[go: up one dir, main page]

WO2019077143A1 - Procédés et compositions pour prédire et diagnostiquer précocement une forme active chronique d'abmr avec une glomérulopathie de greffe et une perte de greffe rénale - Google Patents

Procédés et compositions pour prédire et diagnostiquer précocement une forme active chronique d'abmr avec une glomérulopathie de greffe et une perte de greffe rénale Download PDF

Info

Publication number
WO2019077143A1
WO2019077143A1 PCT/EP2018/078795 EP2018078795W WO2019077143A1 WO 2019077143 A1 WO2019077143 A1 WO 2019077143A1 EP 2018078795 W EP2018078795 W EP 2018078795W WO 2019077143 A1 WO2019077143 A1 WO 2019077143A1
Authority
WO
WIPO (PCT)
Prior art keywords
subject
expression
abmr
fibronectin
collagen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2018/078795
Other languages
English (en)
Inventor
Yi-Chun XU-DUBOIS
Alexandre HERTIG
Eric RONDEAU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Assistance Publique Hopitaux de Paris APHP
Institut National de la Sante et de la Recherche Medicale INSERM
Sorbonne Universite
Original Assignee
Assistance Publique Hopitaux de Paris APHP
Institut National de la Sante et de la Recherche Medicale INSERM
Sorbonne Universite
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Assistance Publique Hopitaux de Paris APHP, Institut National de la Sante et de la Recherche Medicale INSERM, Sorbonne Universite filed Critical Assistance Publique Hopitaux de Paris APHP
Publication of WO2019077143A1 publication Critical patent/WO2019077143A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854—Immunoglobulins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/24—Immunology or allergic disorders
    • G01N2800/245—Transplantation related diseases, e.g. graft versus host disease

