Publications by authors named "Adriana Zeevi"

181 Publications

Donor-derived regulatory dendritic cell infusion results in host cell cross-dressing and T cell subset changes in prospective living donor liver transplant recipients.

Am J Transplant 2020 Nov 10. Epub 2020 Nov 10.

Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Regulatory dendritic cells (DCreg) promote transplant tolerance following their adoptive transfer in experimental animals. We investigated the feasibility, safety, fate, and impact on host T cells of donor monocyte-derived DCreg infused into prospective, living donor liver transplant patients, 7 days before transplantation. The DCreg expressed a tolerogenic gene transcriptional profile, high cell surface programed death ligand-1 (PD-L1):CD86 ratios, high IL-10/no IL-12 productivity and poor ability to stimulate allogeneic T cell proliferation. Target DCreg doses (range 2.5-10 × 10 cells/kg) were achieved in all but 1 of 15 recipients, with no infusion reactions. Following DCreg infusion, transiently elevated levels of donor HLA and immunoregulatory PD-L1, CD39, and CD73 were detected in circulating small extracellular vesicles. At the same time, flow and advanced image stream analysis revealed intact DCreg and "cross-dressing" of host DCs in blood and lymph nodes. PD-L1 co-localization with donor HLA was observed at higher levels than with recipient HLA. Between DCreg infusion and transplantation, T-bet Eomes memory CD8 T cells decreased, whereas regulatory (CD25 CD127 Foxp3 ): T-bet Eomes CD8 T cell ratios increased. Thus, donor-derived DCreg infusion may induce systemic changes in host antigen-presenting cells and T cells potentially conducive to modulated anti-donor immune reactivity at the time of transplant.
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http://dx.doi.org/10.1111/ajt.16393DOI Listing
November 2020

Donor-specific antibody characteristics, including persistence and complement-binding capacity, increase risk for chronic lung allograft dysfunction.

J Heart Lung Transplant 2020 Dec 10;39(12):1417-1425. Epub 2020 Sep 10.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address:

Background: Chronic lung allograft dysfunction (CLAD) is the major complication limiting long-term survival in lung transplant recipients (LTRs), with those developing donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) previously found to have increased risk for CLAD. However, as DSA responses vary in timing of development, specificity, breadth, persistence, and complement-binding capacity, we hypothesized that these characteristics would impact CLAD and survival outcomes.

Methods: We retrospectively analyzed DSA characteristics and outcomes in a single-center cohort of 582 LTRs who had serum samples collected prospectively from 2010 to 2016. Luminex-based single antigen bead assays were performed to assess DSA.

Results: DSAs were detected in 247 LTRs (42%), of which 124 (21.3%) were de novo DSAs and 53 (9.1%) were complement-binding (C1q+). CLAD developed in 208 LTRs (35.7%) during the follow-up period, with 67.8% determined as bronchiolitis obliterans syndrome phenotype and 32.2% as restrictive allograft syndrome phenotype. We found a shorter time to CLAD in LTRs with persistent DSAs (p = 0.04) and HLA-DQ-specific DSAs (p = 0.03). LTRs who developed C1q+ DSAs had significantly shorter time to CLAD (p < 0.001), with 100% of C1q+ DSAs being persistent and no differences between CLAD phenotypes. CLAD-free survival was significantly reduced in LTRs who developed C1q+ DSAs (p = 0.001), HLA-DQ-specific DSAs (p = 0.03), and multiple DSAs (p = 0.02).

Conclusions: Together, our findings demonstrate that DSA characteristics of persistence, HLA-DQ specificity, and C1q+ DSAs are associated with shorter time to CLAD. Additionally, C1q+, HLA-DQ-specific, and multiple DSAs are associated with decreased CLAD-free survival. These characteristics may improve DSA risk stratification for deleterious outcomes in LTRs.
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http://dx.doi.org/10.1016/j.healun.2020.09.003DOI Listing
December 2020

Coordinated Circulating T Follicular Helper and Activated B Cell Responses Underlie the Onset of Antibody-Mediated Rejection in Kidney Transplantation.

J Am Soc Nephrol 2020 10 28;31(10):2457-2474. Epub 2020 Jul 28.

Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Background: Although antibody-mediated rejection (ABMR) has been long recognized as a leading cause of allograft failure after kidney transplantation, the cellular and molecular processes underlying the induction of deleterious donor-specific antibody (DSA) responses remain poorly understood.

Methods: Using high-dimensional flow cytometry, assays, and RNA sequencing, we concomitantly investigated the role of T follicular helper (T) cells and B cells during ABMR in 105 kidney transplant recipients.

Results: There were 54 patients without DSAs; of those with DSAs, ABMR emerged in 20 patients, but not in 31 patients. We identified proliferating populations of circulating T cells and activated B cells emerging in blood of patients undergoing ABMR. Although these circulating T cells comprised heterogeneous phenotypes, they were dominated by activated (ICOSPD-1) and early memory precursor (CCR7CD127) subsets, and were enriched for the transcription factors IRF4 and c-Maf. These circulating T cells produced large amounts of IL-21 upon stimulation with donor antigen and induced B cells to differentiate into antibody-secreting cells that produced DSAs. Combined analysis of the matched circulating T cell and activated B cell RNA-sequencing profiles identified highly coordinated transcriptional programs in circulating T cells and B cells among patients with ABMR, which markedly differed from those of patients who did not develop DSAs or ABMR. The timing of expansion of the distinctive circulating T cells and activated B cells paralleled emergence of DSAs in blood, and their magnitude was predictive of IgG3 DSA generation, more severe allograft injury, and higher rate of allograft loss.

Conclusions: Patients undergoing ABMR may benefit from monitoring and therapeutic targeting of T cell-B cell interactions.
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http://dx.doi.org/10.1681/ASN.2020030320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608995PMC
October 2020

Early subclinical tubulitis and interstitial inflammation in kidney transplantation have adverse clinical implications.

Kidney Int 2020 08 25;98(2):436-447. Epub 2020 Apr 25.

