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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.

Yolcu E.S.,University of Louisville | Leventhal J.R.,Comprehensive Transplant Center | Ildstad S.T.,University of Louisville | Ildstad S.T.,Regenerex, Llc
Current Opinion in Organ Transplantation | Year: 2015

PURPOSE OF REVIEW: To describe the clinical outcomes and science behind a CD8/TCR facilitating cell-based hematopoietic stem cell transplant approach (termed FCRx) to induce tolerance to renal allografts without graft-versus-host disease (GVHD) and avoidance of long-term immunosuppressant drugs in living donor kidney transplant recipients. RECENT FINDINGS: Successful solid organ transplantation currently requires the life-long use of medications to suppress the immune system to prevent transplant rejection. Drug-based immunosuppression significantly increases the risk of infection and cancer, as well as being very costly. Development of new therapies to minimize or eliminate entirely the need for antirejection drugs is of great interest to the transplant community. Therapeutic cell transfer for the control of the human immune system represents a compelling approach to reduce or eliminate the need for antirejection drugs. SUMMARY: Establishment of durable hematopoietic macrochimerism under nonmyeloablative conditioning is achievable in mismatched recipients using facilitating cells and stem cells obtained from donor mobilized peripheral blood mononuclear cells. Persistently chimeric recipients developed donor-specific tolerance and were weaned off of immunosuppressive drugs over 12 months. They maintained stable renal function without development of acute or chronic GVHD. © 2015 Wolters Kluwer Health, Inc.

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.

Leventhal J.,Comprehensive Transplant Center | Huang Y.,University of Louisville | Xu H.,University of Louisville | Goode I.,University of Louisville | Ildstad S.T.,University of Louisville
BMC Medicine | Year: 2012

Graft-versus-host disease is one of the major transplant-related complications in allogeneic hematopoietic stem cell transplantation. Continued efforts have been made to prevent the occurrence of severe graft-versus-host disease by eliminating or suppressing donor-derived effector T cells. Conventional immunosuppression does not adequately prevent graft-versus-host disease, especially in mismatched transplants. Unfortunately, elimination of donor-derived T cells impairs stem cell engraftment, and delays immunologic reconstitution, rendering the recipient susceptible to post-transplant infections and disease relapse, with potentially lethal consequences. In this review, we discuss the role of dynamic immune regulation in controlling graft-versus-host disease, and how cell-based therapies are being developed using regulatory T cells and other tolerogenic cells for the prevention and treatment of graft-versus-host disease. In addition, advances in the design of cytoreductive conditioning regimens to selectively target graft-versus-host disease-inducing donor-derived T cells that have improved the safety of allogeneic stem cell transplantation are reviewed. Finally, we discuss advances in our understanding of the tolerogenic facilitating cell population, a phenotypically and functionally distinct population of bone marrow-derived cells which promote hematopoietic stem cell engraftment while reducing the risk of graft-versus-host disease. © 2012 Leventhal et al; licensee BioMed Central Ltd.

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.

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