Definitions

  • the invention is in the field of transplantation. More particularly, the invention provides methods to detect whether a renal transplanted subject having the anti-donor specific antibodies (DSA) and/or suffering from an acute form of antibody-mediated rejection (ABMR) is at risk of having or developing a chronic form of ABMR with transplant glomerulopathy (TG).
  • DSA anti-donor specific antibodies
  • ABMR antibody-mediated rejection
  • TG is known mostly as a consequence of persist donor- specific alloantibodies (DSA) positivity with proteinuria, and a rapidly decline of graft function and failure which must patients return to dialysis.
  • DSA persist donor- specific alloantibodies
  • This form of ABMR can develop silently without acute episodes.
  • a TG has already settled typically with double contour of the glomerular basement membrane (GBM) seen by light microscopy, named as chronic active ABMR (caABMR).
  • GBM glomerular basement membrane
  • This lesion results from a chronic activation and/or injury of glomerular endothelial cells trigged by DSA and an continual accumulation of extracellular matrix in the GBM, which is defined precisely by recent Banff classification (2013, 2015 and 2017) as chronic active ABMR (caABMR) [3-5].
  • DSA their presence is a pre -requisite for the diagnosis of ABMR. However it does not necessarily indicate an ABMR. Indeed, some antibodies may be present in the context of accommodation. In contrast, absence of detectable of DSA in some ABMR patients can be due to absorption of DSA by the rejected allograft, thus DSA becomes undetectable in the plasma, or, due to the presence only the anti endothelial cell antibodies which are not included in the present panel of DSA detection.
  • endothelial cell activation it may present in a relative late stage of disease; last, a small amount of inflammatory cells in the capillaries may be difficult to be assessed by routine morphology analysis or to be evaluated as the evidence for the diagnosis of ABMR. Consequently, the proportion of patients diagnosed for ABMR using the capillaritis as criterion could be like the tip of iceberg.
  • Another reason for the no consensus of management of chronic active ABMR is due to lacking a consistent improvement on the renal graft outcome with current acute ABMR treatment protocols, such as using IGIV, plasmapheresis, antibody against B lymphocytes surface antigen CD20 rituximab, DSA producing plasma cell depletion bortezomib to reduce DSA; complement 5 inhibitor eculizumab to reduce the graft injury. It is mostly due to too advanced glomerular lesion and too important graft fibrosis once TG was diagnosed by light microscopy which is used in most transplant centers.
  • fascin an actin-bundling protein involved in cell motility
  • fibronectin is an important extracellular matrix (ECM) protein and essential for vascular morphogenesis.
  • ECM extracellular matrix
  • FN fibronectin
  • ECM extracellular matrix
  • FN is incorporated between endothelial and perivascular cells. It plays important role in cell adhesion, migration, growth and differentiation. Its expression is highly up-regulated during embryogenesis around newly developing vasculature. In some pathological conditions such as atherosclerosis and tumorigenesis, a large amount of FN deposition under endothelium was found around the vasculature. Because FN is produced at time of dynamic tissue remodeling, formation or repair [8,9], the over-expression of FN could be a sensitive marker reflecting a pathological condition or an activation of endothelial cells during ABMR.
  • ECM is known to have many effects beyond providing structure support.
  • abnormal accumulation of ECM can be account to give inputs into cells and modify cellular behaviors through adhesion receptors such as integrins and DDR tyrosine kinase receptor or indirectly through regulating the activity of growth factors attached or stocked on the surface of ECM.
  • adhesion receptors such as integrins and DDR tyrosine kinase receptor
  • abnormal deposition of FN under endothelial cells is not only a sensitive marker of endothelial cell activation, but also can play a role of activator for these cells.
  • Type IV collage (coll4) is a major constituent of GBM. Its expression was up- regulated during diabetic glomerulopathy. The thickening of GBM in the diabetic nephropathy is due to accumulation of coll4 and alteration in its structure and composition.
  • the invention relates to a method for predicting whether a renal transplant subject having the anti-donor specific antibodies (DSA) and/or suffering from an acute active form of antibody-mediated rejection (ABMR), , is at risk of having or developing late a chronic active form of ABMR (caABMR) with transplant glomerulopathy (TG), comprising the steps of: i) measuring the expression of fibronectin and/or type IV collagen in a biological sample obtained from said subject; ii) comparing the expression pattern and level measured at step i with its predetermined reference value, and iii) concluding that the subject is at risk of having or developing a chronic active form of ABMR with transplant glomerulopathy (TG) when a linear expression of fibronectin and/or type IV collagen is observed along the GBM and the level of expression is higher than its predetermined reference value or concluding that the subject is not at risk of developing a chronic form of ABMR with transplant glomerulopathy (TG) when the expression pattern and level of fibronectin and/or type IV
  • fibronectin and collagen type IV (coll4) expression pattern in the glomeruli and the importance of expression in the glomerular basement membrane (GBM) was semi quantified in all biopsies.
  • the pattern of expression of fibronectin and coll4 in the glomeruli was changed from a focal, irregular expression in the mesangial area of glomeruli in the normal kidneys to an up-regulated and linear expression along the GBM in glomeruli in the renal graft with antibody mediated rejection (ABMR), especially higher in the chronic form of ABMR (cABMR) with transplant glomerulopathy (TG).
  • ABMR antibody mediated rejection
  • fibronectin and coll4 were significantly correlated with the level of donor specific antibodies (DSA) detected in the recipients at time of biopsy. They also observed a modified expression pattern of fascin in the glomeruli (from a weak and limited peri-nuclear localization in normal kidney to an up- regulated and diffused cytoplasmic expression in the glomerular endothelial cells in the renal grafts with ABMR). The level of glomerular fascin expression was correlated with those of FN and coll4 in GBM. Notably, the expression of these markers can predict the risk of developing late chronic form of ABMR with transplant glomerulopathy (TG). These sensitive markers can also predict strongly late graft loss. Particularly in the recipients in whom the diagnosis of caABMT cannot be made because of lacking of TG determined with the conventional method by light microscope. TG lesion is undetectable by the conventional method with light microscopy.
  • TG lesion is undetectable by the conventional method with light microscopy.
  • fibronectin and collagen type IV (coll4) in the subject suffering from glomerulopathy of the allograft is linear along the GBM in glomeruli. Whereas in the control subject, they do not observe such linear expression of fibronectin and collagen type IV (coll4). Accordingly, inventors have found a new tool to diagnose early stage and active state of glomerulopathy, thrombotic microangiopathy or hepatitis C infection related renal pathologies.
  • the invention relates to a method for predicting whether a transplant subject having the anti-donor specific antibodies (DSA) and/or suffering from an acute form of antibody-mediated rejection (ABMR) is at risk of having or developing a chronic form of ABMR with transplant glomerulopathy (TG), comprising the steps of: i) measuring the expression of fibronectin and/or type IV collagen in a biological sample obtained from said subject; ii) comparing the expression pattern and level measured at step i with its predetermined reference value, and iii) concluding that the subject is at risk of having or developing chronic active form of ABMR with transplant glomerulopathy (TG) when the expression pattern is different and level of fibronectin and/or type IV collagen is higher than its predetermined reference value or concluding that the subject is not at risk of developing a chronic form of ABMR with transplant glomerulopathy (TG) when the expression pattern and level of fibronectin and/or type IV collagen is the same as its predetermined reference value.
  • DSA anti-donor specific antibodies
  • the invention relates to a method for predicting whether a transplant subject having the anti-donor specific antibodies (DSA) and/or suffering from an acute form of antibody-mediated rejection (ABMR) is at risk of having or developing a chronic active form of ABMR with transplant glomerulopathy (TG), comprising the steps of: i) measuring the expression of fibronectin and/or type IV collagen in a biological sample obtained from said subject; ii) comparing the expression pattern and level measured at step i with its predetermined reference value, and iii) concluding that the subject is at risk of having or developing chronic form of ABMR with transplant glomerulopathy (TG) when a linear expression of fibronectin and/or type IV collagen is observed along the GBM and the level of expression of fibronectin and/or type IV collagen is higher than its predetermined reference value or concluding that the subject is not at risk of developing a chronic form of ABMR with transplant glomerulopathy (TG) when the expression pattern and level of fibronectin and/