Division of Transplant Nephrology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

This prospective observational cohort study compared the impact of subclinical tubulitis with or without interstitial inflammation to interstitial inflammation alone and to no inflammation in early post kidney transplant biopsies. A study cohort of 415 patients (living and deceased donor recipients) was divided into three groups on the basis of their three-month biopsy: 149 patients with No Inflammation (NI), 83 patients with Isolated Interstitial Inflammation (IIF), and 183 patients with Tubulitis [(with or without interstitial inflammation) (TIF) but not meeting criteria for Banff IA]. TIF was further divided into 56 patients with tubulitis without interstitial inflammation (TIF0) and 127 patients with tubulitis alongside interstitial inflammation (TIF1). TIF was significantly associated with higher incidence of subsequent T-cell mediated rejection (clinical or subclinical) at one year compared to IIF (31% vs 15%) and NI (31% vs 17%). Chronicity on one-year biopsy was significantly higher in TIF compared to IIF (22% vs 11%) and NI (22% vs 7%). De novo donor-specific antibody development was significantly higher in TIF compared to NI (6% vs 0.7%). Tubulitis subgroups (TIF0 and TIF1) revealed comparable effects on de novo donor-specific antibody and interstitial fibrosis/tubular atrophy development. However, tubulitis with interstitial inflammation had a significantly higher incidence of subsequent rejection and posed an increased hazard for the composite end point (subsequent acute rejection and death censored graft loss) compared to other groups [adjusted hazard 2.1 (95% confidence interval 1.2-3.5)]. Thus, subclinical tubulitis is a marker of adverse immunological events, but tubulitis with interstitial inflammation has a worse prognosis. Hence, the Banff 1997 (TIF1) and Banff 2005 classifications (TIF) for borderline change may have different implications.
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http://dx.doi.org/10.1016/j.kint.2020.03.028DOI Listing
August 2020

Precision transplant pathology.

Curr Opin Organ Transplant 2020 08;25(4):412-419

Thomas E. Starzl Transplantation Institute, University of Pittsburgh.

Purpose Of Review: Transplant pathology contributes substantially to personalized treatment of organ allograft recipients. Rapidly advancing next-generation human leukocyte antigen (HLA) sequencing and pathology are enhancing the abilities to improve donor/recipient matching and allograft monitoring.

Recent Findings: The present review summarizes the workflow of a prototypical patient through a pathology practice, highlighting histocompatibility assessment and pathologic review of tissues as areas that are evolving to incorporate next-generation technologies while emphasizing critical needs of the field.

Summary: Successful organ transplantation starts with the most precise pratical donor-recipient histocompatibility matching. Next-generation sequencing provides the highest resolution donor-recipient matching and enables eplet mismatch scores and more precise monitoring of donor-specific antibodies (DSAs) that may arise after transplant. Multiplex labeling combined with hand-crafted machine learning is transforming traditional histopathology. The combination of traditional blood/body fluid laboratory tests, eplet and DSA analysis, traditional and next-generation histopathology, and -omics-based platforms enables risk stratification and identification of early subclinical molecular-based changes that precede a decline in allograft function. Needs include software integration of data derived from diverse platforms that can render the most accurate assessment of allograft health and needs for immunosuppression adjustments.
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http://dx.doi.org/10.1097/MOT.0000000000000772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737245PMC
August 2020

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

Hospital readmission following pediatric heart transplantation.

Pediatr Transplant 2019 11 4;23(7):e13561. Epub 2019 Sep 4.

Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.

The frequency, indications, and outcomes for readmission following pediatric heart transplantation are poorly characterized. A better understanding of this phenomenon will help guide strategies to address the causes of readmission. Data from the Clinical Trials in Organ Transplantation for Children (CTOTC-04) multi-institutional collaborative study were utilized to determine incidence of, and risk factors for, hospital readmission within 30 days and 1 year from initial hospital discharge. Among 240 transplants at 8 centers, 227 subjects were discharged and had follow-up. 129 subjects (56.8%) were readmitted within one year; 71 had two or more readmissions. The 30-day and 1-year freedom from readmission were 70.5% (CI: 64.1%, 76.0%) and 42.2% (CI: 35.7%, 48.7%), respectively. The most common indications for readmissions were infection followed by rejection and fever without confirmed infection, accounting for 25.0%, 10.6%, and 6.2% of readmissions, respectively. Factors independently associated with increased risk of first readmission within 1 year (Cox proportional hazard model) were as follows: transplant in infancy (P = .05), longer transplant hospitalization (P = .04), lower UNOS urgency status (2/IB vs 1A) at transplant (P = .04), and Hispanic ethnicity (P = .05). Hospital readmission occurs frequently in the first year following discharge after heart transplantation with highest risk in the first 30 days. Infection is more common than rejection as cause for readmission, with death during readmission being rare. A number of patient factors are associated with higher risk of readmission. A fuller understanding of these risk factors may help tailor strategies to reduce unnecessary hospital readmission.
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http://dx.doi.org/10.1111/petr.13561DOI Listing
November 2019

Early outcomes for low-risk pediatric heart transplant recipients and steroid avoidance: A multicenter cohort study (Clinical Trials in Organ Transplantation in Children - CTOTC-04).

J Heart Lung Transplant 2019 09 20;38(9):972-981. Epub 2019 Jun 20.

Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.

Background: Immunosuppression strategies have changed over time in pediatric heart transplantation. Thus, comorbidity profiles may have evolved. Clinical Trials in Organ Transplantation in Children-04 is a multicenter, prospective, cohort study assessing the impact of pre-transplant sensitization on outcomes after pediatric heart transplantation. This sub-study reports 1-year outcomes among recipients without pre-transplant donor-specific antibodies (DSAs).

Methods: We recruited consecutive candidates (<21 years) at 8 centers. Sensitization status was determined by a core laboratory. Immunosuppression was standardized as follows: Thymoglobulin induction with tacrolimus and/or mycophenolate mofetil maintenance. Steroids were not used beyond 1 week. Rejection surveillance was by serial biopsy.

Results: There were 240 transplants. Subjects for this sub-study (n = 186) were non-sensitized (n = 108) or had no DSAs (n = 78). Median age was 6 years, 48.4% were male, and 38.2% had congenital heart disease. Patient survival was 94.5% (95% confidence interval, 90.1-97.0%). Freedom from any type of rejection was 67.5%. Risk factors for rejection were older age at transplant and presence of non-DSAs pre-transplant. Freedom from infection requiring hospitalization/intravenous anti-microbials was 75.4%. Freedom from rehospitalization was 40.3%. New-onset diabetes mellitus and post-transplant lymphoproliferative disorder (PTLD) occurred in 1.6% and 1.1% of subjects, respectively. There was no decline in renal function over the first year. Corticosteroids were used in 14.5% at 1 year.

