Publications by authors named "Rex N Smith"

10 Publications

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The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

Am J Transplant 2020 09 28;20(9):2318-2331. Epub 2020 May 28.

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.
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http://dx.doi.org/10.1111/ajt.15898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496245PMC
September 2020

Banff 2019 Meeting Report: Molecular diagnostics in solid organ transplantation-Consensus for the Banff Human Organ Transplant (B-HOT) gene panel and open source multicenter validation.

Am J Transplant 2020 09 27;20(9):2305-2317. Epub 2020 Jun 27.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

This meeting report from the XV Banff conference describes the creation of a multiorgan transplant gene panel by the Banff Molecular Diagnostics Working Group (MDWG). This Banff Human Organ Transplant (B-HOT) panel is the culmination of previous work by the MDWG to identify a broadly useful gene panel based on whole transcriptome technology. A data-driven process distilled a gene list from peer-reviewed comprehensive microarray studies that discovered and validated their use in kidney, liver, heart, and lung transplant biopsies. These were supplemented by genes that define relevant cellular pathways and cell types plus 12 reference genes used for normalization. The 770 gene B-HOT panel includes the most pertinent genes related to rejection, tolerance, viral infections, and innate and adaptive immune responses. This commercially available panel uses the NanoString platform, which can quantitate transcripts from formalin-fixed paraffin-embedded samples. The B-HOT panel will facilitate multicenter collaborative clinical research using archival samples and permit the development of an open source large database of standardized analyses, thereby expediting clinical validation studies. The MDWG believes that a pathogenesis and pathway based molecular approach will be valuable for investigators and promote therapeutic decision-making and clinical trials.
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http://dx.doi.org/10.1111/ajt.16059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496585PMC
September 2020

Phospholipase A2 receptor-associated membranous nephropathy in a patient with IgG4-related disease: A case report.

Medicine (Baltimore) 2019 May;98(20):e15616

Division of Nephrology.

Rationale: IgG4-related disease (IgG4-RD) is a multiorgan disease of unestablished prevalence that is characterized histopathologically by a dense lymphoplasmacytic infiltrate enriched with IgG4-expressing plasma cells and associated with storiform fibrosis. Tubulointerstitial nephritis (TIN) is the most common renal manifestation of IgG4-RD, but membranous nephropathy (MN) has also been described and often occurs in the context of concurrent TIN. Patients with IgG4-related MN have been characteristically negative for autoantibodies to the phospholipase A2 receptor (PLA2R).

Patient Concerns: A 45-year-old man presented with abdominal pain and lower extremity edema.

Diagnosis: Histopathological evaluation of pancreas and liver biopsies established a diagnosis of IgG4-RD. Renal biopsy confirmed a diagnosis of PLA2R-associated MN without evidence of concurrent TIN.

Interventions: The patient was treated with rituximab, a short course of low-dose, oral cyclophosphamide, and a rapid glucocorticoid taper.

Outcomes: The patient achieved remission of MN after 8 months of therapy and maintained remission of IgG4-RD.

Lessons: PLA2R-associated MN may be a rare manifestation of IgG4-RD. Systematic evaluation of larger cohorts of IgG4-RD patients for the presence of PLA2R autoantibodies and the investigation of PLA2R-associated MN cohorts for evidence of IgG4-RD would facilitate the understanding of the nature of the relationship between these observations.
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http://dx.doi.org/10.1097/MD.0000000000015616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531114PMC
May 2019

Immunomics of Renal Allograft Acute T Cell-Mediated Rejection Biopsies of Tacrolimus- and Belatacept-Treated Patients.

Transplant Direct 2019 Jan 20;5(1):e418. Epub 2018 Dec 20.

Department of Internal Medicine, Division of Nephrology and Transplantation, Rotterdam Transplant Group, Erasmus MC, Rotterdam, the Netherlands.

Background: Belatacept-based therapy in kidney transplant recipient has been shown to increase long-term renal allograft and patient survival compared with calcineurin inhibitor-based therapy, however, with an increased risk of acute T cell-mediated rejection (aTCMR). An improved understanding of costimulation blockade-resistant rejections could lead to a more personalized approach to belatacept therapy. Here, immunomic profiles of aTCMR biopsies of patients treated with either tacrolimus or belatacept were compared.