  • the invention in a second aspect, relates to a method for early diagnosing whether a transplant subject having the anti-donor specific antibodies (DSA) and/or suffering from an acute form of antibody-mediated rejection (ABMR) is having a chronic form of ABMR with transplant glomerulopathy (TG), comprising the steps of: i) measuring the expression of fibronectin and/or type IV collagen in a biological sample obtained from said subject; ii) comparing the expression pattern and level measured at step i) with its predetermined reference value, and iii) concluding that the subject is having chronic active form of ABMR with transplant glomerulopathy (TG) when the expression pattern is different and level of fibronectin and/or type IV collagen is higher than its predetermined reference value or concluding that the subject is not having a chronic form of ABMR with transplant glomerulopathy (TG) when the expression pattern and level of fibronectin and/or type IV collagen is the same as its predetermined reference value.
  • DSA anti-donor specific antibodies
  • ABMR
  • the term "predicting" means that the subject to be analyzed by the method of the invention is allocated either into the group of subjects who will have a chronic form of ABMR with transplant glomerulopathy, or into a group of subjects who will not have chronic form of ABMR with transplant glomerulopathy. Typically, said risk is elevated as compared to the average risk in a cohort of transplanted subjects.
  • the risk of having a chronic form of ABMR with transplant glomerulopathy in a subject shall be predicted.
  • the term "predicting the risk”, as used herein, refers to assessing the probability according to which the patient as referred to herein will have a chronic form of ABMR with transplant glomerulopathy.
  • the p-values are, preferably, 0.1, 0.05, 0.01, 0.005, or 0.0001.
  • the probability envisaged by the invention allows that the prediction of an increased risk will be correct for at least 60%, at least 70%, at least 80%), or at least 90% of the subjects of a given cohort or population.
  • the term preferably, relates to predicting whether or not there is an increased risk of having a chronic form of ABMR with transplant glomerulopathy in a population of subjects rather than giving a precise probability for the said risk.
  • the term "early diagnosing” means that the subject to be analyzed by the method of the invention is allocated either into the group of subjects who have a chronic but active form of ABMR with transplant glomerulopathy, or into a group of subjects who do not have chronic active form of ABMR with transplant glomerulopathy.
  • DSA refers to antibodies which are anti-HLA antibodies, specifically generated against donor cells.
  • ABMR antibody-mediated rejection,
  • the term “antibody-mediated rejection, (ABMR)” refers to a type of rejection of transplant tissue or organ by the recipient's immune system. The rejection of a transplanted tissue or organ is triggered by the action of anti-donor's antibodies developed in the recipients against antigens found on the endothelial surface of blood vessels of graft.
  • ABMR body-mediated rejection
  • acute active ABMR and chronic active ABMR.
  • the ABMR is an acute ABMR.
  • acute rejection refers to an acute episode of tissue or transplanted organ injury.
  • the method is suitable to predict the risk and diagnose early caABMR in a subject having DSA and/or suffering from acute active form of ABMR.
  • the term “chronic active ABMR” refers to a long-term loss of function in transplanted tissues or organs via fibrosis of the transplanted tissue because of ongoing chronic vascular lesions and subsequently chronic organ ischemia.
  • the chronic active ABMR is associated with a transplant glomerulopathy (TG).
  • TG transplant glomerulopathy
  • transplant glomerulopathy refers to a disease of the glomeruli in transplanted kidneys.
  • TG is characterized by duplication of the glomerular basement membrane assessed by light or electronic microscopy, this pattern of injury may result from a number of disease processes affecting the glomerular endothelium.
  • the chronic active ABMR is a chronic active antibody mediated rejection (caABMR).
  • caABMR refers to a chronic form of ABMR but in an active state of disease, which destroy progressively and actively the grafted organ and ended by the graft loss.
  • caABMR is identified clinically by progressively decreased function of the transplanted organ and often associated with proteinuria in the case of renal transplantation.
  • Lesions at the site of the transplant characteristically are double contour of GBM with inflammatory cells and c4d deposition in the glomerular and peritubular capillaries in the case of renal transplantation.
  • the invention is to sensitize the early diagnosis and suitable to predict the risk of having or developing late a chronic active form of ABMR with transplant glomerulopathy (TG).
  • TG transplant glomerulopathy
  • transplant subject also called as grafted subject, refers to a subject who has received an organ transplantation.
  • organ transplantation refers to the procedure of replacing diseased organs, parts of organs, or tissues by healthy organs or tissues.
  • Transplanted organs may be artificial or natural, whole (such as kidney, heart and liver) or partial (such as heart valves, skin and bone).
  • the subject is a renal transplanted subject.
  • said renal transplanted subject may further have been grafted with the pancreas, and optionally a piece of duodenum, of the kidney donor.
  • Said subject is treated with immunosuppressive drugs or another drugs that are currently known in the art or that will be identified in the future.
  • the subject is under immunosuppressive treatment, which means that the subject is administered with one or more immunosuppressive drugs.
  • fibronectin refers to a glycoprotein present in a soluble dimeric form in plasma and in a dimeric or multimeric form at the cell surface and in extracellular matrix. FN mediates a wide variety of cellular interactions with the extracellular matrix (ECM) and plays important roles in cell adhesion, migration, growth and differentiation. FN plays a crucial role in wound healing, FN stops the bleeding by forming a blood clot.
  • ECM extracellular matrix
  • the naturally occurring human fibronectin gene has a nucleotide sequence as shown in Genbank Accession numbers: NM_001306129.1, NM_001306130.1, NM_001306131.1, NM_001306132.1, NM_002026.3, NM_054034.2, NM_212474.2, NM_212476.2, NM_212478.2 and NM_212482.2.
  • NP_001293058.1 NP_001293059.1, NP_001293060.1, NP_001293061.1, NP_002017.1, NP_473375.2, NP_997639.1, NP_997641.1, NP_997643.1 and NP_997647.1.
  • Collagen IV refers to Type IV collagen, also known as ColIV or Col4.
  • Collagen IV is the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen.
  • the collagen IV C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel.
  • the naturally occurring human fibronectin gene has a nucleotide sequence as shown in Genbank Accession numbers: NM_001303110.1, NM_001845.5, NM_000495.4, NMJB3380.2, NM_000091.4, NM_001846.3 and NM_000092.4.
  • the naturally occurring human fibronectin protein has an aminoacid sequence as shown in Genbank Accession numbers: NP .001290039.1, NP_001836.3, NP .000486.1, NP .203699.1, NP_000082.2, NP_001837.2 and NP_000083.3.
  • the term "expression pattern and level” refers to both qualitative as well as quantitative differences in the temporal and tissue expression patterns of a gene or a protein in transplant tissue or organ versus normal adjacent tissue or organ.
  • a differential in the expression pattern, observed and defined by morphological studies, and level of the fibronectin and/or collagen IV between the biological sample and the reference value is indicative that said subject suffers from an active state of ABMR.
  • the expression pattern is particularly observed in the glomeruli.
  • a healthy subject has a focal and irregular expression of FN and/or coll4 in the mesangial area in the glomeruli
  • the subject having a chronic active form of ABMR with transplant glomerulopathy (TG) has an up- regulated and linear expression of these extra cellular matrix along the GBM in the glomeruli.
  • the method is suitable for the patients who has not developed or cannot be diagnosed as chronic active ABMR in the early stage of disease because of lacking the detectable TG (has not double contour of GBM) examined with the conventional method by light microscope.
  • Determining the expression pattern and level of fibronectin and/or collagen IV level is mainly defined by the immune-staining on the tissue with specific antibodies and observed by light microscopy. But the increased expression level of these extracellular matrix during disease may be assessed also by any of a wide variety of well-known methods for detecting expression of a transcribed nucleic acid or translated protein.
  • the fibronectin and/or collagen IV expression level is assessed by analyzing the expression of the protein translated from said gene.
  • Said analysis can be assessed using an antibody (e.g., a radio-labeled, chromophore- labeled, fluoroph ore-labeled, or enzyme-labeled antibody), an antibody derivative (e.g., an antibody conjugate with a substrate or with the protein or ligand of a protein of a protein/ligand pair (e.g., biotin- strep tavidin)), or an antibody fragment (e.g., a single-chain antibody, an isolated antibody hypervariable domain, etc.) which binds specifically to the protein translated from the gene encoding for the biomarker.
  • an antibody e.g., a radio-labeled, chromophore- labeled, fluoroph ore-labeled, or enzyme-labeled antibody
  • an antibody derivative e.g., an antibody conjugate with a substrate or with the protein or ligand of a protein of a protein/ligand pair (e.g., biotin-
  • the term "biological sample” refers to any sample obtained from a transplanted subject, such as a serum sample, a plasma sample, a urine sample, a blood sample, a lymph sample, or a tissue biopsy.
  • the biological sample is a biopsy.
  • the biopsy refers to an extraction of tissues from the transplant or no transplant tissue or organ for examination to determine expression pattern and level of fibrinogen and collagen IV.