Conclusions: Pediatric heart transplantation recipients without DSAs at transplant and managed with a steroid avoidance regimen have excellent short-term survival and a low risk of first-year diabetes mellitus and PTLD. Rehospitalization remains common. These contemporary observations allow for improved caregiver and/or patient counseling and provide the necessary outcomes data to help design future randomized controlled trials.
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http://dx.doi.org/10.1016/j.healun.2019.06.006DOI Listing
September 2019

Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell-mediated rejection and non-adherence.

Kidney Int 2019 07 20;96(1):202-213. Epub 2019 Mar 20.

Renal and Electrolyte Division, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. Electronic address:

Post-transplant donor specific antibody (DSA) is associated with poor renal allograft outcomes. However, variable timing of DSA assessment and inclusion of patients who undergo desensitization treatments have hindered our understanding of its consequences and limited its predictive value. Here we prospectively studied non-desensitized patients to determine factors associated with poor four-year outcomes in patients who developed post-transplant DSA. Using serial monitoring, 67 of 294 patients were found to develop DSA by one year. Compared to patients who do not develop DSA, those with DSA exhibit an increased incidence of both clinical and subclinical T-cell-mediated rejection (TCMR). The combination of TCMR plus DSA led to an almost three-fold increase in graft loss compared to either DSA or TCMR alone. Moreover, DSA was associated with higher Banff grade TCMR and chronic changes at one year. Antibody-mediated rejection was uncommon and always associated with TCMR. Amongst factors independently associated with DSA plus TCMR; non-adherence is potentially modifiable. Non-adherence, measured as intra-patient variability of calcineurin trough levels during the first post-transplant year, further risk-stratified patients with DSA plus TCMR such that about 75% of these patients had impending graft loss by four years, whereas adherent patients with DSA plus TCMR had outcomes comparable to other patient groups. Thus, early post-transplant DSA, especially in non-adherent patients, is associated with increased incidence of TCMR and represents a high-risk group of patients who might benefit from targeted therapeutic interventions.
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http://dx.doi.org/10.1016/j.kint.2019.01.033DOI Listing
July 2019

Impact of Induction Therapy on Circulating T Follicular Helper Cells and Subsequent Donor-Specific Antibody Formation After Kidney Transplant.

Kidney Int Rep 2019 Mar 8;4(3):455-469. Epub 2018 Dec 8.

Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Introduction: The cellular events that contribute to generation of donor-specific anti-HLA antibodies (DSA) post-kidney transplantation (KTx) are not well understood. Characterization of such mechanisms could allow tailoring of immunosuppression to benefit sensitized patients.

Methods: We prospectively monitored circulating T follicular helper (cT) cells in KTx recipients who received T-cell depleting (thymoglobulin,  = 54) or T-cell nondepleting (basiliximab,  = 20) induction therapy from pre-KTx to 1 year post-KTx and assessed their phenotypic changes due to induction and DSA occurrence, in addition to healthy controls ( = 13), for a total of 307 blood samples.

Results: Before KTx, patients displayed comparable levels of resting, central memory cT cells with similar polarization to those of healthy controls. Unlike basiliximab induction, thymoglobulin induction significantly depleted cT cells, triggered lymphopenia-induced proliferation that skewed cT cells toward increased Th1 polarization, effector memory, and elevated programmed cell death protein 1 (PD-1) expression, resembling activated phenotypes. Regardless of induction, patients who developed DSA post-KTx, harbored pre-KTx donor-reactive memory interleukin (IL)-21 cT cells and showed higher % cT and lower % of T regulatory (T) cells post-KTx resulting in elevated cT:T ratio at DSA occurrence.

Conclusion: Induction therapy distinctly shapes cT cell phenotype post-KTx. Monitoring cT cells before and after KTx may help detect those patients prone to DSA generation post-KTx.
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http://dx.doi.org/10.1016/j.ekir.2018.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409398PMC
March 2019

Sensitization in Heart Transplantation: Emerging Knowledge: A Scientific Statement From the American Heart Association.

Circulation 2019 03;139(12):e553-e578

Sensitization, defined as the presence of circulating antibodies, presents challenges for heart transplant recipients and physicians. When present, sensitization can limit a transplantation candidate's access to organs, prolong wait time, and, in some cases, exclude the candidate from heart transplantation altogether. The management of sensitization is not yet standardized, and current therapies have not yielded consistent results. Although current strategies involve antibody suppression and removal with intravenous immunoglobulin, plasmapheresis, and antibody therapy, newer strategies with more specific targets are being investigated.
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http://dx.doi.org/10.1161/CIR.0000000000000598DOI Listing
March 2019

Detrimental Association of Hypogammaglobulinemia With Chronic Lung Allograft Dysfunction and Death Is Not Mitigated by On-Demand Immunoglobulin G Replacement After Lung Transplantation.

Prog Transplant 2018 Dec 11:1526924818817028. Epub 2018 Dec 11.

2 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Background:: Hypogammaglobulinemia (HGG), immunoglobulin G (IgG) <700 mg/dL, is associated with infections, chronic lung allograft dysfunction, and death following lung transplantation. This study evaluates the use of on-demand intravenous IgG in lung transplant recipients with HGG.

Materials And Methods:: This single-center retrospective cohort study of adult lung recipients evaluated 3 groups, no, untreated (u), or treated (t) HGG at first IgG administration or a matched time posttransplant. Primary outcome was freedom from allograft dysfunction. Secondary outcomes included development of advanced dysfunction, rejection, infection burden, and mortality.

Results:: Recipients included 484 (no HGG: 76, uHGG: 192, tHGG: 216). Freedom from chronic allograph dysfunction was highest in the non-HGG group 2 years post-enrollment (no HGG 77.9% vs uHGG 56.4% vs tHGG 52.5%; P = .002). Freedom from advanced dysfunction was significantly different 2 years post-enrollment (no HGG 90.5% vs uHGG 84.7% vs tHGG 75.4%; P = .017). Patients without HGG and those with uHGG had less mortality at 2 years post-enrollment (no HGG 84.2% vs uHGG 81.3% vs tHGG 64.8%; P < .001). Gram-negative pneumonias occurred more often in the tHGG group ( P = .02).

