Person: Fishman, Jay
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Fishman
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Jay
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Fishman, Jay
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Publication Genome-wide inactivation of porcine endogenous retroviruses (PERVs)(American Association for the Advancement of Science (AAAS), 2015) Yang, Luhan; Guell, Marc; Niu, D.; George, H.; Lesha, E.; Grishin, Dennis; Aach, John; Shrock, Ellen; Xu, W.; Poci, Jurgen; Cortazio, R.; Wilkinson, R. A.; Fishman, Jay; Church, GeorgeThe shortage of organs for transplantation is a major barrier to the treatment of organ failure. While porcine organs are considered promising, their use has been checked by concerns about transmission of porcine endogenous retroviruses (PERVs) to humans. Here, we describe the eradication of all PERVs in a porcine kidney epithelial cell line (PK15). We first determined the PK15 PERV copy number to be 62. Using CRISPR-Cas9, we disrupted all 62 copies of the PERV pol gene and demonstrated a > 1000-fold reduction in PERV transmission to human cells using our engineered cells. Our study shows that CRISPR-Cas9 multiplexability can be as high as 62 and demonstrates the possibility that PERVs can be inactivated for clinical application of porcine- to-human xenotransplantation.Publication HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression(New England Journal of Medicine (NEJM/MMS), 2008) Kawai, Tatsuo; Cosimi, A.; Spitzer, Thomas; Tolkoff-Rubin, Nina; Suthanthiran, Manikkam; Saidman, Susan; Shaffer, Juanita; Preffer, Frederic; Ding, Ruchuang; Sharma, Vijay; Fishman, Jay; Dey, Bimalangshu; Ko, Dicken; Hertl, Martin; Goes, Nelson B.; Wong, Waichi; Williams, Winfred; Colvin, Robert; Sykes, Megan; Sachs, DavidFive patients with end-stage renal disease received combined bone marrow and kidney transplants from HLA single-haplotype mismatched living related donors, with the use of a nonmyeloablative preparative regimen. Transient chimerism and reversible capillary leak syndrome developed in all recipients. Irreversible humoral rejection occurred in one patient. In the other four recipients, it was possible to discontinue all immunosuppressive therapy 9 to 14 months after the transplantation, and renal function has remained stable for 2.0 to 5.3 years since transplantation. The T cells from these four recipients, tested in vitro, showed donor-specific unresponsiveness and in specimens from allograft biopsies, obtained after withdrawal of immunosuppressive therapy, there were high levels of P3 (FOXP3) messenger RNA (mRNA) but not granzyme B mRNA.Publication The Microbiome, Systemic Immune Function, and Allotransplantation(American Society for Microbiology, 2015) Nellore, Anoma; Fishman, JayDiverse effects of the microbiome on solid organ transplantation are beginning to be recognized. In allograft recipients, microbial networks are disrupted by immunosuppression, nosocomial and community-based infectious exposures, antimicrobial therapies, surgery, and immune processes. Shifting microbial patterns, in- cluding acute infectious exposures, have dynamic and reciprocal interactions with local and systemic immune systems. Both indi- vidual microbial species and microbial networks have central roles in the induction and control of innate and adaptive immune re- sponses, in graft rejection, and in ischemia-reperfusion injury. Understanding the diverse interactions between the microbiome and the immune system of allograft recipients may facilitate clin- ical management in the future.Publication High Incidence of Xenogenic Bone Marrow Engraftment in Pig-to-Baboon Intra-Bone Bone Marrow Transplantation(Wiley-Blackwell, 2015) Tasaki, M.; Wamala, I.; Tena, A.; Villani, V.; Sekijima, M.; Pathiraja, V.; Wilkinson, R. A.; Pratts, S.; Cormack, T.; Clayman, E.; Arn, J. S.; Shimizu, A.; Fishman, Jay; Sachs, David; Yamada, KazuhikoPrevious attempts of α-1,3-galactocyltransferase knockout (GalTKO) pig bone marrow (BM) transplantation (Tx) into baboons have demonstrated a loss of macro-chimerism within 24 h in most cases. In order to achieve improved engraftment with persistence of peripheral chimerism, we have developed a new strategy of intra-bone BM (IBBM) Tx. Six baboons received GalTKO BM cells, with one-half of the cells transplanted into the bilateral tibiae directly and the remaining cells injected intravenously (IBBM/BM-Tx) with a conditioning immunosuppressive regimen. In order to assess immune responses induced by the combined IBBM/BM-Tx, three recipients received donor SLA-matched GalTKO kidneys in the peri-operative period of IBBM/BM-Tx (Group 1), and the others received kidneys 2 months after IBBM/BM-Tx (Group 2). Peripheral macro-chimerism was continuously detectable for up to 13 days (mean 7.7 days; range 3–13) post- IBBM/BM-Tx