  • the biological sample is glomeruli which is obtained by biopsy. The expression pattern and level of fibronectin and/or collagen IV are measured in the glomeruli.
  • predetermined reference value refers to a threshold value or a cut-off value, which was defined after analysing the normal tissue from the normal kidney samples obtained from the healthy part of kidney removed because of a renal cancer and also a great quantity of normal renal graft samples from protocol biopsy.
  • the invention relates method for predicting and early diagnosing whether a transplant subject having the anti-donor specific antibodies (DSA) and/or suffering from an acute form of antibody-mediated rejection (ABMR) is at risk of having or developing a late a chronic active form of ABMR with transplant glomerulopathy (TG), comprising the steps of: i) measuring the expression pattern and level of fibronectin, collagen IV and/or fascin in a biological sample obtained from said subject; ii) comparing the expression pattern and level measured at step i with its predetermined reference value, and iii) concluding that the subject is of having or developing a chronic form of ABMR with transplant glomerulopathy (TG), when a linear expression of fibronectin and/or type IV collagen is observed along the GBM and/or a diffused cytoplasmic expression of fascin in the glomerular endothelial cells, and the level of expression ishigher than its predetermined reference value or concluding that the subject is not at risk of having or developing a
  • Fascin refers to an endothelial to mesenchymal transition marker, an actin-bundling protein involved in cell motility, in the peri-tubular capillary endothelial cells in the renal grafts with ABMR. Fascin proteins organize F-actin into parallel bundles, and are required for the formation of actin-based cellular protrusions.
  • the naturally occurring human fascin gene has a nucleotide sequence as shown in Genbank Accession number NM_003088.3 and the naturally occurring human fascin protein has an aminoacid sequence as shown in Genbank Accession number NP_003079.1.
  • the method of the invention as described above is also suitable to predict whether a subject suffering from thrombotic microangiopathy is at risk of having or developing a glomerular sclerosis and/or obsolescence.
  • the invention relates to a method for predicting whether a subject suffering from thrombotic microangiopathy has the glomerular involvement and/or is at risk of having or developing a glomerular sclerosis and/or glomerular obsolescence, comprising the steps of: i) measuring the expression of fibronectin and/or type IV collagen in the glomeruli in a biological sample obtained from said subject; ii) comparing the expression pattern and level measured at step i) with its predetermined reference value, and iii) concluding that the subject is at risk of having or developing glomerular sclerosis and/or glomerular obsolescence when the expression pattern is different and level of fibronectin and/or type IV collagen is higher than its predetermined reference value or concluding that the subject is not at risk of developing glomerular sclerosis and/or glomerular obsolescence when the expression pattern and level of fibronectin and/or type IV collagen is the same as its predetermined reference value.
  • the invention relates to a method for predicting whether a subject suffering from thrombotic microangiopathy is at risk of having or developing a glomerular sclerosis and/or glomerular obsolescence, comprising the steps of: i) measuring the expression of fibronectin and/or type IV collagen in the glomeruli in a biological sample obtained from said subject; ii) comparing the expression pattern and level measured at step i) with its predetermined reference value, and iii) concluding that the subject is at risk of having or developing glomerular sclerosis and/or glomerular obsolescence when a linear expression of fibronectin and/or type IV collagen is observed along the GBM and the level of expression is higher than its predetermined reference value or concluding that the subject is not at risk of developing glomerular sclerosis and/or glomerular obsolescence when the expression pattern and level of fibronectin and/or type IV collagen is the same as its predetermined reference value.
  • thrombotic microangiopathy refers to a pattern of damage that can occur in the smallest blood vessels inside many of vital organs.
  • the endothelial cells of capillaries become damaged, blood flow through the kidney slows.
  • glomerular sclerosis and/or glomerular obsolescence refers to a morphological term caused by long term or serious glomerular injuries which result of destruction of normal glomerular architecture and then replaced by the fibrotic tissue or fibro sclerosis or hyalinosis and finally resulting of glomerular function loss.
  • the invention is suitable to predict whether a subject suffering from hepatitis C infection has the glomerular involvement and/or is at risk of having or developing a glomerular sclerosis and/or glomerular obsolescence.
  • the invention relates to a method for predicting whether a subject suffering from hepatitis C infection is at risk of having or developing a glomerular sclerosis and/or glomerular obsolescence, comprising the steps of: i) measuring the expression of fibronectin and/or type IV collagen in the glomeruli in a biological sample obtained from said subject; ii) comparing the expression pattern and level measured at step i) with its predetermined reference value, and iii) concluding that the subject is at risk of having or developing glomerular sclerosis and/or glomerular obsolescence when a linear expression of fibronectin and/or type IV collagen is observed along the GBM and the level of expression is higher than its predetermined reference value or concluding that the subject is not
  • the invention in a fourth aspect, relates to a method for predicting whether a transplanted subject is at risk of graft loss comprising the steps of: i) measuring the expression pattern and level of fibronectin and/or collagen IV in a biological sample obtained from said subject; ii) comparing the expression pattern and level measured at step i) with its predetermined reference value, and iii) concluding that the subject is at risk of graft loss when a linear expression of fibronectin and/or type IV collagen is observed along the GBM and the level of expression is higher than its predetermined reference value or concluding that the subject is not at risk of graft loss when the expression pattern and level of fibronectin and/or collagen IV is not different from its predetermined reference value.
  • the term "predicting" means that the subject to be analyzed by the method of the invention is allocated either into the group of subjects who will lose his graft, or into a group of subjects who will not lose his graft. Typically, said risk is elevated as compared to the average risk in a cohort of transplanted subjects.
  • the risk of graft loss in a subject shall be predicted.
  • the term "predicting the risk”, as used herein, refers to assessing the probability according to which the patient as referred to herein will lose graft. As will be understood by those skilled in the art, such an assessment is usually not intended to be correct for 100% of the subjects to be investigated.
  • the probability envisaged by the invention allows that the prediction of an increased risk will be correct for at least 60%, at least 70%, at least 80%), or at least 90% of the subjects of a given cohort or population.
  • the term preferably, relates to predicting whether or not there is an increased risk of having chronic ABMR compared to the average risk of chronic ABMR in a population of subjects rather than giving a precise probability for the said risk.
  • graft loss also known as graft failure or transplant loss, refers to loss of function in a transplanted organ or tissue.
  • the invention relates to a method for predicting whether a transplanted subject is at risk of graft loss comprising the steps of: i) measuring the expression pattern and level of fibronectin, collagen IV and/or fascin in a biological sample obtained from said subject; ii) comparing the expression pattern and level measured at step i) with its predetermined reference value, and iii) concluding that the subject is at risk of graft loss when the expression pattern and level of fibronectin, collagen IV and/or fascin is different and higher than its predetermined reference value or concluding that the subject is not at risk of graft loss when the expression pattern and level of fibronectin and/or collagen IV is not different from its predetermined reference value.
  • the invention relates to a method for predicting whether a transplanted subject is at risk of graft loss comprising the steps of: i) measuring the expression pattern and level of fibronectin, collagen IV and/or fascin in a biological sample obtained from said subject; ii) comparing the expression pattern and level measured at step i) with its predetermined reference value, and iii) concluding that the subject is at risk of graft loss when a linear expression of fibronectin and/or type IV collagen is observed along the GBM and/or a diffused cytoplasmic expression of fascin in the glomerular endothelial cells, and the level of expression is higher than its predetermined reference value or concluding that the subject is not at risk of graft loss when the expression pattern and level of fibronectin and/or collagen IV is not different from its predetermined reference value.
  • a differential in the expression pattern and level of the fibronectin, collagen IV and/or fascin between the biological sample and the reference value is indicative that said subject is at risk of having a graft loss.
  • the expression pattern and level of fibronectin and/or collagen IV and fascin is determined by the methods as described above.