Conclusions:: Development of chronic lung allograft dysfunction, patient survival, rejection burden, and key infectious outcomes in lung transplant recipients were still problematic in the context of on-demand IgG therapy. Prospective studies are warranted.
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http://dx.doi.org/10.1177/1526924818817028DOI Listing
December 2018

Therapeutic Human IgG Preparations Contain Mixture of HLA Antibodies to Native HLA Antigens and Cryptic Epitopes With Little Clinical Significance.

Transplantation 2018 12;102(12):2126-2132

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.

Background: Human immunoglobulins (H-Ig) are widely used in solid organ transplantation for immunoglobulin G (IgG) replacement and for desensitization and treatment of antibody-mediated rejection. They are obtained from plasma pools and may contain HLA antibodies that can be detrimental to transplant recipients. The goal of this study was to evaluate HLA antibodies in multiple lots of 2 commercial H-Ig preparations by Luminex single-antigen bead (SAB) and cell-based crossmatch assays.

Methods: Thirty lots of 2 commercial H-Ig products (CSL Behring, King of Prussia, PA) were evaluated: 6 Hizentra and 24 Privigen. All were adsorbed and diluted 1:10 before testing. HLA IgG antibodies were determined by 2 Luminex SAB kits and C1q screen for complement-binding capability. Lots were tested for the presence of antibody to denatured vs. intact class I HLA alleles using acid-treated SAB. Surrogate T and B-cell flow cytometry crossmatches (FCXM) were performed with peripheral blood lymphocytes from 2 healthy donors.

Results: Twenty-two (73%) lots at 1:10 showed SAB reactivity with mean fluorescent intensity of 2000 or greater for HLA class I, 67% (20/30 lots) for class II. The reactivity pattern was similar using both SAB kits. Acid treatment revealed antibodies to denatured class I: the majority of HLA-C, half of HLA-B and few HLA-A alleles. No C1q reactivity was observed. Surrogate flow cytometry crossmatch results were positive (>150 median channel shift), but were fourfold to eightfold lower than expected.

Conclusions: The H-Ig products tested consisted of low titer, non-complement-binding HLA class I and class II antibodies; most of the observed class I HLA reactivity was toward denatured HLA antigens.
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http://dx.doi.org/10.1097/TP.0000000000002312DOI Listing
December 2018

Complement-binding anti-HLA antibodies are independent predictors of response to treatment in kidney recipients with antibody-mediated rejection.

Kidney Int 2018 10 22;94(4):773-787. Epub 2018 May 22.

Paris Translational Research Center for Organ Transplantation, Institut national de la santé et de la recherche médicale, Unité mixte de recherche-S970, Paris, France; Department of Nephrology and Kidney Transplantation, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address:

A major hurdle to improving clinical care in the field of kidney transplantation is the lack of biomarkers of the response to antibody-mediated rejection (ABMR) treatment. To discover these we investigated the value of complement-binding donor-specific anti-HLA antibodies (DSAs) for evaluating the response to treatment. The study encompassed a prospective cohort of 139 kidney recipients with ABMR receiving the standard of care treatment, including plasma exchange, intravenous immunoglobulin and rituximab. Patients were systematically assessed at the time of diagnosis and three months after treatment initiation for clinical and allograft histological characteristics and anti-HLA DSAs, including their C1q-binding ability. After adjusting for clinical and histological parameters, post-treatment C1q-binding anti-HLA DSA was an independent and significant determinant of allograft loss (adjusted hazard ratio 2.57 (95% confidence interval 1.29-5.12). In 101 patients without post-treatment C1q-binding anti-HLA DSA there was a significantly improved glomerular filtration rate with significantly reduced glomerulitis, peritubular capillaritis, interstitial inflammation, tubulitis, C4d deposition, and endarteritis compared with 38 patients with posttreatment C1q-binding anti-HLA DSA. A conditional inference tree model identified five prognostic groups at the time of post-treatment evaluation based on glomerular filtration rate, presence of cg lesion and C1q-binding anti-HLA DSA (cross-validated accuracy: 0.77). Thus, circulating complement-binding anti-HLA DSAs are strong and independent predictors of allograft outcome after standard of care treatment in kidney recipients with ABMR.
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http://dx.doi.org/10.1016/j.kint.2018.03.015DOI Listing
October 2018

Complement-activating donor-specific anti-HLA antibodies and solid organ transplant survival: A systematic review and meta-analysis.

PLoS Med 2018 05 25;15(5):e1002572. Epub 2018 May 25.

Paris Translational Research Center for Organ Transplantation INSERM Unit 970, Paris, France.

Background: Anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) are recognized as a major barrier to patients' access to organ transplantation and the major cause of graft failure. The capacity of circulating anti-HLA DSAs to activate complement has been suggested as a potential biomarker for optimizing graft allocation and improving the rate of successful transplantations.

Methods And Findings: To address the clinical relevance of complement-activating anti-HLA DSAs across all solid organ transplant patients, we performed a meta-analysis of their association with transplant outcome through a systematic review, from inception to January 31, 2018. The primary outcome was allograft loss, and the secondary outcome was allograft rejection. A comprehensive search strategy was conducted through several databases (Medline, Embase, Cochrane, and Scopus). A total of 5,861 eligible citations were identified. A total of 37 studies were included in the meta-analysis. Studies reported on 7,936 patients, including kidney (n = 5,991), liver (n = 1,459), heart (n = 370), and lung recipients (n = 116). Solid organ transplant recipients with circulating complement-activating anti-HLA DSAs experienced an increased risk of allograft loss (pooled HR 3.09; 95% CI 2.55-3.74, P = 0.001; I2 = 29.3%), and allograft rejection (pooled HR 3.75; 95% CI: 2.05-6.87, P = 0.001; I2 = 69.8%) compared to patients without complement-activating anti-HLA DSAs. The association between circulating complement-activating anti-HLA DSAs and allograft failure was consistent across all subgroups and sensitivity analyses. Limitations of the study are the observational and retrospective design of almost all included studies, the higher proportion of kidney recipients compared to other solid organ transplant recipients, and the inclusion of fewer studies investigating allograft rejection.

Conclusions: In this study, we found that circulating complement-activating anti-HLA DSAs had a significant deleterious impact on solid organ transplant survival and risk of rejection. The detection of complement-activating anti-HLA DSAs may add value at an individual patient level for noninvasive biomarker-guided risk stratification.

