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Shin B.-H.,Comprehensive Transplant Center | Ge S.,Comprehensive Transplant Center | Karasyov A.,Comprehensive Transplant Center | Vo A.,Cedars Sinai Medical Center | And 2 more authors.
Transplantation | Year: 2014

BACKGROUND: It was demonstrated that human natural killer (NK) cells, via antibody-dependent cellular cytotoxicity (ADCC)-like mechanism, increase IFNγ production after exposure to alloantigens. This finding was associated with an increased risk for antibody-mediated rejection (ABMR). Although the effects of various immunosuppressive drugs on T cells and B cells have been extensively studied, their effects on NK cells are less clear. This study reports the effect of immunosuppressive agents on antibody-mediated NK cell activation in vitro. METHODS: Whole blood from normal individuals was incubated with irradiated peripheral blood mononuclear cells (PBMCs) pretreated with anti-HLA antibody+ sera (in vitro ADCC), with or without immunosuppressive agents. The %IFNγ+ and CD107a+ (degranulation marker) in CD56+ NK cells were enumerated by flow cytometry. RESULTS: Cyclosporine A and tacrolimus significantly reduced IFNγ production in a dose-dependent manner (53%-83%), but showed minimal effect on degranulation (20%). Prednisone significantly reduced both IFNγ production and degranulation (50%-66% reduction at maximum therapeutic levels). Calcineurin inhibitors (CNIs) in combination with prednisone additively suppressed IFNγ production and degranulation. The effect of sirolimus or mycophenolate mofetil on NK cells was minimal. CONCLUSIONS: These results suggest that potent suppressive effects of CNIs and prednisone on antibody-mediated NK cell activation may contribute to the reduction of ADCC in sensitized patients and possibly reduce the risk for ADCC-mediated ABMR. These further underscore the importance of medication compliance in prevention of ABMR and possibly chronic rejection, and suggest that ADCC-mediated injury may increase in strategies aimed at CNI or steroid minimization or avoidance. © 2014 Lippincott Williams & Wilkins.


PubMed | University of Washington, University of Chicago, CSIC - Biological Research Center, Murdoch Childrens Research Institute and 8 more.
Type: | Journal: Journal of the American Society of Nephrology : JASN | Year: 2017

(Re)Building a Kidney is a National Institute of Diabetes and Digestive and Kidney Diseases-led consortium to optimize approaches for the isolation, expansion, and differentiation of appropriate kidney cell types and the integration of these cells into complex structures that replicate human kidney function. The ultimate goals of the consortium are two-fold: to develop and implement strategies for in vitro engineering of replacement kidney tissue, and to devise strategies to stimulate regeneration of nephrons in situ to restore failing kidney function. Projects within the consortium will answer fundamental questions regarding human gene expression in the developing kidney, essential signaling crosstalk between distinct cell types of the developing kidney, how to derive the many cell types of the kidney through directed differentiation of human pluripotent stem cells, which bioengineering or scaffolding strategies have the most potential for kidney tissue formation, and basic parameters of the regenerative response to injury. As these projects progress, the consortium will incorporate systematic investigations in physiologic function of in vitro and in vivo differentiated kidney tissue, strategies for engraftment in experimental animals, and development of therapeutic approaches to activate innate reparative responses.