  • the subject can be also no renal transplanted recipients and thrombotic microangiopathy or hepatitis C infection related renal pathologies can developed on their own kidneys.
  • the invention relates to a method of treating the transplant recipients to prevent the occurrence of chronic active form of ABMR with transplant glomerulopathy (TG) in a subject comprising a step of administering to said subject a therapeutically effective amount of immunosuppressive drugs.
  • TG transplant glomerulopathy
  • the invention is suitable to treat early and to prevent late chronic active form of ABMR with transplant glomerulopathy.
  • the invention relates to a method of treating early and to prevent late or active chronic form of ABMR with transplant glomerulopathy (TG) in a subject comprising following steps: i) identifying whether a subject is at risk of having or developing chronic active form of ABMR with transplant glomerulopathy (TG) as described above and ii) administering to said subject as diagnosed a therapeutically effective amount of immunosuppressive drugs and an anti-ABMR therapy.
  • TG transplant glomerulopathy
  • the method according to the invention is suitable to treat the transplant recipients and prevent subsequently the progression of graft injury and fibrosis.
  • the invention is suitable to treat an endothelial activation related disease.
  • the method according to the invention is suitable to prevent the graft loss.
  • the invention relates to a method of preventing the graft loss in subject, comprising: i) identifying whether a transplanted subject is at risk of graft loss according to the method as described above and ii) treating said subject with a therapeutically effective amount of immunosuppressive drugs. More particularly, such subject as identified can also be treated with an anti-ABMR therapy.
  • the term "subject” refers to a grafted subject (also known as transplanted subject). Particularly, the subject who has received an organ transplantation.
  • the method as described above are suitable to use in a subject no renal transplanted recipients and thrombotic microangiopathy or hepatitis C infection related renal pathologies can developed on their own kidneys.
  • treating refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subject at risk of contracting the disease or suspected to have contracted the disease as well as subject who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria).
  • administering refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body (e.g., immunosuppressive drug) into the subject, such as by mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery and/or any other method of physical delivery described herein or known in the art.
  • a substance as it exists outside the body (e.g., immunosuppressive drug) into the subject, such as by mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery and/or any other method of physical delivery described herein or known in the art.
  • administration of the substance typically occurs after the onset of the disease or symptoms thereof.
  • administration of the substance typically occurs before the onset of the disease or symptoms thereof.
  • a “therapeutically effective amount” is intended for a minimal amount of active agent which is necessary to impart therapeutic benefit to a subject.
  • a “therapeutically effective amount” to a subject is such an amount which induces, ameliorates or otherwise causes an improvement in the pathological symptoms, disease progression or physiological conditions associated with or resistance to succumbing to a disorder. It will be understood that the total daily usage of the compounds of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific compound employed; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • immunosuppressive drugs also known as immunosuppressive agents or antirejection medications are drugs that inhibit or prevent the activity of immune system.
  • the subject is treated with immunosuppressive drugs or other drugs that are currently known in the art or that will be identified in the future.
  • the subject is under immunosuppressive treatment, which means that the subject is administered with one or more immunosuppressive drugs.
  • Immunosuppressive drugs that may be employed in transplantation procedures include corticosteroids, calcineurin inhibitors (cyclosporin, tacrolimus), azathioprine, mycophenolate mofetil and tyrosin kinase inhibitors (everolimus, sirolimus). These drugs may be used in monotherapy or in combination therapies.
  • anti-ABMR therapy includes plasmapheresis in association with high dose of intravenous immunoglobulins and rituximab (antibody against B lymphocyte surface antigen CD20), Bortezomib, (a proteasome inhibitor for depleting DSA producing cells (plasma cells) to reduce DSA level; eculizumab for complement C5 inhibition to reduce DSA associated graft injury as well as splenectomy.
  • the present invention relates to a kit for predicting of chronic active form of ABMR with transplant glomerulopathy TG in a subject comprising at least one reagent for the determination of an expression level of fibronectin and/or collagen IV.
  • the invention relates to a kit for use in predicting of chronic active form of ABMR with transplant glomerulopathy TG comprising antibodies specific for fibronectin and/or collagen IV.
  • Said kit is optimized for immunohistochemistry.
  • the kit according to the invention further comprises a component for antigen retrieval, and immunohistochemistry visualization.
  • the present invention relates to a kit for early diagnosing of chronic active form of ABMR with transplant glomerulopathy TG in a subject comprising at least one reagent for the determination of an expression level of fibronectin and/or collagen IV.
  • the invention relates to a kit for use in diagnosing of chronic active form of ABMR with transplant glomerulopathy TG comprising antibodies specific for fibronectin and/or collagen IV.
  • a reagent for the determination of an expression level is meant a reagent which specifically allows for the determination of said expression level, i.e. a reagent specifically intended for the specific determination of the expression level of fibronectin and/or collagen IV comprised in the expression profile.
  • This definition excludes generic reagents useful for the determination of the expression level of any gene, such as taq polymerase or an amplification buffer, although such reagents may also be included in a kit according to the invention.
  • the kit according to the invention may comprise instructions for determining whether a subject is at risk of having or developing chronic active ABMR, more particularly a caABMR with TG.
  • the instructions for determining whether a subject has ABMR may include at least one reference expression profile.
  • At least one reference expression profile is a stable expression profile.
  • at least one reference expression profile may be a graft non- tolerant expression profile (e.g. expression profile obtained from a healthy subject).
  • the kit as described above is also used to predict the risk of having graft loss.
  • FIGURES are a diagrammatic representation of FIGURES.
  • Figure 1 The level of expression of fibronectin and coll4 in GBM was significantly higher in the graft with ABMR (p ⁇ 0.0001), and the highest in the graft with chronic ABMR (p ⁇ 0.0001).
  • Figure 2 The expression of fibronectin (figure 2A) or coll4 (figure 2B) was determinant for the late graft dysfunction in the groups of patients with or without ABMR.
  • Figure 3 A predictive value of fibronectin detected in the GBM in the grafts with or without ABMR for graft loss.
  • Figure 4 Expression of pattern of fibronectin and collagen IV in a subject having healthy graft and a subject having an active ABMR.
  • Example 1 Assessment of the expression of fibronectin and collagen type IV for the early diagnosis of chronic antibody mediated rejection in human renal engrafted patients and their predictive value for long term graft loss
  • fibronectin and collagen type IV (coll4) as well as fascin expression pattern in the glomeruli was analyzed and the importance of expression in the glomerular basement membrane (GBM) was semi quantified in all biopsies. And then, the expression was compared with that from control groups including 3 normal kidney samples obtained from the healthy part of kidneys removed because of a renal cancer, and 66 protocol biopsies for the graft surveillance without morphological lesions included in this studied cohort.
  • fascin was limited in the perinuclear area of glomerular endothelial cells in normal kidney ( Figure 4) or in the protocol renal graft biopsies without morphological lesions. But in the grafts with ABMR, we can see a strong and diffused cytoplasmic expression of fascin in the glomerular endothelial cells in the glomeruli and in the peri-tubular capillaries ( Figure 4).
  • DSA donor specific antibodies
  • the level of expression of fibronectin and coll4 in GBM was significantly high in the graft with ABMR, and particularly higher in the graft with chronic ABMR (figure 1).
  • Example 2 A predictive value of fibronectin and/or coll4 in the GBM for late occurrence of TG To study the value of detection of fibronectin and/or coll4 expression in GBM for late caABMT prediction, we followed the patients who had not TG at time of biopsy examined by light microscope, and who had the subsequent biopsies to assess the late TG development during their transplant course, according to the fibronectin and/or coll4 GBM expression in their first biopsies.
  • Table 1 Independent risk factors for renal graft loss by Logistic regression model analysis. Fibronectin and/or coll4 expression in the GBM, microvasculature inflammation measured by g+ptc scores and pre-existent graft interstitial fibrosis ci score at time of biopsy are 3 independent risk factors associated with renal graft loss.