Trial Registration: National Clinical Trial protocol ID: NCT03438058.
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http://dx.doi.org/10.1371/journal.pmed.1002572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969739PMC
May 2018

Association Between Thiopurine S-Methyltransferase () Genetic Variants and Infection in Pediatric Heart Transplant Recipients Treated With Azathioprine: A Multi-Institutional Analysis.

J Pediatr Pharmacol Ther 2018 Mar-Apr;23(2):106-110

Objectives: Bone marrow suppression is a common adverse effect of the immunosuppressive drug azathioprine. Polymorphisms in the gene encoding thiopurine -methyltransferase (TPMT) can alter the metabolism of azathioprine, resulting in marrow toxicity and life-threatening infection. In a multicenter cohort of pediatric heart transplant (HT) recipients, we determined the frequency of genetic variation and assessed whether azathioprine-treated recipients with variants were at increased risk of infection.

Methods: We genotyped in 264 pediatric HT recipients for the presence of the , , and variant alleles. Data on infection episodes and azathioprine use were collected as part of each patient's participation in the Pediatric Heart Transplant Study. We performed unadjusted Kaplan-Meier analyses comparing infection outcomes between groups.

Results: variants were identified in 26 pediatric HT recipients (10%): (n = 17), (n = 8), and (n = 1). Among those with a variant allele, was most prevalent in black patients (4 of 5) and most prevalent among white and Hispanic patients (16 of 20). Among 175 recipients (66%) who received azathioprine as part of the initial immunosuppressive regimen, we found no difference in the number of infections at 1 year after HT (0.7 ± 1.3; range, 0-6 versus 0.5 ± 0.9; range, 0-3; p = 0.60) or in freedom from infection and bacterial infection between non-variant and variant carriers. There was 1 infection-related death in each group.

Conclusions: In this multicenter cohort of pediatric HT recipients, the prevalence of variants was similar across racial/ethnic groups to what has been previously reported in non-pediatric HT populations. We found no association between variant alleles and infection in the first year after HT. Because clinically detected cytopenia could have prompted dose adjustment or cessation, we recommend future studies assess the relationship of genotype to leukopenia/neutropenia in the pediatric transplantation population.
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http://dx.doi.org/10.5863/1551-6776-23.2.106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916437PMC
May 2018

Sensitization in Transplantation: Assessment of Risk (STAR) 2017 Working Group Meeting Report.

Am J Transplant 2018 07 22;18(7):1604-1614. Epub 2018 May 22.

University of Manitoba, Winnipeg, MB, Canada.

The presence of preexisting (memory) or de novo donor-specific HLA antibodies (DSAs) is a known barrier to successful long-term organ transplantation. Yet, despite the fact that laboratory tools and our understanding of histocompatibility have advanced significantly in recent years, the criteria to define presence of a DSA and assign a level of risk for a given DSA vary markedly between centers. A collaborative effort between the American Society for Histocompatibility and Immunogenetics and the American Society of Transplantation provided the logistical support for generating a dedicated multidisciplinary working group, which included experts in histocompatibility as well as kidney, liver, heart, and lung transplantation. The goals were to perform a critical review of biologically driven, state-of-the-art, clinical diagnostics literature and to provide clinical practice recommendations based on expert assessment of quality and strength of evidence. The results of the Sensitization in Transplantation: Assessment of Risk (STAR) meeting are summarized here, providing recommendations on the definition and utilization of HLA diagnostic testing, and a framework for clinical assessment of risk for a memory or a primary alloimmune response. The definitions, recommendations, risk framework, and highlighted gaps in knowledge are intended to spur research that will inform the next STAR Working Group meeting in 2019.
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http://dx.doi.org/10.1111/ajt.14752DOI Listing
July 2018

Increasing tacrolimus time-in-therapeutic range is associated with superior one-year outcomes in lung transplant recipients.

Am J Transplant 2018 06 6;18(6):1527-1533. Epub 2018 Apr 6.

Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.

Calcineurin inhibitors (CNIs) are the backbone of traditional immunosuppressive regimens for lung transplant recipients (LTR). The CNIs are both narrow therapeutic index drugs with significant interpatient and intrapatient variability that require therapeutic drug monitoring to ensure safety and effectiveness. We hypothesized that tacrolimus time-in-therapeutic range (TTR) affects acute and chronic rejection rates in LTRs. This was a single-center, observational, cross-sectional study of 292 adult LTRs. Subjects who received tacrolimus posttransplant for the first year were included. TTR was calculated at 1 year using protocol goal ranges (12-15 mg/mL months 0-6; 10-12 mg/mL for months 7-12). The primary outcome was acute cellular rejection (ACR) burden at 1 year. Chronic lung allograft dysfunction (CLAD), mortality, and infection rate were assessed as secondary outcomes at 1 year. Primary and secondary outcomes were assessed using logistic regression. Increasing TTR by 10% was associated with a significantly lower likelihood of high-burden ACR at 1 year on univariable (OR 0.46, 95% CI 0.40-0.54, P < .001) and multivariable (OR 0.64, 95% CI 0.47-0.86, P = .003) assessment, controlling for age and induction agent. Increasing TTR by 10% was also associated with lower rates of CLAD (P < .001) and mortality (P < .001) at 1 year. Prospective studies confirming these findings appear warranted.
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http://dx.doi.org/10.1111/ajt.14723DOI Listing
June 2018

Study rationale, design, and pretransplantation alloantibody status: A first report of Clinical Trials in Organ Transplantation in Children-04 (CTOTC-04) in pediatric heart transplantation.

Am J Transplant 2018 09 23;18(9):2135-2147. Epub 2018 Mar 23.

Division of Pediatric Cardiology, Monroe Carrell Jr. Children's Hospital at Vanderbilt, Nashville, TN, USA.