Methods: Formalin-fixed paraffin-embedded renal transplant biopsies were used for immunohistochemistry and gene expression analysis using the innovative NanoString technique. To validate NanoString, transcriptomic profiles of patients with and without biopsy-proven aTCMR were compared. Biopsies from 31 patients were studied: 14 tacrolimus-treated patients with aTCMR, 11 belatacept-treated patients with aTCMR, and 6 controls without rejection.

Results: A distinct pattern was seen in biopsies with aTCMR compared to negative controls: 78 genes had a higher expression in the aTCMR group (false discovery rate value <.05 to 1.42e-05). The most significant were T cell-associated genes (CD3, CD8, and CD4; < 1.98e-04), γ-interferon-inducible genes (CCL5, CXCL9, CXCL11, CXCL10, TBX21; < 1.33e-04) plus effector genes (GNLY, GZMB, ITGAX; < 2.82e-03). Immunophenotypical analysis of the classic immune markers of the innate and adaptive immune system was comparable between patients treated with either tacrolimus or belatacept. In addition, the transcriptome of both groups was not significantly different.

Conclusions: In this small pilot study, no difference was found in immunomics of aTCMR biopsies of tacrolimus- and belatacept-treated patients. This suggests that clinically diagnosed aTCMR reflects a final common pathway of allorecognition which is unaffected by the type of immunosuppressive therapy.
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http://dx.doi.org/10.1097/TXD.0000000000000857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324913PMC
January 2019

Long-term Nonhuman Primate Renal Allograft Survival Without Ongoing Immunosuppression in Recipients of Delayed Donor Bone Marrow Transplantation.

Transplantation 2018 04;102(4):e128-e136

Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Background: We have previously reported successful induction of renal allograft tolerance in nonhuman primates (NHP) after an initial posttransplant period of conventional immunosuppression (delayed tolerance) using a nonmyeloablative conditioning regimen consisting of anti-CD154 and anti-CD8 mAbs plus equine antithymocyte globulin (Atgam) and donor bone marrow transplantation (DBMT). Because these reagents are not currently clinically available, the protocol was revised to be applicable to human recipients of deceased donor allografts.

Method: Four cynomolgus monkeys received major histocompatibility complex-mismatched kidney allografts with conventional immunosuppression for 4 months. The recipients were then treated with a nonmyeloablative conditioning regimen consisting of thymoglobulin, belatacept, and DBMT. The results were compared with recipients treated with conditioning regimen consisting of Atgam and anti-CD154 mAb, with and without anti-CD8 mAb.

Results: In 4 consecutive NHP recipients treated with the modified conditioning regimen, homeostatic recovery of CD8 TEM was delayed until after day 20 and multilineage chimerism was successfully induced. Three of the 4 recipients achieved long-term allograft survival (>728, >540, >449 days) without ongoing maintenance immunosuppression. Posttransplant MLR showed loss of antidonor CD8 T cell and CD4 IFNγ responses with expansion of CD4FOXP3 regulatory T cells. However, the late development of donor-specific antibody in NHP recipients confirms the need for additional anti-B-cell depletion with agents, such as rituximab, as has been shown in our clinical trials.

Conclusions: This study provides proof of principle that induction of mixed chimerism and long-term renal allograft survival without immunosuppression after delayed DBMT is possible with clinically available reagents.
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http://dx.doi.org/10.1097/TP.0000000000002078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860973PMC
April 2018

Testing of microencapsulated porcine hepatocytes in a new model of fulminant liver failure in baboons.

Xenotransplantation 2017 05 5;24(3). Epub 2017 Mar 5.

Department of Surgery, University Hospitals of Geneva, Geneva, Switzerland.

Background: There is no standard therapy for acute liver failure. Hepatocyte transplantation has been proposed for temporary liver function support, while the injured liver regenerates or while waiting for transplantation. We have previously shown such efficacy for microencapsulated porcine hepatocytes in mice with fulminant liver failure. We aimed to establish a large animal model for fulminant liver failure to assess the efficacy of microencapsulated porcine hepatocytes in temporary liver function support.

