Assessing transplant rejection status by analysis of t-cell receptor subunit repertoire diversity
Inventors
SARWAL, Minnie • Sirota, Marina • Pineda San Juan, Silvia
Assignees
University of California San Diego UCSD
Publication Number
US-12351874-B2
Publication Date
2025-07-08
Expiration Date
2039-03-12
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Abstract
Disclosed are novel methods of assessing transplant rejection status in a transplant recipient, such as a kidney transplant recipient. The diagnostic method identifies stable subjects, subjects undergoing cell mediated rejection processes, and subjects undergoing antibody mediated rejection processes using measurement of TCR subunit repertoire diversity. The proportion of unique TCR alpha and beta subunit sequences to total unique TCR subunit sequences (total sequences for alpha, beta, delta, and gamma subunits) provides a diagnostic measure that can identify stable subjects, subjects undergoing cell mediated rejection processes, and subjects undergoing antibody mediated rejection processes. Methods of treatment include administration of a suitable treatment if antibody mediated rejection or cell mediated rejection is detected.
Core Innovation
The invention provides novel methods to assess transplant rejection status in transplant recipients by analyzing the diversity of T-cell receptor (TCR) subunits. The diagnostic approach differentiates stable transplant recipients from those undergoing cell-mediated rejection (CMR) or antibody-mediated rejection (AMR). It does so by calculating a diagnostic ratio of unique alpha and beta TCR subunit clonotypes relative to total unique clonotypes of all TCR subunits (alpha, beta, gamma, delta).
This method addresses the problem in the art where kidney transplant rejection, which exists in two major forms—AMR and CMR—requires different treatments and has different prognoses, but current diagnostic approaches often rely on invasive graft biopsies. The invention provides a non-invasive, peripheral blood-based assay to identify not only the presence of rejection but also distinguish between rejection types by measuring TCR subunit repertoire diversity.
The diagnostic ratio (Nα+Nβ):(Nα+Nβ+Nδ+Nγ), where Nα, Nβ, Nδ, and Nγ correspond to unique clonotype counts for alpha, beta, delta, and gamma subunits respectively, is a key measure found to correlate strongly with transplant rejection status. Lower ratio values correlate with stable graft status, intermediate values with CMR, and higher values with AMR. The invention further includes establishing statistically validated thresholds for this ratio to categorize rejection status accurately.
Claims Coverage
The patent claims encompass methods of assessing transplant rejection status through TCR subunit diversity analysis and corresponding treatment methods, focusing primarily on the diagnostic ratio and associated treatment regimens.
Diagnosis of rejection status by TCR subunit diversity ratio
The method comprises determining the transplant rejection status of a subject by measuring the ratio (Nα+Nβ):(Nα+Nβ+Nδ+Nγ) from a sample, where Nα, Nβ, Nδ, and Nγ represent counts of unique alpha, beta, delta, and gamma TCR sequences respectively, and comparing this ratio to threshold values indicative of CMR or AMR rejection statuses.
Treatment administration based on rejection status determination
Administering specific treatments depending on the rejection status determined by the diagnostic ratio; corticosteroids and/or T cell-depleting agents if CMR is detected, or plasmapheresis, intravenous immune globulin, and/or B cell depletion therapy if AMR is detected.
Applicability to various transplant types
The method applies not only to kidney transplant recipients but broadly to transplant recipients of organs, tissues, cells, and various graft types including heart, lung, liver, skin, cornea, intestine, pancreas, limb, digit, bone, ligament, cartilage, and tendon.
Use of RNA-Seq for sequence diversity assessment
The sequence diversity of TCR subunits (Nα, Nβ, Nδ, Nγ) can be assessed by RNA-Seq methodology as part of the diagnostic process.
The independent inventive features center on a diagnostic method for transplant rejection status based on measuring the TCR alpha and beta subunit diversity ratio relative to total TCR diversity, coupled with treatment regimens tailored according to this diagnostic assessment, applicable across multiple graft types and utilizing RNA-Seq for sequence analysis.
Stated Advantages
Provides a non-invasive and facile method to assess transplant rejection status using peripheral blood samples.
Enables discrimination between different types of transplant rejection, specifically distinguishing antibody-mediated rejection from cell-mediated rejection.
Allows early detection of rejection processes by monitoring TCR subunit repertoire diversity.
Facilitates appropriate and targeted treatment of transplant rejection based on accurate rejection type diagnosis.
Documented Applications
Assessment of transplant rejection status in kidney transplant recipients.
Diagnosis and treatment decision-making for antibody-mediated rejection and cell-mediated rejection in transplant recipients.
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