News Article | October 29, 2015
Site: news.yahoo.com

The number of transplant surgeries from donor organs hasn't grown during the last 10 years, and transplants from living donors have declined nearly 16 percent. Because there's a critical shortage of organs, doctors at The Ohio State University More Dr. Todd Pesavento is medical director of kidney and pancreas transplantation and interim executive director of the Comprehensive Transplant Center at The Ohio State University Wexner Medical Center. Pesavento contributed this article to Live Science's Expert Voices: Op-Ed & Insights. Every 10 minutes, another name goes on the list of Americans waiting for an organ transplant. Currently, the list of patients awaiting a donation is more than 122,000 names long. Most of those patients will have to wait months or even years before finding a donor organ, and unfortunately, some never will. By the end of the day, 22 more people will die while awaiting a donor organ. The problem is, there simply aren't enough donors to meet demand. Most states have tried to bring attention to the issue by giving drivers the opportunity to become donors upon getting or renewing their driver's licenses. In May, the U.S. Senate introduced the Organ Donation Awareness and Promotion Act of 2015, and though it's yet to be voted on, it would fund efforts to further promote organ donation and raise awareness of the ongoing shortage. Despite those efforts, according to the U.S. Department of Health and Human Services (HHS), the number of donors available nationwide has remained stagnant over the last decade. In 2005, there were 14,497; last year, there were 14,415. And the number of living donors from whom organs were recovered actually dropped over the same time period, by more than 16 percent. Not content to just sit and wait, patients are increasingly taking matters into their own hands and actively looking for potential living donors. Finding donors, any way we can At the Comprehensive Transplant Center in The Ohio State University's Wexner Medical Center, we're seeing patients use everything from signs to social media to elicit donors. After one of our patients was put on a waiting list for a kidney , for example, his wife took to Facebook to share her husband's story and ask for donors. In less than a week, he had one. A former classmate of his wife's came forward to donate a kidney, and this past July, the couple celebrated the fifth anniversary of the transplant. [The 9 Most Interesting Transplants ] Another patient in need of a kidney at our center not only has a Facebook page, but also painted a plea for help on her SUV, providing details of her situation, her phone number and even her blood type. Though she's yet to find a suitable donor, she's generated dozens of phone calls and, on a broader scale, raised awareness among passersby about the possibility of becoming a living donor. I find in my practice that many people want to help, but they simply didn't know they could. Whenever someone comes forward to donate to one of my patients, I ask how they learned about becoming a living donor. Invariably, they say they saw a story on the news, read something in a newspaper or, increasingly, happened to notice something on social media. Hopefully, if you're one of those who didn't know you could become a living donor, perhaps you'll sign up after reading this. The good news is that the donor pool has broadened considerably over the last two decades. In the past, because of the risk of the recipient's body rejecting the transplanted organ, it was thought that only immediate family members could be donors. Today, advancements in surgical techniques such as vascular anastomosis and the use of robotics requiring less invasive incisions, combined with improvements in anti-rejection medications, there are fewer limits to who can donate — especially for kidneys. According to HHS, in the United States, there is a far greater need for kidney transplants than for any other organ. More than 100,000 people are waiting for donor kidneys, four times as many as all other organs combined. That's where living donors could make such a big impact. According to the United Network for Organ Sharing, kidneys are the most common organ transplanted from living donors; the United States just doesn't have enough of them. Ohio State is one of the larger transplant centers in the country. Currently, we have about 800 people on the wait list for a kidney, and next year we anticipate evaluating 800 more patients for transplant. Every year, we perform transplants for about 240 people, with about half of those patients receiving transplants from a living donor.


PubMed | University of California at Los Angeles and Comprehensive Transplant Center
Type: Journal Article | Journal: HLA | Year: 2016

HLA-C*08:121N results from two-nucleotide loss compared with its closest allele HLA-C*08:01:01.


Savaryn J.P.,Chemistry of Life Processes Institute | Catherman A.D.,Chemistry of Life Processes Institute | Thomas P.M.,Chemistry of Life Processes Institute | Abecassis M.M.,Comprehensive Transplant Center | And 2 more authors.
Genome Medicine | Year: 2013

Proteomic technology has advanced steadily since the development of 'soft-ionization' techniques for mass-spectrometry-based molecular identification more than two decades ago. Now, the large-scale analysis of proteins (proteomics) is a mainstay of biological research and clinical translation, with researchers seeking molecular diagnostics, as well as protein-based markers for personalized medicine. Proteomic strategies using the protease trypsin (known as bottom-up proteomics) were the first to be developed and optimized and form the dominant approach at present. However, researchers are now beginning to understand the limitations of bottom-up techniques, namely the inability to characterize and quantify intact protein molecules from a complex mixture of digested peptides. To overcome these limitations, several laboratories are taking a whole-protein-based approach, in which intact protein molecules are the analytical targets for characterization and quantification. We discuss these top-down techniques and how they have been applied to clinical research and are likely to be applied in the near future. Given the recent improvements in mass-spectrometry-based proteomics and stronger cooperation between researchers, clinicians and statisticians, both peptide-based (bottom-up) strategies and whole-protein-based (top-down) strategies are set to complement each other and help researchers and clinicians better understand and detect complex disease phenotypes. © 2013 BioMed Central Ltd.