Anti-HLA donor-specific antibodies are associated with worse outcomes after organ transplantation. Among sensitized pediatric heart candidates, requirement for negative donor-specific cytotoxicity crossmatch increases wait times and mortality. However, transplantation with positive crossmatch may increase posttransplantation morbidity and mortality. We address this clinical challenge in a prospective, multicenter, observational cohort study of children listed for heart transplantation (Clinical Trials in Organ Transplantation in Children-04 [CTOTC-04]). Outcomes were compared among sensitized recipients who underwent transplantation with positive crossmatch, nonsensitized recipients, and sensitized recipients without positive crossmatch. Positive crossmatch recipients received antibody removal and augmented immunosuppression, while other recipients received standard immunosuppression with corticosteroid avoidance. This first CTOTC-04 report summarizes study rationale and design and relates pretransplantation sensitization status using solid-phase technology. Risk factors for sensitization were explored. Of 317 screened patients, 290 were enrolled and 240 underwent transplantation. Core laboratory evaluation demonstrated that more than half of patients were anti-HLA sensitized. Greater than 80% of sensitized patients had class I (with or without class II) HLA antibodies, and one-third of sensitized patients had at least 1 HLA antibody with median fluorescence intensity of ≥8000. Logistic regression models demonstrated male sex, weight, congenital heart disease history, prior allograft, and ventricular assist device are independent risk factors for sensitization.
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http://dx.doi.org/10.1111/ajt.14695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093810PMC
September 2018

Immune Responses of HLA Highly Sensitized and Nonsensitized Patients to Genetically Engineered Pig Cells.

Transplantation 2018 05;102(5):e195-e204

Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA.

Background: We investigated in vitro whether HLA highly sensitized patients with end-stage renal disease will be disadvantaged immunologically after a genetically engineered pig kidney transplant.

Methods: Blood was drawn from patients with a calculated panel-reactive antibody (cPRA) 99% to 100% (Gp1, n = 10) or cPRA 0% (Gp2, n = 12), and from healthy volunteers (Gp3, n = 10). Serum IgM and IgG binding was measured (i) to galactose-α1-3 galactose and N-glycolylneuraminic acid glycans by enzyme-linked immunosorbent assay, and (ii) to pig red blood cell, pig aortic endothelial cells, and pig peripheral blood mononuclear cell from α1,3-galactosyltransferase gene-knockout (GTKO)/CD46 and GTKO/CD46/cytidine monophosphate-N-acetylneuraminic acid hydroxylase-knockout (CMAHKO) pigs by flow cytometry. (iii) T-cell and B-cell phenotypes were determined by flow cytometry, and (iv) proliferation of T-cell and B-cell carboxyfluorescein diacetate succinimidyl ester-mixed lymphocyte reaction.

Results: (i) By enzyme-linked immunosorbent assay, there was no difference in IgM or IgG binding to galactose-α1-3 galactose or N-glycolylneuraminic acid between Gps1 and 2, but binding was significantly reduced in both groups compared to Gp3. (ii) IgM and IgG binding in Gps1 and 2 was also significantly lower to GTKO/CD46 pig cells than in healthy controls, but there were no differences between the 3 groups in binding to GTKO/CD46/CMAHKO cells. (iii and iv) Gp1 patients had more memory T cells than Gp2, but there was no difference in T or B cell proliferation when stimulated by any pig cells. The proliferative responses in all 3 groups were weakest when stimulated by GTKO/CD46/CMAHKO pig peripheral blood mononuclear cell.

Conclusions: (i) End-stage renal disease was associated with low antipig antibody levels. (ii) Xenoreactivity decreased with increased genetic engineering of pig cells. (iii) High cPRA status had no significant effect on antibody binding or T-cell and B-cell response.
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http://dx.doi.org/10.1097/TP.0000000000002060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924598PMC
May 2018

Charges and resource utilization for pediatric heart transplantation across a positive virtual and/or cytotoxicity crossmatch.

Pediatr Transplant 2018 02 18;22(1). Epub 2017 Dec 18.

Pediatric Cardiology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.

There is growing acceptance of transplantation across a positive crossmatch for highly allosensitized pediatric HT candidates. While survival may be similar to patients transplanted across a negative crossmatch, costs are unknown. Among 60 HT recipients at our center from 5/07 to 6/12, we analyzed hospital charges and length of stay from the day of HT to discharge and through the first year after transplant. Median age at HT was 6.2 years (15 days-20.5 years). Charges in the first year post-HT were greater for crossmatch-positive patients ($907 678 vs $549 754; P = .017), with a trend toward higher charges for the HT hospitalization ($537 640 vs $407 374; P = .07). Plasmapheresis was more common in crossmatch-positive patients during the HT hospitalization (80% vs 4%, P < .001). In the first year after HT, crossmatch-positive patients had a greater number of endomyocardial biopsies (10 vs 7.5, P = .03) and episodes of treated rejection (2 vs 0, P = .004). Pediatric HT across a positive crossmatch is associated with higher first-year costs, including increased use of plasmapheresis and care around an increased number of rejections. These novel data will help inform decision and policymaking regarding care practices for the growing population of highly sensitized pediatric HT candidates.
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http://dx.doi.org/10.1111/petr.13095DOI Listing
February 2018

Short-term adverse effects of early subclinical allograft inflammation in kidney transplant recipients with a rapid steroid withdrawal protocol.

Am J Transplant 2018 07 17;18(7):1710-1717. Epub 2018 Jan 17.

Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

The impact of subclinical inflammation (SCI) noted on early kidney allograft biopsies remains unclear. This study evaluated the outcome of SCI noted on 3-month biopsy. A total of 273/363 (75%) kidney transplant recipients with a functioning kidney underwent allograft biopsies 3-months posttransplant. Among those with stable allograft function at 3 months, 200 biopsies that did not meet the Banff criteria for acute rejection were identified. These were Group I: No Inflammation (NI, n = 71) and Group II: Subclinical Inflammation (SCI, n = 129). We evaluated differences in kidney function at 24-months and allograft histology score at 12-month biopsy. SCI patients had a higher serum creatinine (1.6 ± 0.7 vs 1.38 ± 0.45; P = .02) at 24-months posttransplant, and at last follow-up at a mean of 42.5 months (1.69 ± 0.9 vs 1.46 ± 0.5 mg/dL; P = .027). The allograft chronicity score (ci + ct + cg + cv) at 12-months posttransplant was higher in the SCI group (2.4 ± 1.35 vs 1.9 ± 1.2; P = .02). The incidence of subsequent rejections within the first year in SCI and NI groups was 24% vs 10%, respectively (P = .015). De novo donor-specific antibody within 12 months was more prevalent in the SCI group (12/129 vs 1/71, P = .03). SCI is likely not a benign finding and may have long-term implications for kidney allograft function.
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http://dx.doi.org/10.1111/ajt.14627DOI Listing
July 2018

Expression of Mitochondrial-Encoded Genes in Blood Differentiate Acute Renal Allograft Rejection.