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Biotechnology (AREA)
  • Analytical Chemistry (AREA)
  • Cell Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un procédé facilement applicable dans un laboratoire de routine, l'immunohistochimie, par lequel les inventeurs ont analysé le motif et le niveau d'expression de la fibronectine, du collagène IV et de la fascine dans des glomérules dans des greffes rénales. Ils ont observé un motif d'expression modifié avec une expression linéaire et à la hausse de la fibronectine et du collagène IV le long de la membrane basale glomérulaire (GBM) et l'expression cytoplasmique diffusée de fascine dans les cellules endothéliales glomérulaires dans les greffes rénales avec ABMR, notamment, dans un stade précoce de caABMR, dans lequel une lésion TG n'est pas détectable par le procédé classique avec un microscope optique. En conséquence, les inventeurs ont découvert un nouvel outil pour diagnostiquer un stade précoce de la glomérulopathie, chez un sujet ayant les anticorps spécifiques anti-donneur (DSA) et/ou souffrant d'une forme aiguë de rejet à médiation par anticorps (ABMR). Cet outil de diagnostic peut également être utilisé pour aider au diagnostic précoce de la microangiopathie thrombotique ou des glomérulopathies rénales associées à une infection par l'hépatite C.
PCT/EP2018/078795 2017-10-20 2018-10-19 Procédés et compositions pour prédire et diagnostiquer précocement une forme active chronique d'abmr avec une glomérulopathie de greffe et une perte de greffe rénale Ceased WO2019077143A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP17306454.4 2017-10-20
EP17306454 2017-10-20