PubMed | Northwestern University Transplant Outcomes Research Collaborative, 51 East Huron Street Galter Suite 3 150 and Comprehensive Transplant Center
Type: Journal Article | Journal: Human immunology | Year: 2016

Historically, hepatitis B virus (HBV) liver transplantation (LT) recipients have less acute cellular rejection (ACR) than those without HBV. We questioned whether this has persisted in an era of decreased Hepatitis B immunoglobulin use (HBIG) given its in vitro immunoregulatory effects. We compared the incidence, risk factors and outcomes of ACR among 40,593 primary LT recipients with HBV, hepatitis C, steatohepatitis, and immune liver disease (OPTN 2000-2011). We also assessed the in vitro effect of HBIG on alloimmune lymphoproliferation and regulatory T cell generation using mixed lymphocyte reactions. In multivariate analysis, HBV status remained a strong independent predictor of freedom from ACR (OR 0.58, 95% CI: 1.5-2.1). Patient (67.7% vs 72.3%) and graft (60.8% vs 69.1%) survival were significantly lower in patients with ACR versus no ACR for all causes except HBV. HBIG use had no statistical association with ACR. In vitro, HBIG at concentrations equivalent to clinical dosing did not inhibit lymphoproliferation or promote regulatory T cell development. In summary, the incidence and impact of ACR is lower now for HBV LT and does not appear to be secondary to HBIG by our in vitro and in vivo analyses. Rather, it may be due to the innate immunosuppressive properties of chronic HBV infection.


Jordan S.C.,Comprehensive Transplant Center | Jordan S.C.,Cedars Sinai Medical Center | Toyoda M.,Comprehensive Transplant Center | Toyoda M.,Cedars Sinai Medical Center | Vo A.,Comprehensive Transplant Center
Current Opinion in Organ Transplantation | Year: 2011

PURPOSE OF REVIEW: The introduction of B-cell-directed therapies for autoimmune diseases illuminated the biologic relevance of B cells in mediation of autoimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation and the production of immune stimulating and immune modulatory cytokines. These advances clearly have implications for patients receiving solid organ transplants, especially those who are ABO incompatible, sensitized to human leukocyte antigen (HLA) pretransplant, or develop anti-HLA antibodies posttransplant. RECENT FINDINGS: Here, we will review the current and evolving agents developed for B-cell depletion or modulation and discuss their potential for modification of alloimmunity in transplant recipients. We will focus on data from humans and animal models in which B cells and antibodies are targeted to reduce inflammation in transplantation. This will include a review of the immunomodulatory drug intravenous immunoglobulin, anti-CD20 (rituximab) where more clinical experience has been reported. Finally, we will discuss emerging B-cell-directed therapies which include those directed at the B-cell activating factor of the tumor necrosis family/A proliferation inducing ligand, anti-CD22, newer anti-CD20 monoclonals and antibodies to the interleukin 6 receptor (tocilizumab). SUMMARY: The primary objective of this review is to define the critical role of B cells in development of alloimmunity and how this can be modified by B-cell-directed therapies. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Menon V.G.,Comprehensive Transplant Center | Puri V.C.,Comprehensive Transplant Center | Annamalai A.A.,Comprehensive Transplant Center | Tuli R.,Cedars Sinai Medical Center | Nissen N.N.,Comprehensive Transplant Center
American Surgeon | Year: 2013

Extension of pancreatic adenocarcinoma into adjacent vasculature often necessitates resection of the portal vein (PV) and/or superior mesenteric vein (SMV) during pancreaticoduodenectomy (PD). The vein is reconstructed primarily by end-to-end anastomosis of vein remnants or venoplasty or by use of autologous or synthetic vein grafts. The objective of this study was to review outcomes in patients undergoing PD for pancreatic adenocarcinoma, specifically comparing the short- and long-term outcomes between the patients undergoing vascular resection and those undergoing standard PD. All patients undergoing PD for pancreatic adenocarcinoma by a single surgeon between 2007 and 2012 were reviewed. Of the 61 patients identified, 18 patients underwent vascular resection of the PV (four patients), SMV (10 patients), or both (four patients). The remaining 43 patients had standard PD. Demographic, perioperative, pathological, and longterm outcomes data were collected and both vascular and standard groups were compared. Both groups had similar demographics. The vascular group had significantly longer operative times (529 vs 406 minutes; P<0.01) with a trend to greater estimated blood loss (0.64 vs 0.53 L; P = 0.06). Pathological analysis showed no difference between the two groups with regard to lymph node status/ratio and rate of R0 resection (94 vs 91%; P = 0.57); however, the size of the tumor was significantly greater in the vascular group (4.2 vs 3 cm; P < 0.01). Short-term outcomes were similar in the vascular group and standard group, respectively, with no difference in pancreatic fistula rate (6 vs 7%; P = 1.0), transfusion rate (44 vs 35%; P = 0.57), and median length of stay (8 vs 7 days; P = 0.10), and there was no 30-day mortality in either group. Based on Kaplan-Meier methods, the median recurrence-free survival was 18 versus 23 months (P = 0.37) in the vascular and standard groups, respectively, and the overall survival was almost identical in both groups, each with a median of 31 months (P = 0.91). In our experience, mesenteric and PV resection during PD was performed safely and without compromise of short- or longer-term outcomes. It can be performed safely and patients have no significant difference in perioperative outcomes or overall survival. © Southeastern Surgical Congress. All rights reserved.


