In Vitro AMVR Detection via Endothelial Antigen Panels

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Solution Overview

Problem

Current methods struggle to accurately diagnose and predict acute microvascular rejection (AMVR) in renal allografts, particularly those without detectable anti-HLA donor-specific antibodies, due to the difficulty in identifying non-HLA anti-endothelial cell antibodies (AECAs), which are associated with significant microvascular inflammation and graft dysfunction.

Innovation Solution

An in vitro method involving the measurement of antibodies against specific target antigens such as ZG16B, LMOD1, BMPR1A, MBP, APEX2, CCBE1, EPHA5, TLE4, EV15L, PLEKHA1, TGM2, ERC1, ZBTB14, TMOD2, MAPK1IP1L, TFEB, PFKFB2, and EPHB6, and an endothelial cell crossmatch assay to determine the likelihood of AMVR by assessing seroreactivity levels in patient samples.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If current diagnostic methods are used to detect AMVR, then anti-HLA DSAs can be detected, but non-HLA AECAs cannot be identified leading to false-negative diagnoses

Engineering Contradiction:

Improvedetection accuracy of AMVRVSAvoidability to detect different antibody types

Core Design Contradiction:

Measurement precisionVSAdaptability or versatility

Solution Approach 1:

The patent applies universality by developing a diagnostic method that can detect multiple types of antibodies (both anti-HLA DSAs and non-HLA AECAs) using a single comprehensive assay system. The method employs panels of endothelial cell antigens that serve multiple detection purposes, enabling the same test platform to identify different antibody classes responsible for AMVR, thereby eliminating false-negative diagnoses while maintaining high detection accuracy

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The patent applies segmentation by dividing the diagnostic approach into distinct components: specific panels of endothelial cell antigens are segmented and organized to target different antibody types. The method segments the detection process into identifying anti-HLA antibodies versus non-HLA AECAs through separate but complementary assay pathways, allowing precise differentiation and accurate diagnosis of AMVR cases

Inventive Principle:

Principle #1Segmentation

2Reliability

If traditional AMR diagnostic criteria are applied, then cases with DSA and histological lesions can be diagnosed, but cases without detectable DSA are misclassified

Engineering Contradiction:

Improvediagnostic reliability of AMRVSAvoidcomplexity of diagnostic criteria

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by modifying the diagnostic criteria from relying solely on anti-HL A DSA detection to including detection of non-HLA AECAs against endothelial cell antigens. This parameter change in the diagnostic approach allows accurate identification of AMVR cases previously misclassified, improving diagnostic reliability while the standardized assay panels keep the complexity manageable

Inventive Principle:

Principle #35Parameter changes

3Measurement precision

If sensitive assays for DSA are used, then anti-HLA antibodies can be detected, but non-HLA antibodies remain undetectable

Engineering Contradiction:

Improvesensitivity of DSA detectionVSAvoiddifficulty in detecting non-HLA AECAs

Core Design Contradiction:

Measurement precisionVSDifficulty of detecting and measuring

Solution Approach 1:

The patent applies the intermediary principle by using panels of endothelial cell antigens as mediators to detect non-HLA AECAs. These antigen panels serve as intermediaries that bridge the detection gap, allowing indirect identification of non-HLA antibodies through their binding to specific endothelial cell antigens, thereby making previously undetectable antibodies measurable with high sensitivity

Inventive Principle:

Principle #24Intermediary (Mediator)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This approach allows for the sensitive and reliable identification of AMVR cases, even in the absence of anti-HLA DSAs, reducing false-negative and false-positive diagnoses and enabling early intervention to prevent graft rejection.

Implementation Method 1

measuring, in a sample previously collected from the said individual, the levels of antibodies directed against one or more target antigens

Methodology Applied

Scientific EffectAntigen-antibody binding:

Data Source

PatentUS20220404356A1In vitro method for determining the likelihood of occurrence of an acute microvascular rejection (AMVR) against a renal allograft in an individual

Publication Date: 2022.12.22 UNIV DE NANTES

AI summary

The present invention relates to the field of organ transplant and the issues associated with transplant rejection. Anti-body-mediated rejection (AMR) is associated with a poor transplant outcome. Pathogenic alloantibodies are usually directed against human leucocyte antigens (HLAs). However, evidence of AMR in the absence of anti-HLA antibodies suggests the presence of non-anti-HLA antibodies, identified as anti-endothelial cell antibodies (AECAs). The inventors have demonstrated that kidney recipients who experienced acute rejection with microvascular inflammation within the first 3 months after transplantation in the absence of anti-HLA donor-specific antibodies, carried, before transplantation, unknown AECAs in their sera that specifically targeted the glomerular microvascular endothelium. Thus, the present invention relates to in vitro methods and kits for determining the likelihood of occurrence of an acute microvascular rejection (AMVR) against a renal allograft in an individual.