Publications (1)

Publication Number Publication Date
WO2019077143A1 true WO2019077143A1 (fr) 2019-04-25

Family

ID=60201968

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2018/078795 Ceased WO2019077143A1 (fr) 2017-10-20 2018-10-19 Procédés et compositions pour prédire et diagnostiquer précocement une forme active chronique d'abmr avec une glomérulopathie de greffe et une perte de greffe rénale

Country Status (1)

Country Link
WO (1) WO2019077143A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024068521A1 (fr) * 2022-09-26 2024-04-04 Fundación Para La Formación E Investigación Sanitaria De La Región De Murcia Procédé in vitro pour prédiction de rejet de greffe d'organe

Non-Patent Citations (51)

* Cited by examiner, † Cited by third party
Title
"GENBANK", Database accession no. NM_000091.4
"GENBANK", Database accession no. NM_000092.4
"GENBANK", Database accession no. NM_000495.4
"Genbank", Database accession no. NM_001303110.1
"Genbank", Database accession no. NM_001306129.1
"GENBANK", Database accession no. NM_001306130.1
"GENBANK", Database accession no. NM_001306131.1
"GENBANK", Database accession no. NM_001306132.1
"GENBANK", Database accession no. NM_001845.5
"GENBANK", Database accession no. NM_001846.3
"GENBANK", Database accession no. NM_002026.3
"Genbank", Database accession no. NM_003088.3
"GENBANK", Database accession no. NM_033380.2
"GENBANK", Database accession no. NM_054034.2
"GENBANK", Database accession no. NM_212474.2
"GENBANK", Database accession no. NM_212476.2
"GENBANK", Database accession no. NM_212478.2
"GENBANK", Database accession no. NM_212482.2
"GENBANK", Database accession no. NP_000082.2
"GENBANK", Database accession no. NP_000083.3
"GENBANK", Database accession no. NP_000486.1
"Genbank", Database accession no. NP_001290039.1
"Genbank", Database accession no. NP_001293058.1
"GENBANK", Database accession no. NP_001293059.1
"GENBANK", Database accession no. NP_001293060.1
"GENBANK", Database accession no. NP_001293061.1
"GENBANK", Database accession no. NP_001836.3
"GENBANK", Database accession no. NP_001837.2
"GENBANK", Database accession no. NP_002017.1
"Genbank", Database accession no. NP_003079.1
"GENBANK", Database accession no. NP_203699.1
"GENBANK", Database accession no. NP_473375.2
"GENBANK", Database accession no. NP_997639.1
"GENBANK", Database accession no. NP_997641.1
"GENBANK", Database accession no. NP_997643.1
"GENBANK", Database accession no. NP_997647.1
ANGASWAMY N ET AL: "Immune responses to collagen-IV and fibronectin in renal transplant recipients with transplant glomerulopathy", AMERICAN JOURNAL OF TRANSPLANTATION, WILEY INTERSCIENCE, vol. 14, no. 3, 28 February 2014 (2014-02-28), pages 685 - 693, XP009502016, ISSN: 1600-6143, [retrieved on 20140110], DOI: 10.1111/AJT.12592 *
CHIHARA RAY K ET AL: "Fibronectin from alpha 1,3-galactosyltransferase knockout pigs is a xenoantigen", JOURNAL OF SURGICAL RESEARCH, ACADEMIC PRESS INC., SAN DIEGO, CA, US, vol. 184, no. 2, 30 September 2013 (2013-09-30), pages 1123 - 1133, XP009502018, ISSN: 0022-4804, DOI: 10.1016/J.JSS.2013.04.012 *
COSIO FG; GLOOR JM; SETHI S; STEGALL MD: "Transplant glomerulopathy", AM J TRANSPLANT, vol. 8, 2008, pages 492 - 496
D KOYA ET AL: "Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes", FASEB JOURNAL : OFFICIAL PUBLICATION OF THE FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY, 1 March 2000 (2000-03-01), UNITED STATES, pages 439 - 447, XP055429697, Retrieved from the Internet <URL:http://www.fasebj.org/content/14/3/439.full.pdf> [retrieved on 20171213] *
DISCHER DE; MOONEY DJ; ZANDSTRA PW: "Growth factors, matrices, and forces combine and control stem cells", SCIENCE, vol. 324, 2009, pages 1673 - 1677, XP055344209, DOI: doi:10.1126/science.1171643
DOWDY; WEARDEN: "Statistics for Research", 1983, JOHN WILEY & SONS
GEIGER B; SPATZ JP; BERSHADSKY AD: "Environmental sensing through focal adhesions", NAT REV MOL CELL BIOL, vol. 10, 2009, pages 21 - 33
HAAS M; LOUPY A; LEFAUCHEUR C; ROUFOSSE C; GLOTZ D; SERON D; NANKIVELL BJ; HALLORAN PF; COLVIN RB; AKALIN E: "The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials", AM J TRANSPLANT, vol. 18, 2018, pages 293 - 307
HAAS M; MIROCHA J: "Early ultrastructural changes in renal allografts: correlation with antibody-mediated rejection and transplant glomerulopathy", AM J TRANSPLANT, vol. 11, 2011, pages 2123 - 2131
HAAS M; SIS B; RACUSEN LC; SOLEZ K; GLOTZ D; COLVIN RB; CASTRO MC; DAVID DS; DAVID-NETO E; BAGNASCO SM: "Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions", AM J TRANSPLANT, vol. 14, 2014, pages 272 - 283
JEFFREY H MINER ED - RUAS JORGE ET AL: "The glomerular basement membrane", EXPERIMENTAL CELL RESEARCH, ELSEVIER, AMSTERDAM, NL, vol. 318, no. 9, 24 February 2012 (2012-02-24), pages 973 - 978, XP028413003, ISSN: 0014-4827, [retrieved on 20120305], DOI: 10.1016/J.YEXCR.2012.02.031 *
JEONG H J ET AL: "Alterations in extracellular matrix components in transplant glomerulopathy", VIRCHOWS ARCHIV, SPRINGER INTERNATIONAL, BERLIN, DE, vol. 437, no. 1, 1 July 2000 (2000-07-01), pages 69 - 73, XP009501989, ISSN: 0945-6317, DOI: 10.1007/S004280000193 *
KAMAL L; BROIN PO; BAO Y; AJAIMY M; LUBETZKY M; GUPTA A; DE BOCCARDO G; PULLMAN J; GOLDEN A; AKALIN E: "Clinical, Histological, and Molecular Markers Associated With Allograft Loss in Transplant Glomerulopathy Patients", TRANSPLANTATION, vol. 99, 2015, pages 1912 - 1918
LOUPY A; HAAS M; SOLEZ K; RACUSEN L; GLOTZ D; SERON D; NANKIVELL BJ; COLVIN RB; AFROUZIAN M; AKALIN E: "The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology", AM J TRANSPLANT, vol. 17, 2017, pages 28 - 41
XU-DUBOIS YC; PELTIER J; BROCHERIOU I; SUBERBIELLE-BOISSEL C; DJAMALI A; REESE S; MOONEY N; KEUYLIAN Z; LION J; OUALI N: "Hertig A: Markers of Endothelial-to-Mesenchymal Transition: Evidence for Antibody- Endothelium Interaction during Antibody-Mediated Rejection in Kidney Recipients", J AM SOC NEPHROL, vol. 27, 2015, pages 324 - 332, XP055455475, DOI: doi:10.1681/ASN.2014070679