Tambur A.R.,Comprehensive Transplant Center | Rosati J.,Comprehensive Transplant Center | Roitberg S.,Comprehensive Transplant Center | Glotz D.,Nephrology and Transplantation Service | And 2 more authors.
Transplantation | Year: 2014

BACKGROUND: Human leukocyte antigen (HLA)-DQ has emerged as the alloantibody most frequently associated with the generation of de novo donor-specific antibody (DSA), antibody-mediated-rejection, and unfavorable transplantation outcome. METHODS: The generation of HLA-DQ de novo DSA was interrogated in 40 transplant recipients who were immunologically naive before their failed transplantation. Eplet and epitope analyses were performed using HLAMatchmaker and Cn3D software. RESULTS: Ten DQA and thirteen DQB eplets or eplet combinations were identified. All but one revealed an epitope footprint that includes both the DQα and DQβ chains. Four examples are illustrated in detail, representing a range of different epitope landscapes. A disparity between antigen density and mean fluorescence intensity values for some alleles within an eplet group was noted, with mean fluorescence intensity values of the lowest fluorescence bead being one tenth of the highest fluorescence bead, despite the fact that the amount of antigen on these beads were not significantly different. CONCLUSION: Our data support the need for changing the manner in which HLA-DQ antigens and antibodies are evaluated for organ transplantation. The current nomenclature system does not reflect the true nature of HLA-DQ polymorphism. Moreover, epitope immunogenicity likely involves more than the mere presence of a specific eplet. Because our field contemplates the use of epitope matching as an approach to improve organ allocation and overall outcomes, it is imperative to have accurate characterization of the immunogenicity of each epitope. This will pave the way to identifying acceptable mismatches and will allow risk stratification for generating de novo HLA-DSA after transplantation. Copyright © 2014 by Lippincott Williams & Wilkins.


Jay C.L.,Comprehensive Transplant Center | Lyuksemburg V.,Comprehensive Transplant Center | Ladner D.P.,Comprehensive Transplant Center | Wang E.,Comprehensive Transplant Center | And 4 more authors.
Annals of Surgery | Year: 2011

Objective: To conduct a meta-analysis to enhance understanding of the risks of biliary complications, particularly ischemic cholangiopathy (IC), after donation after cardiac death (DCD) compared with donation after brain death (DBD) liver transplantation. Background: Biliary complications after liver transplantation have profound health and economic implications which merit further investigation. Methods: The MELDINE (1950-2009), EMBASE, and Cochrane Library databases were searched and supplemented by review of conference proceedings and publication bibliographies. All original single institution studies reporting outcomes for DCD and DBD liver transplant recipients were considered. Odds ratios (OR) and 95% confidence intervals (CI) based on random effects models were calculated. Results: Eleven publications, all retrospective cohort studies, involving 489 DCD and 4455 DBD recipients, were included. Donation after cardiac death recipients had a 2.4 times increased odds of biliary complications (95% CI = 1.8-3.4) and a 10.8 times increased odds of IC (95% CI = 4.8-24.2). Ischemic cholangiopathy was present in 16% of DCD compared with 3% of DBD recipients. Donation after cardiac death recipients also experienced higher odds of 1-year patient mortality (OR = 1.6, 95% CI = 1.04-2.5) and graft failure (OR = 2.1, 95% CI = 1.5-2.8). Conclusions: Donation after cardiac death liver transplantation is marred by inferior outcomes including higher rates of biliary complications and IC as well as increased mortality and graft failure. Despite current federal mandates to increase DCD donation, these serious complications translate into poor outcomes for individuals and increased healthcare costs. These risks should be considered in decisions regarding the utilization of these grafts. Copyright © 2011 by Lippincott Williams & Wilkins.

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