Front Med (Lausanne) 2017 1;4:185. Epub 2017 Nov 1.

Department of Surgery, University of California, San Francisco, San Francisco, CA, United States.

Despite potent immunosuppression, clinical and biopsy confirmed acute renal allograft rejection (AR) still occurs in 10-15% of recipients, ~30% of patients demonstrate subclinical rejection on biopsy, and ~50% of them can show molecular inflammation, all which increase the risk of chronic dysfunction and worsened allograft outcomes. Mitochondria represent intracellular endogenous triggers of inflammation, which can regulate immune cell differentiation, and expansion and cause antigen-independent graft injury, potentially enhancing the development of acute rejection. In the present study, we investigated the role of mitochondrial DNA encoded gene expression in biopsy matched peripheral blood (PB) samples from kidney transplant recipients. Quantitative PCR was performed in 155 PB samples from 115 unique pediatric (<21 years) and adult (>21 years) renal allograft recipients at the point of AR ( = 61) and absence of rejection ( = 94) for the expression of 11 mitochondrial DNA encoded genes. We observed increased expression of all genes in adult recipients compared to pediatric recipients; separate analyses in both cohorts demonstrated increased expression during rejection, which also differentiated borderline rejection and showed an increasing pattern in serially collected samples (0-3 months prior to and post rejection). Our results provide new insights on the role of mitochondria during rejection and potentially indicate mitochondria as targets for novel immunosuppression.
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http://dx.doi.org/10.3389/fmed.2017.00185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5671971PMC
November 2017

Complement-Activating Anti-HLA Antibodies in Kidney Transplantation: Allograft Gene Expression Profiling and Response to Treatment.

J Am Soc Nephrol 2018 02 17;29(2):620-635. Epub 2017 Oct 17.

Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France.

Complement-activating anti-HLA donor-specific antibodies (DSAs) are associated with impaired kidney transplant outcome; however, whether these antibodies induce a specific rejection phenotype and influence response to therapy remains undetermined. We prospectively screened 931 kidney recipients for complement-activating DSAs and used histopathology, immunostaining, and allograft gene expression to assess rejection phenotypes. Effector cells were evaluated using human cell cultures. Additionally, we assessed the effect of complement inhibition on kidney allograft rejection phenotype and the clinical response to complement inhibition in 116 independent kidney recipients with DSAs at transplant receiving rejection prophylaxis with eculizumab or standard of care (plasma exchange and intravenous Ig) at ten international centers. The histomolecular rejection phenotype associated with complement-activating DSA was characterized by complement deposition and accumulation of natural killer cells and monocytes/macrophages in capillaries and increased expression of five biologically relevant genes (, , , , and ) indicative of endothelial activation, IFN response, CD16-mediated natural killer cell activation, and monocyte/macrophage activation. Compared with standard of care, eculizumab specifically abrogated this histomolecular rejection phenotype and associated with a decreased 3-month rejection incidence rate in patients with complement-activating DSAs (56%; 95% confidence interval [95% CI], 38% to 74% versus 19%; 95% CI, 8% to 35%; =0.001) but not in those with noncomplement-activating DSAs (9%; 95% CI, 2% to 25% versus 13%; 95% CI, 2% to 40%; =0.65). In conclusion, circulating complement-activating anti-HLA DSAs are associated with a specific histomolecular kidney allograft rejection phenotype that can be abrogated by complement inhibition.
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http://dx.doi.org/10.1681/ASN.2017050589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791056PMC
February 2018

Maintenance Belatacept-Based Immunosuppression in Lung Transplantation Recipients Who Failed Calcineurin Inhibitors.

Transplantation 2018 01;102(1):171-177

Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA.

Background: Traditional immunosuppressive regimens (ISR) used in lung transplantation rely on calcineurin inhibitors (CNI) that occasionally cause severe adverse reactions necessitating discontinuation. Belatacept is a novel costimulation antagonist approved for use in renal transplantation which lacks data in lung transplantation. This series aims to describe the response to belatacept ISR in 11 lung transplantation recipients after CNI failure.

Methods: Single-center, retrospective medical record review of adult lung transplant recipients (LTR) before and after conversion to belatacept-based ISR. Patients were evaluated at fixed time points before and after belatacept initiation. Primary outcome was incidence of acute cellular rejection (ACR). Secondary outcomes included incidence of infection, chronic lung allograft dysfunction (CLAD) progression, death, change in mean arterial pressure, and estimated glomerular filtration rate.

Results: Eleven LTRs received belatacept with a mean of 246 (91-1064) days of follow-up after conversion. Four were changed to belatacept for thrombotic thrombocytopenic purpura, 3 for posterior reversible encephalopathy syndrome, 2 for recurrent ACR, 1 for CLAD, and 1 for renal-sparing. ACR was not different before and after belatacept (P = 0.17). Mean estimated glomerular filtration rate was significantly higher postbelatacept (32.53 vs 45.26, P = 0.04). Mean incidence of infections (24.4% vs 16.0%, P = 0.55) and mean arterial pressure (97.5 vs 92.1 P = 0.38) were not different. Progression of CLAD occurred in 2 patients. At the end of follow-up, 7 of 11 patients were alive.

Conclusions: Belatacept-based ISR appear to produce reasonable results in LTRs who fail CNI-based ISR. Larger prospective trials appear warranted in lung transplantation.
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http://dx.doi.org/10.1097/TP.0000000000001873DOI Listing
January 2018

Effect of aerosolized antipseudomonals on Pseudomonas positivity and bronchiolitis obliterans syndrome after lung transplantation.

Transpl Infect Dis 2017 Jun 17;19(3). Epub 2017 Apr 17.

Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.

Purpose: To describe the effects of aerosolized antipseudomonals (AAPs) on Pseudomonas (PS) culture positivity, bronchiolitis obliterans syndrome (BOS), and acute cellular rejection (ACR) in lung transplant recipients (LTRs).

Methods: Single-center, retrospective cohort study was performed of adult LTRs treated with either AAP for ≥28 days vs no AAP therapy or AAP therapy <28 days, indexed to a matched median date post lung transplantation (LT). Primary outcome was freedom from PS positivity by positive bronchoalveolar lavage or bronchial wash at 1 year. Secondary outcomes were freedom from BOS or BOS progression and ACR burden (defined by the novel composite rejection standardized score. Normality was assessed, and univariate and multivariate parametric and non-parametric statistical tests were used to assess baseline characteristics and outcomes, where appropriate. Freedom from events was compared using the Kaplan-Meier method with log-rank conversion and risk was assigned using multivariable Cox proportional hazards (PH) modeling.