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024068521A1 (fr) * 2022-09-26 2024-04-04 Fundación Para La Formación E Investigación Sanitaria De La Región De Murcia Procédé in vitro pour prédiction de rejet de greffe d'organe

Similar Documents

Publication Publication Date Title
EP2707055B1 (fr) Réduction du récepteur soluble de l&#39;urokinase dans la circulation
Katsuma et al. Histopathological findings in transplanted kidneys
KR20160048196A (ko) 교모세포종의 치료를 위한 진단 방법 및 조성물
EP1977234B1 (fr) Collagène de type V à utiliser dans une méthode de traitement de la fibrose pulmonaire idiopathique
US20110318762A1 (en) Graft-Versus-Host Disease Predicting Marker and Use Thereof
AU2013334493B2 (en) Use of endocytosis inhibitors and antibodies for cancer therapy
Dejban et al. Inflammatory cells in nephrectomy tissue from patients without and with a history of urinary stone disease
Arias et al. Antibody-mediated rejection: analyzing the risk, proposing solutions
JP2020508351A (ja) ファルネシルトランスフェラーゼ阻害剤を用いてがんを治療する方法
WO2019077143A1 (fr) Procédés et compositions pour prédire et diagnostiquer précocement une forme active chronique d&#39;abmr avec une glomérulopathie de greffe et une perte de greffe rénale
US20150118224A1 (en) Endothelial cells activation biomarkers characterizing antibody mediated rejection and uses thereof
US20210253705A1 (en) Methods and agents for treating organ injury and transplant rejection
US10639307B2 (en) Methods relating to the diagnosis and treatment of preeclampsia comprising administration of ADAMTS13 polypeptides
US20200355684A1 (en) Asprv1 as a neutrophil-specific marker and therapeutic target for inflammatory diseases
US20240067717A1 (en) Diagnosis and treatment of primary graft dysfunction following lung transplant
Aziz et al. Immunobiology, Diagnosis, and Treatment of Rejection
Culek et al. Maturation of Decay Accelerating Activity Response Across the Natural History of C3 Glomerulopathy: PO1460
Meloni et al. The Complex Spectrum of Chronic Allograft Rejection
Okon et al. Đcheck for updates
Mitsui et al. Inhibition of De Novo Autoantibody Production Attenuates Chronic Antibody-Mediated Rejection of Kidney Allografts Despite Maintenance of High Donor-Specific Antibody Titers
US20220229072A1 (en) Use of cd9 as a biomarker and as a biotarget in glomerulonephritis or glomerulosclerosis
Lee et al. Effects of Treating Subclinical Rejection 2 Weeks After Kidney Transplantation, as Determined by Analyzing 1-Year Histologic Outcomes
Manfredini Definition of Clinical and Immunological Phenotypes of Graft Dysfunction in Heart Transplant Recipients: Prognostic Implications and Role of Antibody Mediated Rejection
Busch A view of type I and II Na+/P (i) transporters through microelectrodes.
Zhang et al. ENHANCED EXPRESSION OF KIDNEY INJURY MOLECULE-1 (KIM-1) IN INJURED PROXIMAL TUBULES OF RENAL TRANSPLANT BIOPSIES CORRELATES WITH RENAL DYSFUNCTION.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18789146

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18789146

Country of ref document: EP

Kind code of ref document: A1