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Personalized Transplant Care Through Precision Medicine

Heart and Lung

Reading Human Biopsies using mRNA Expression

Includes a summary of the clinical trials.

The Molecular Microscope Diagnostic System (Presented at ISHLT 2018)

Presentation displayed at ISHLT 2018 which demonstrates the system procedural workflow and provides samples of result reports and case studies.

Publications: 2015 - 2019
Molecular assessment of rejection and injury in lung transplant biopsies

Molecular assessment of single-piece TBBs can be used to classify lung transplant biopsies and correlated with rejection histology. Two or 3 pieces for each TBB will probably be needed to offset sampling variance.

Kieran M. Halloran, et al.

J Heart Lung Transplant. 2019 Feb;38(5):504-513.

A molecular biopsy test based on arteriolar under-hyalinosis reflects increased probability of rejection related to under-immunosuppression.

Calcineurin inhibitor immunosuppressive drugs induce changes such as arteriolar hyalinosis (ah) in kidney transplants, raising the possibility that molecular changes in biopsies related to histologic ah can ...

Einecke G, Reeve J, Halloran PF.

Am J Transplant. 2018 Apr;18(4):821-831.

Review: The transcripts associated with organ allograft rejection.

The molecular mechanisms operating in human organ transplant rejection are best inferred from the mRNAs expressed in biopsies because the corresponding proteins often have low expression and short half-lives, while small non-coding RNAs lack specificity...

Halloran PF, Venner JM, Madill-Thomsen KS, Einecke G, Parkes MD, Hidalgo LG, Famulski KS.

J Transplant. 2018 Apr;18(4):785-795.

Response by Loupy et al to Letters Regarding Article, "Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection".

Our studies in mouse kidney isografts and allografts show that macrophages infiltrate isografts and allografts very early, and that this is accelerated as TCMR emerges. However, on a statistical basis, T-cell molecules are more strongly associated with TCMR...

Loupy A, Hidalgo L, Duong JP, Bruneval P, Jouven X, Halloran PF.

Circulation. 2017 Aug 15;136(7):698-699.

The Effect of Cortex/Medulla Proportions on Molecular Diagnoses in Kidney Transplant Biopsies: Rejection and Injury Can Be Assessed in Medulla.

Histologic assessment of kidney transplant biopsies relies on cortex rather than medulla, but for microarray studies, the proportion cortex in a biopsy is typically unknown and could affect the molecular readings...

Madill-Thomsen KS, Wiggins RC, Eskandary F, Böhmig GA, Halloran PF.

Am J Transplant. 2017 Aug;17(8):2117-2128.

Comprehensive Analysis of Transcript Changes Associated With Allograft Rejection: Combining Universal and Selective Features.

We annotated the top transcripts associated with kidney transplant rejection by p-value, either universal for all rejection or selective for T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR; ClinicalTrials.gov NCT01299168)...

Halloran PF, Venner JM, Famulski KS.

Am J Transplant. 2017 Jul;17(7):1754-1769

Assessing rejection-related disease in kidney transplant biopsies based on archetypal analysis of molecular phenotypes.

Microarray data from 1,208 kidney transplant biopsies were collected prospectively from 13 centers. Cross-validated classifier scores predicting the presence of antibody-mediated rejection (ABMR), T cell–mediated rejection (TCMR), and 5 related histologic lesions were generated using supervised machine learning methods ...

Reeve J, Böhmig GA, Eskandary F, Einecke G, Lefaucheur C, Loupy A, Halloran PF; MMDx-Kidney study group.

JCI Insight. 2017 Jun 15;2(12).

Hyalinosis Lesions in Renal Transplant Biopsies: Time-Dependent Complexity of Interpretation.

Because calcineurin inhibitor (CNI) immunosuppressive drugs induce arteriolar hyalinosis (ah) in kidney transplants, ah lesions can potentially provide information about drug exposure...

Einecke G, Reeve J, Halloran PF.

Am J Transplant. 2017 May;17(5):1346-1357

Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection.

