circulating T cells of patients with long-term (≥9 years) renal allograft survival with (LTS-IS) and without immunosuppression (LTS-NoIS). T cells of LTS patients exhibited strongly altered TCR Vß usage, including an increased frequency of oligoclonality and a decreased frequency of polyclonality. All 3 LTS-NoIS and 12 of 16 LTS-IS patients demonstrated oligoclonality in at least three or more TCR Vß families, and the frequency of oligoclonality in these patients was significantly higher as compared to patients with well-functioning grafts at 3 years (p < 0.005 both), an uncomplicated course during the first year (p < 0.0001, both), acute rejection (p < 0.0001, both), chronic allograft nephropathy at 7 (p < 0.0001, both) or 13 years (p < 0.0001, both), dialysis patients (p < 0.0001, both) or healthy controls (p < 0.0001, both). In contrast to LTS patients, all other studied patient groups exhibited a polyclonal TCR repertoire. Our data indicate that TCR alteration is a common feature of long-term allograft outcome, which might be explained by clonal deletion, exhaustion of alloreactive T cells or predominant expression of particular T-cell subpopulations, such as regulatory T cells.

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Different Qualitative and Quantitative Regulation of Vβ TCR Transcripts During Early Acute Allograft Rejection and Tolerance Induction

Cited by 39 publications

References 44 publications

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

How Can We Measure Immunologic Tolerance in Humans?

Evaluation of T-Cell Receptor Repertoires in Patients with Long-Term Renal Allograft Survival

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