Methods: The model was developed in baboons; for testing microencapsulated hepatocytes, the best condition was 75% hepatectomy and 60 min warm ischemia time. Fulminant liver failure was characterized by steep increases in liver biochemical parameters, severe steatosis, and massive hepatocyte necrosis during the first 10 days. Hepatocytes from miniature swine were microencapsulated in alginate-poly-l-lysine microspheres, and transplanted intraperitoneally immediately after hepatectomy and warm ischemia (80-120 mL packed hepatocytes in 200-350 mL microspheres, about 30%-50% of the baboon's native liver volume).

Results: In the control group, three of five animals were sacrificed after 6-10 days because of fulminant liver failure, and two of five animals recovered normal liver function and survived until elective euthanasia (28 days). In the treatment group of four animals, one animal developed liver failure but survived to 21 days, and three animals recovered completely with normal liver function.

Conclusions: The results indicate that microencapsulated porcine hepatocytes provide temporary liver function support in baboons with fulminant liver failure. These data support development of this cell therapy product toward clinical trials in patients with acute liver failure.
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http://dx.doi.org/10.1111/xen.12297DOI Listing
May 2017

Tissue Doppler imaging for rejection surveillance in pediatric heart transplant recipients.

J Heart Lung Transplant 2013 Oct 9;32(10):1027-33. Epub 2013 Aug 9.

Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts. Electronic address:

Background: Most transplant centers perform serial cardiac biopsies for rejection surveillance in pediatric heart transplant (HT) recipients. We sought to assess tissue Doppler imaging (TDI) findings during biopsy specimen-proven rejection in pediatric HT recipients and to develop TDI criteria for absence of rejection with high predictive accuracy.

Methods: We included the 122 HT recipients in follow-up at our center (median age at HT, 8.7 years). We identified all echocardiograms with adequate TDI data performed within 24 hours of a cardiac biopsy during 2005 to 2011. Rejection was defined as Grade ≥ 2R cellular rejection or antibody-mediated rejection. Paired comparisons of TDI velocities were made using patients' baseline velocities as the control.

Results: Overall, 647 specimen-pairs were identified where there was no rejection at baseline. In 24 of these, the second biopsy specimen demonstrated rejection. Using receiver operating characteristic curve analysis of percentage change from baseline, we identified < 15% decline in left ventricular (LV) S' velocity and < 5% decline in LV A' velocity to individually predict non-rejection with > 99% accuracy. When joint criteria were used, the predictive accuracy was 100%, and no rejection event was misclassified. More than 75% of TDI pairs met these criteria for non-rejection.

Conclusions: Biopsy specimen-proven rejection is associated with a significant decline in biventricular TDI velocities from baseline in pediatric HT recipients. By using well-defined TDI criteria to predict non-rejection, a substantial proportion of planned biopsies may be deferred or avoided at minimal risk to pediatric HT recipients.
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http://dx.doi.org/10.1016/j.healun.2013.06.016DOI Listing
October 2013

Cardiac arrest during long-distance running races.

N Engl J Med 2012 Jan;366(2):130-40

Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Background: Approximately 2 million people participate in long-distance running races in the United States annually. Reports of race-related cardiac arrests have generated concern about the safety of this activity.

Methods: We assessed the incidence and outcomes of cardiac arrest associated with marathon and half-marathon races in the United States from January 1, 2000, to May 31, 2010. We determined the clinical characteristics of the arrests by interviewing survivors and the next of kin of nonsurvivors, reviewing medical records, and analyzing postmortem data.

Results: Of 10.9 million runners, 59 (mean [±SD] age, 42-13 years; 51 men) had cardiac arrest (incidence rate, 0.54 per 100,000 participants; 95% confidence interval [CI], 0.41 to 0.70). Cardiovascular disease accounted for the majority of cardiac arrests. The incidence rate was significantly higher during marathons (1.01 per 100,000; 95% CI, 0.72 to 1.38) than during half-marathons (0.27; 95% CI, 0.17 to 0.43) and among men (0.90 per 100,000; 95% CI, 0.67 to 1.18) than among women (0.16; 95% CI, 0.07 to 0.31). Male marathon runners, the highest-risk group, had an increased incidence of cardiac arrest during the latter half of the study decade (2000-2004, 0.71 per 100,000 [95% CI, 0.31 to 1.40]; 2005-2010, 2.03 per 100,000 [95% CI, 1.33 to 2.98]; P=0.01). Of the 59 cases of cardiac arrest, 42 (71%) were fatal (incidence, 0.39 per 100,000; 95% CI, 0.28 to 0.52). Among the 31 cases with complete clinical data, initiation of bystander-administered cardiopulmonary resuscitation and an underlying diagnosis other than hypertrophic cardiomyopathy were the strongest predictors of survival.