We prospectively monitored 617 heart transplant recipients referred from 4 French transplant centers (January 1, 2006-January 1, 2011) for AMR. We compared patients with AMR (n=55) with a matched control group of 55 patients without AMR.

Loupy A, Duong Van Huyen JP, Hidalgo L, Reeve J, Racapé M, Aubert O, Venner JM, Falmuski K, Bories MC, Beuscart T, Guillemain R, François A, Pattier S, Toquet C, Gay A, Rouvier P, Varnous S, Leprince P2, Empana JP, Lefaucheur C, Bruneval P, Jouven X, Halloran PF.

Circulation. 2017 Mar 7;135(10):917-935. 

Heart transplantation at 50

​Intriguingly, rejection associated transcript expression in endomyocardial biopsy specimens to cluster specific molecular patterns into T-cell mediated or antibody-mediated rejection are being studied...

Mandeep R Mehra

Lancet. 2017 Dec 2;390(10111):e43-e45

Real Time Central Assessment of Kidney Transplant Indication Biopsies by Microarrays: The INTERCOMEX Study.

The authors conducted a prospective trial to assess the feasibility of real time central molecular assessment of kidney transplant biopsy samples from 10 North American or European centers...

Halloran PF, et al.

Am J Transplant. 2017 Nov;17(11):2851-2862

Building a tissue-based molecular diagnostic system in heart transplant rejection: The heart Molecular Microscope Diagnostic (MMDx) System.

We analyzed 331 protocol or for-cause EMB specimens from 221 subjects in 3 centers (Edmonton, Bologna, and Paris). Unsupervised principal component analysis (PCA) and archetype analysis used rejection-associated transcripts (RATs) shown in kidney transplants to be associated with antibody-mediated rejection (ABMR) or T cell-mediated rejection (TCMR), or both...

Halloran PF, Potena L, Van Huyen JD, Bruneval P, Leone O, Kim DH, Jouven X, Reeve J, Loupy A.

J Heart Lung Transplant. 2017 Nov;36(11):1192-1200.

Molecular assessment of disease states in kidney transplant biopsy samples.

Study of the relationship between gene expression and clinical phenotypes in kidney transplant biopsy samples has led to the development of a system that enables diagnoses of specific disease states on the basis of messenger RNA levels in the biopsy sample...

Halloran PF, Famulski KS, Reeve J.

Nat Rev Nephrol. 2016 Sep;12(9):534-48 

Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants.

The key lesions in antibody-mediated kidney transplant rejection (ABMR) are microcirculation inflammation (peritubular capillaritis and/or glomerulitis lesions, abbreviated "pg") and glomerular double contours (cg lesions)...

Halloran PF, Merino Lopez M, Barreto Pereira A

Am J Transplant. 2016 Mar;16(3):908-20

Relationships among injury, fibrosis, and time in human kidney transplants

Expression microarrays from 681 kidney transplant indication biopsies taken either early (n = 282, <1 year) or late (n = 399, >1 year) after transplant were used to analyze the molecular landscape of fibrosis in relationship to histologic fibrosis and diseases...

Venner JM, Famulski KS, Reeve J, Chang J, Halloran PF.

JCI Insight. 2016 Jan 21;1(1)

Disappearance of T Cell-Mediated Rejection Despite Continued Antibody-Mediated Rejection in Late Kidney Transplant Recipients.

The prevalent renal transplant population presents an opportunity to observe the adaptive changes in the alloimmune response over time, but such studies have been limited by uncertainties in the conventional biopsy diagnosis of T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR)...

Halloran PF, Chang J, Famulski K, Hidalgo LG, Salazar ID, Merino Lopez M, Matas A, Picton M, de Freitas D, Bromberg J, Serón D, Sellarés J, Einecke G, Reeve J.

Am Soc Nephrol. 2015 Jul;26(7):1711-20.

The molecular landscape of antibody-mediated kidney transplant rejection: evidence for NK involvement through CD16a Fc receptors.

We used microarray analysis of kidney transplant biopsies to identify the changes in pure ABMR. We found that the ABMR transcript changes in the initial Discovery Set were strongly conserved in a subsequent Validation Set...

