Dataset Information

Absence of Intragraft B Cells in Rejection Biopsies After Rituximab Induction Therapy: Consequences for Clinical Outcome.

ABSTRACT:

Background

The pathophysiological role of intragraft B cells during renal allograft rejection is unclear.

Methods

We studied B-cell infiltration during acute rejection in 53 patients who participated in a clinical trial in which adult renal transplant patients were randomized between a single intraoperative dose of rituximab (375 mg/m²) or placebo as induction therapy. Two independent pathologists scored all biopsies in a blinded fashion according to the Banff classification and scored for the presence of B cells and plasma cells using CD79a and CD138 as markers.

Results

The majority of acute rejections were T cell-mediated. The proportion of acute rejections with an antibody-mediated component tended to be lower in rituximab-treated patients (4/23, 17.4%) than in placebo-treated patients (11/30, 36.7%; P = 0.14). Biopsies of rituximab-treated patients had significantly lower scores for B cells (0.00; range, 0.00-0.50 vs 1.70; range, 0.60-3.30; P < 0.0001) and plasma cells (0.10; range, 0.00-1.90 vs 0.40; range, 0.00-7.50; P = 0.006). During acute rejection, intragraft clusters of B cells were not observed after rituximab induction therapy. However, the depletion of intragraft B cells during acute rejection did not affect steroid resistance, proteinuria, graft function at 2 years follow-up, or patient and graft survival at a median follow-up of 4.1 years (range, 2.0-6.2 years).

Conclusions

These data do not support a harmful influence of intragraft B cells present during acute allograft rejection on the clinical course within the first few years after renal transplantation.

SUBMITTER: van den Hoogen MW

PROVIDER: S-EPMC5381736 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Publications

Absence of Intragraft B Cells in Rejection Biopsies After Rituximab Induction Therapy: Consequences for Clinical Outcome.

van den Hoogen Martijn W F MW Steenbergen Eric J EJ Baas Marije C MC Florquin Sandrine S Hilbrands Luuk B LB

Transplantation direct 20170310 4

<h4>Background</h4>The pathophysiological role of intragraft B cells during renal allograft rejection is unclear.<h4>Methods</h4>We studied B-cell infiltration during acute rejection in 53 patients who participated in a clinical trial in which adult renal transplant patients were randomized between a single intraoperative dose of rituximab (375 mg/m<sup>2</sup>) or placebo as induction therapy. Two independent pathologists scored all biopsies in a blinded fashion according to the Banff classific ...[more]

PMID: 28405599

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Project description:BACKGROUND: Xenotransplantation holds the promise of providing an unlimited supply of donor organs for terminal patients with organ failure. Pre-existing natural antibodies to the Galalpha1,3Galbeta1,4GlcNac-R (alphaGal) carbohydrate xenoantigen, however, bind rapidly to the graft endothelium and initiate hyperacute rejection of wild type pig grafts in humans. Experimental procedures designed to prevent xenoantibody-mediated rejection have been tested in gal knockout mice. These mice produce anti-gal xenoantibodies and are widely used as small animal models for xenotransplantation research. In this model, chimerism for cells expressing the gal carbohydrate can be achieved by transplantation of mixed cells or by transduction of bone marrow cells with viral vectors expressing a functional alpha1,3 galactosyltransferase gene. Chimerism induces tolerance to heart grafts expressing alphaGal. The mechanisms by which tolerance is achieved include systemic changes such as clonal deletion and/or anergy. Intragraft changes that occur during the early stages of tolerance induction have not been characterized. RESULTS: Cytoprotective genes heme oxygenase-1 (HO-1), Bcl2, and A20 that have been reported to contribute to long-term graft survival in various models of accommodation were not expressed at high levels in tolerant heart grafts. Intragraft gene expression at both early (Day 10) and late (>2 month) time points after heart transplant were examined by real-time PCR and microarray analysis was used to identify changes associated with the induction of tolerance. Intragraft gene expression profiling using microarray analysis demonstrated that genes identified in the functional categories of stress and immunity and signal transduction were significantly up-regulated in early tolerant grafts compared with syngeneic control grafts. Biological process classification showed lower binomial p-values in the categories of "response to biotic stimulus, defense response, and immune response" suggesting that up-regulated genes identified in these grafts promote survival in the presence of an immune response. The expression of the incompatible carbohydrate antigen (alphaGal) was reduced by 2 months post-transplant when compared with the expression of this gene at Day 10 post-transplant. These results suggest that the gal carbohydrate antigen is downmodulated over time in grafts that demonstrate tolerance. CONCLUSION: Our study suggests that tolerance is associated with intragraft gene expression changes that render the heart resistant to immune-mediated rejection. Genes associated with stress and immunity are up-regulated, however cytoprotective genes HO-1, Bcl2 and A20 were not up-regulated. The expression of the gal carbohydrate, the key target initiating an immune response in this model, is down-regulated in the post-transplant period.

Dataset Information

Absence of Intragraft B Cells in Rejection Biopsies After Rituximab Induction Therapy: Consequences for Clinical Outcome.

Background

Methods

Results

Conclusions

Publications

Absence of Intragraft B Cells in Rejection Biopsies After Rituximab Induction Therapy: Consequences for Clinical Outcome.

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