Conclusions: Marathons and half-marathons are associated with a low overall risk of cardiac arrest and sudden death. Cardiac arrest, most commonly attributable to hypertrophic cardiomyopathy or atherosclerotic coronary disease, occurs primarily among male marathon participants; the incidence rate in this group increased during the past decade.
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http://dx.doi.org/10.1056/NEJMoa1106468DOI Listing
January 2012

Disordered pancreatic inflammatory responses and inhibition of fibrosis in CD39-null mice.

Gastroenterology 2008 Jan 25;134(1):292-305. Epub 2007 Oct 25.

Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA.

Background & Aims: Extracellular nucleotides are released from injured cells and bind purinergic-type 2 receptors (P2-Rs) that modulate inflammatory responses. Ectonucleotidases, such as CD39/nucleoside triphosphate diphosphohydrolase-1, hydrolyze extracellular nucleotides to integrate purinergic signaling responses. Because the role of extracellular nucleotides and CD39 in mediating inflammation and fibrosis are understood poorly, we studied the impact of CD39 gene deletion in a model of pancreatic disease.

Methods: Pancreatitis was induced by cyclosporine pretreatment, followed by cerulein injections (50 mug/kg, 6 intraperitoneal injections/day, 3 times/wk); mice were killed at day 2, week 3, and week 6. Experimental parameters were correlated with cytokine levels in blood, RNA, and protein expression of purinergic and fibrosis markers in tissues. Immunohistochemistry and pancreatic morphometry of fibrosis were performed in wild-type and CD39-null mice. Effects of CD39 deletion on proliferation of primary pancreatic stellate cells (PSCs) were investigated in vitro.

Results: Wild-type mice developed morphologic features of pancreatitis with the anticipated development of parenchymal atrophy and fibrosis. CD39 and P2-R became overexpressed in vascular and adventitious wild-type tissues. In contrast, CD39-null mice had inflammatory reactions but developed only minor pancreatic atrophy and limited fibrosis. Interferon-gamma became significantly increased in tissues and plasma of CD39-null mice. Wild-type PSCs expressed high levels of CD39 and P2-R. CD39-null PSCs showed decreased rates of proliferation and the expression of procollagen-alpha1 was inhibited significantly in vitro (P < .03).

Conclusions: CD39 deletion decreases fibrogenesis in experimental pancreatitis. Our data implicate extracellular nucleotides as modulators of PSC proliferation and collagen production in pancreatitis.
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http://dx.doi.org/10.1053/j.gastro.2007.10.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189558PMC
January 2008

The role of autoimmunity in islet allograft destruction: major histocompatibility complex class II matching is necessary for autoimmune destruction of allogeneic islet transplants after T-cell costimulatory blockade.

Diabetes 2002 Nov;51(11):3202-10

Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Although it has often been assumed that transplanted allogeneic islets can be destroyed by recurrent autoimmunity in recipients with type 1 diabetes, definitive evidence is lacking and the settings in which this may occur have not been defined. To address these issues, we compared the survival of islet transplants (subject to tissue-specific autoimmunity) with cardiac transplants (not subject to tissue-specific autoimmunity) from various major histocompatibility complex (MHC)-matched and -mismatched donors transplanted into autoimmune NOD recipients. We found that when recipients were treated with combined B7 and CD154 T-cell costimulatory blockade, hearts survived best with better MHC matching, whereas islets survived worst when the donor and recipient shared MHC class II antigens. In the absence of full or MHC class II matching, there was no difference in the survival of islet and cardiac allografts. We also found that the tendency of NOD mice to resist tolerance induction by costimulation blockade is mediated by both CD4+ and CD8+ T-cells, not directly linked to the presence of autoimmunity, and conferred by non-MHC background genes. These findings have clinical importance because they suggest that under some circumstances, avoiding MHC class II sharing may provide better islet allograft survival in recipients with autoimmune diabetes, since mismatched allogeneic islets may be resistant to recurrent autoimmunity. Our results may have implications for the design of future clinical trials in islet transplantation.
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http://dx.doi.org/10.2337/diabetes.51.11.3202DOI Listing
November 2002