Venner JM, Hidalgo LG, Famulski KS, Chang J, Halloran PF.

Am J Transplant. 2015 May;15(5):1336-48

 
Publications: 2014 - Prior
 
Fundamental Concepts Regarding Graft Injury and Regeneration: Tissue Injury, Tissue Quality, and Recipient Factors

Kreepala C, Famulski KS, Halloran PF.

Textbook of Organ Transplantation Set,. 2014 Jul;10:99-118

Antibody-mediated rejection, T cell-mediated rejection, and the injury-repair response: new insights from the Genome Canada studies of kidney transplant biopsies.

Halloran PF, Reeve JP, Pereira AB, Hidalgo LG, Famulski KS.

Kidney Int. 2014 Feb;85(2):258-64

Molecular landscape of T cell-mediated rejection in human kidney transplants: prominence of CTLA4 and PD ligands.

Venner JM, Famulski KS, Badr D, Hidalgo LG, Chang J, Halloran PF.

Am J Transplant. 2014 Nov;14(11):2565-76

Molecular diagnosis of T cell-mediated rejection in human kidney transplant biopsies.

Reeve J, Sellarés J, Mengel M, Sis B, Skene A, Hidalgo L, de Freitas DG, Famulski KS, Halloran PF.

Am J Transplant. 2013 Mar;13(3):645-55

Molecular phenotypes of acute kidney injury in kidney transplants.

Famulski KS, de Freitas DG, Kreepala C, Chang J, Sellares J, Sis B, Einecke G, Mengel M, Reeve J, Halloran PF.

J Am Soc Nephrol. 2012 May;23(5):948-58

Concordance among pathologists in the second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II).

Crespo-Leiro MG, et al.

Transplantation. 2012 Dec 15;94(11):1172-7

Pathologic interpretation of transbronchial biopsy for acute rejection of lung allograft is highly variable.

Arcasoy SM, Berry G, Marboe CC, Tazelaar HD, Zamora MR, Wolters HJ, Fang KC, Keshavjee S.

Am J Transplant. 2011 Feb;11(2):320-8

The molecular phenotype of heart transplant biopsies: relationship to histopathological and clinical variables.

Mengel M, Sis B, Kim D, Chang J, Famulski KS, Hidalgo LG, Einecke G, de Freitas DG, Tymchak W, Burton J, Halloran PF.

Am J Transplant. 2010 Sep;10(9):2105-15

Early loss of renal transcripts in kidney allografts: relationship to the development of histologic lesions and alloimmune effector mechanisms.

Einecke G, Broderick G, Sis B, Halloran PF.

Am J Transplant. 2007 May;7(5):1121-30.

Microarray analysis of rejection in human kidney transplants using pathogenesis-based transcript sets.

Mueller TF, Einecke G, Reeve J, Sis B, Mengel M, Jhangri GS, Bunnag S, Cruz J, Wishart D, Meng C, Broderick G, Kaplan B, Halloran PF.

Am J Transplant. 2007 Dec;7(12):2712-22.

Transcriptome analysis reveals heterogeneity in the injury response of kidney transplants.

Famulski KS, Broderick G, Einecke G, Hay K, Cruz J, Sis B, Mengel M, Halloran PF.

Am J Transplant. 2007 Nov;7(11):2483-95.

Changes in the transcriptome in allograft rejection: IFN-gamma-induced transcripts in mouse kidney allografts.

Famulski KS, Einecke G, Reeve J, Ramassar V, Allanach K, Mueller T, Hidalgo LG, Zhu LF, Halloran PF.

Am J Transplant. 2006 Jun;6(6):1342-54.

Expression of CTL associated transcripts precedes the development of tubulitis in T-cell mediated kidney graft rejection.

Einecke G, Melk A, Ramassar V, Zhu LF, Bleackley RC, Famulski KS, Halloran PF.

Am J Transplant. 2005 Aug;5(8):1827-36.

© 2017-2019 by Thermo Fisher Scientific Inc.

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