Scripps Center for Organ and Cell Transplantation

La Jolla, CA, United States

Scripps Center for Organ and Cell Transplantation

La Jolla, CA, United States

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Hewel J.A.,University of Toronto | Mondala T.S.,Scripps Research Institute | Campbell D.,Scripps Research Institute | Head S.R.,Scripps Research Institute | And 2 more authors.
Journal of the American Society of Nephrology | Year: 2010

The most common cause of kidney transplant failure is the poorly characterized histopathologic entity interstitial fibrosis and tubular atrophy (IFTA). There are no known unifying mechanisms, no effective therapy, and no proven preventive strategies. Possible mechanisms include chronic immune rejection, inflammation, drug toxicity, and chronic kidney injury from secondary factors. To gain further mechanistic insight, we conducted a large-scale proteogenomic study of kidney transplant biopsies with IFTA of varying severity. We acquired proteomic data using tandem mass spectrometry with subsequent quantification, analysis of differential protein expression, validation, and functional annotations to known molecular networks. We performed genome-wide expression profiling in parallel. More than 1400 proteins with unique expression profiles traced the progression from normal transplant biopsies to biopsies with mild to moderate and severe disease. Multiple sets of proteins were mapped to different functional pathways, many increasing with histologic severity, including immune responses, inflammatory cell activation, and apoptosis consistent with the chronic rejection hypothesis. Two examples include the extensive population of the alternative rather than the classical complement pathway, previously not appreciated for IFTA, and a comprehensive control network for the actin cytoskeleton and cell signaling of the acute-phase response. In summary, this proteomic effort using kidney tissue contributes mechanistic insight into several biologic processes associated with IFTA. Copyright © 2010 by the American Society of Nephrology.


Modena B.D.,Scripps Research Institute | Kurian S.M.,Scripps Research Institute | Gaber L.W.,The Methodist Hospital | Waalen J.,Scripps Research Institute | And 21 more authors.
American Journal of Transplantation | Year: 2016

Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1-year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long-term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/annual_reports/current/509a_ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty-one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons


Savaryn J.P.,Northwestern University | Toby T.K.,Northwestern University | Catherman A.D.,Northwestern University | Fellers R.T.,Northwestern University | And 7 more authors.
Proteomics | Year: 2016

Recent studies utilizing transcriptomics, metabolomics, and bottom up proteomics have identified molecular signatures of kidney allograft pathology. Although these results make significant progress toward non-invasive differential diagnostics of dysfunction of a transplanted kidney, they provide little information on the intact, often modified, protein molecules present during progression of this pathology. Because intact proteins underpin diverse biological processes, measuring the relative abundance of their modified forms promises to advance mechanistic understanding, and might provide a new class of biomarker candidates. Here, we used top down proteomics to inventory the modified forms of whole proteins in peripheral blood mononuclear cells (PBMCs) taken at the time of kidney biopsy for 40 kidney allograft recipients either with healthy transplants or those suffering acute rejection. Supported by gas-phase fragmentation of whole protein ions during tandem mass spectrometry, we identified 344 proteins mapping to 2905 distinct molecular forms (proteoforms). Using an initial implementation of a label-free approach to quantitative top down proteomics, we obtained evidence suggesting relative abundance changes in 111 proteoforms between the two patient groups. Collectively, our work is the first to catalog intact protein molecules in PBMCs and suggests differentially abundant proteoforms for further analysis. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim


Fischer-Frohlich C.-L.,Region Baden Wurttemberg | Konigsrainer A.,University Hospital of Tuebingen | Schaffer R.,Scripps Center for Organ and Cell Transplantation | Schaub F.,Deutsche Stiftung Organtransplantation | And 4 more authors.
Transplant International | Year: 2012

Although more than 2300 intestinal transplantations (IT) have been performed worldwide, a description of intestinal donor criteria is still missing. This causes confusion among transplant coordinators, OPOs, physicians at intensive care unit and transplant surgeons. A Med-line search looking for publications about donor criteria or donor selection in human IT was performed in December 2011. Retrospective analysis of 39 deceased donors from whom, in the period January 2006-December 2011, 20 isolated intestinal grafts and 19 multivisceral grafts were recovered and successfully transplanted. Review of the Literature: Among 3504 publications about IT, no study reported specifically about intestinal donor profile. The most commonly cited donor criterion was age, while all other criteria were inconsistently discussed. Based on the collected data, we suggest following inclusion criteria for donation of IT grafts: age 0-50 years, ICU-stay <1 week, no blunt abdominal trauma, most recent Sodium <155 mmol/l, no severe ongoing transfusion requirements, standard donor therapy including early enteral nutrition and a compatible donor-recipient size match. By providing simple criteria for intestinal donation from deceased donor, we may help to properly utilize the limited donor pool. © 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.


Grigoryev Y.A.,Scripps Research Institute | Kurian S.M.,Scripps Research Institute | Avnur Z.,Scripps Research Institute | Borie D.,Amgen Inc. | And 17 more authors.
PLoS ONE | Year: 2010

A major challenge for the field of transplantation is the lack of understanding of genomic and molecular drivers of early post-transplant immunity. The early immune response creates a complex milieu that determines the course of ensuing immune events and the ultimate outcome of the transplant. The objective of the current study was to mechanistically deconvolute the early immune response by purifying and profiling the constituent cell subsets of the peripheral blood. We employed genome-wide profiling of whole blood and purified CD4, CD8, B cells and monocytes in tandem with highthroughput laser-scanning cytometry in 10 kidney transplants sampled serially pre-transplant, 1, 2, 4, 8 and 12 weeks. Cytometry confirmed early cell subset depletion by antibody induction and immunosuppression. Multiple markers revealed the activation and proliferative expansion of CD45RO+CD62L- effector memory CD4/CD8 T cells as well as progressive activation of monocytes and B cells. Next, we mechanistically deconvoluted early post-transplant immunity by serial monitoring of whole blood using DNA microarrays. Parallel analysis of cell subset-specific gene expression revealed a unique spectrum of time-dependent changes and functional pathways. Gene expression profiling results were validated with 157 different probesets matching all 65 antigens detected by cytometry. Thus, serial blood cell monitoring reflects the profound changes in blood cell composition and immune activation early post-transplant. Each cell subset reveals distinct pathways and functional programs. These changes illuminate a complex, early phase of immunity and inflammation that includes activation and proliferative expansion of the memory effector and regulatory cells that may determine the phenotype and outcome of the kidney transplant. © 2010 Grigoryev et al.

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