Results: In total, 293 LTRs (105 with AAP, 188 with no AAP) were included. Median ages in AAP and control cohorts were 51 (30-63) and 62 (54-67) years (P<.01). Median AAP duration was 198 (interquartile range 94-395) days. Time to median positive PS culture was similar between AAP (median 1.02 [95% confidence interval {CI} 0.74-1.22] years) and control (median 0.96 [95% CI 0.72-1.21] years). Log-rank test for time-to-PS positivity was similar for both groups (log-rank P=.26). Incidence of PS culture positivity at 1 year was similar in APP vs controls (59.0% vs 54.8%, P=.48). In the non-cystic fibrosis (CF) subgroup, AAP use was protective against PS recurrence on univariate Cox PH model (hazard ratio [HR] 0.55, 95% CI 0.38-0.83) and on multivariate Cox PH adjusting for age and induction (HR 0.56, 95% CI 0.38-0.83). Incidence of new-onset BOS or BOS progression in APP vs control at 1 (17.1% vs 14.9%, P=.61) and 3 (38.1% vs 37.8%, P=.96) years was similar. CRSS was similar in APP vs control group at 1 year (0.42 vs 0.33, P=.41).

Conclusion: AAP use was not associated with less PS positivity, BOS, or ACR in all LTRs. In the non-CF subgroup analysis, treatment with AAPS was associated with protection against recurrent PS. Limitations include retrospective design, heterogeneous AAP therapy among LTRs, and potential convenience sampling of LTRs receiving AAPs for >28 days at our center. Larger assessments and better controlled analyses are required to further define efficacy of AAPs after LT.
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http://dx.doi.org/10.1111/tid.12688DOI Listing
June 2017

Significance of Anti-HLA Antibodies on Adult and Pediatric Heart Allograft Outcomes.

Front Immunol 2017 27;8. Epub 2017 Jan 27.

Division of Transplant Pathology, Department of Pathology, University of Pittsburgh Medical Center , Pittsburgh, PA , USA.

As methods for human leukocyte antigens (HLA) antibody detection have evolved and newer solid phase assays are much more sensitive, the last 15 years has seen a renewed focus on the importance of HLA antibodies in solid organ transplant rejection. However, there is still much controversy regarding the clinical significance of antibody level as depicted by the mean fluorescence intensity of a patient's neat serum. Emerging techniques, including those that identify antibody level and function, show promise for the detection of individuals at risk of allograft rejection, determination of the effectiveness of desensitization prior to transplant, and for monitoring treatment of rejection. Here, we review current publications regarding the relevance of donor-specific HLA antibodies (DSA) in adult and pediatric heart transplantation (HT) with graft survival, development of antibody-mediated rejection and cardiac allograft vasculopathy (CAV). The negative impact of DSA on patient and allograft survival is evident in adult and pediatric HT recipients. Many questions remain regarding the most appropriate frequency of assessment of pre- and posttransplant DSA as well as the phenotype of DSA memory vs. true antibody using large multicenter adult and pediatric cohorts and state-of-the-art methodologies for DSA detection and characterization.
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http://dx.doi.org/10.3389/fimmu.2017.00004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5269448PMC
January 2017

Rescue alemtuzumab for refractory acute cellular rejection and bronchiolitis obliterans syndrome after lung transplantation.

Clin Transplant 2017 04 22;31(4). Epub 2017 Feb 22.

Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Refractory acute cellular rejection (rACR) is associated with death and bronchiolitis obliterans syndrome (BOS) post-lung transplantation. We report the largest cohort of lung transplant recipients (LTRs) treated with rescue alemtuzumab for rACR or BOS. RACR outcomes included burden of ACR 30 days before and 180 days after rescue assessed by a novel composite rejection standardized score (CRSS, range 0-6) and freedom from ≥A2 ACR. BOS outcomes included freedom from BOS progression and FEV1 decline >10%. Univariate parametric and nonparametric statistical approaches were used to assess treatment response. Kaplan-Meier method with log rank conversion was used to assess freedom from events. Fifty-seven alemtuzumab doses (ACR 40 and BOS 17) given to 51 patients were included. Median time to rescue was 722 (IQR 42-1403) days. CRSS declined significantly (3 vs 0.67, P<0.001) after rescue. Freedom from ≥A2 was 62.5% in rACR. Freedom from BOS progression was 52.9% at 180 days in the BOS cohort. Freedom from FEV1 decline >10% was 70% in BOS grade 1 and 14.3% in advanced BOS grades 2-3. Infections developed in 72.5% and 76.5% of rACR and BOS groups. Rescue alemtuzumab appears useful for rACR. Patients with BOS 1 may have transient benefit, and patients with advanced BOS seem not to respond to alemtuzumab.
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http://dx.doi.org/10.1111/ctr.12899DOI Listing
April 2017

Janus kinase inhibition for immunosuppression in solid organ transplantation: Is there a role in complex immunologic challenges?

Hum Immunol 2017 Feb 18;78(2):64-71. Epub 2016 Dec 18.

Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States; Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.

Inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway for immunosuppression in solid organ transplantation is appealing due to its specificity for immune cell function, particularly for JAK3. This is due to its unique association with only the common gamma chain (γ). The γ is an appealing immunosuppression target in transplantation because of the critically important lymphokines that act at it, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Tofacitinib was initially purported to selectively inhibit solely JAK3, but subsequent analyses have also demonstrated its activity at the other members of the JAK family. Clinical outcomes have validated tofacitinib's pan-JAK activity in kidney transplantation after demonstrating an increased risk of infection and malignancy as compared to CNI-based regimens. After these trials, tofacitinib investigation for use in transplantation has effectively ceased. However, a post-hoc analysis has shed new light on the monitoring of tofacitinib exposure in order to predict infection and oncologic events. With new methods to monitor tofacitinib exposure, clinicians may be able to effectively reduce toxicities while providing a high level of immunosuppression. The purpose of this review to identify when, and for whom, JAK inhibitors may provide benefit in solid organ transplantation.
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http://dx.doi.org/10.1016/j.humimm.2016.12.005DOI Listing
February 2017