and in three animals, macro-chimerism reappeared at days 10, 14 and 21. Pig CFUs, indicating porcine progenitor cell engraftment, were detected in the host BM in four of six recipients on days 14, 15, 19 and 28. In addition, anti-pig unresponsiveness was observed by in vitro assays. GalTKO/pCMV-kidneys survived for extended periods (47 and 60 days). This strategy may provide a potent adjunct for inducing xenogeneic tolerance through BM-Tx.Publication Multicenter comparison of laboratory performance in cytomegalovirus and Epstein-Barr virus viral load testing using international standards(Wiley-Blackwell, 2014) Rychert, Jenna; Danziger-Isakov, Lara; Yen-Lieberman, Belinda; Storch, Gregory; Buller, Richard; Sweet, Stewart C.; Mehta, Aneesh K.; Cheeseman, Jennifer A.; Heeger, Peter; Rosenberg, Eric; Fishman, JayBackground—Infections with cytomegalovirus (CMV) and Epstein Barr Virus (EBV) remain important in solid organ transplantation. Quantitative viral nucleic acid testing is a major advance to patient management. These assays are limited by a lack of standardization, resulting in viral load measurements that differ among clinical laboratories. The variability in viral load measurements makes interpretation of multicenter clinical trials data difficult. This study compares the current practices in CMV and EBV viral load testing at four large transplant centers participating in multicenter Clinical Trials in Organ Transplantation (CTOT/CTOTC).Publication Porcine Cytomegalovirus Infection Is Associated With Early Rejection of Kidney Grafts in a Pig to Baboon Xenotransplantation Model(Ovid Technologies (Wolters Kluwer Health), 2014) Yamada, Kazuhiko; Tasaki, Masayuki; Sekijima, Mitsuhiro; Wilkinson, Robert A.; Villani, Vincenzo; Moran, Shannon G.; Cormack, Taylor A.; Hanekamp, Isabel M.; Arn, J. Scott; Fishman, Jay; Shimizu, Akira; Sachs, DavidBackground—Recent survivals of our pig-to-baboon kidney xenotransplants have been markedly shorter than the graft survivals we previously reported. The discovery of high levels of porcine CMV (pCMV) in one of the rejected xenografts led us to evaluate whether this reduction in graft survival might be due to the inadvertent introduction of pCMV into our GalT-KO swine herd. Methods—Archived frozen sections of xeno-kidney grafts over the past 10 years were analyzed for the presence of pCMV, using real-time PCR. Three prospective pig-to-baboon renal transplants using kidneys from swine delivered by caesarian section (C-section) and raised in isolation were likewise analyzed. Results—Kidney grafts from which 8 of the 18 archived samples were derived were found to be pCMV-negative, had a mean graft survival of 48.3 days and were from transplants performed before 2008. None had shown signs of DIC and were lost due to either proteinuria or infectious complications. In contrast, 10 of the archived samples were pCMV positive, were from kidney transplants with a mean graft survival of 14.1 days, had been performed after 2008 and had demonstrated early vascular changes and decreased platelet counts. Three prospective xenografts from swine delivered by C-section were pCMV negative and survived an average of 53.0 days. Conclusions—Decreased survivals of GalT-KO renal xenografts in this laboratory correlate temporally with latent pCMV in the donor animals and pCMV in the rejected xeno-kidneys.Publication Xenotransplantation-associated infectious risk: a WHO consultation(Wiley-Blackwell, 2012) Fishman, Jay; Scobie, Linda; Takeuchi, YasuhiroXenotransplantation carries the potential risk of the transmission of infection with the cells or tissues of the graft. The degree of risk is unknown in the absence of clinical trials. The clinical application of xenotransplantation has important implications for infectious disease surveillance, both at the national and international levels. Preclinical data indicate that infectious disease events associated with clinical xenotransplantation from swine, should they occur, will be rare; data in human trials are limited but have demonstrated no transmission of porcine microorganisms including porcine endogenous retrovirus. Xenotransplantation will necessitate the development of surveillance programs to detect known infectious agents and, potentially, previously unknown or unexpected pathogens. The development of surveillance and safety programs for clinical trials in xenotransplantation is guided by a “Precautionary Principle,” with the deployment of appropriate screening procedures and assays for source animals and xenograft recipients even in the absence of data suggesting infectious risk. All assays require training, standardization and validation, and sharing of laboratory methods and expertise to optimize the quality of the surveillance and diagnostic testing. Investigation of suspected xenogeneic infection events (xenosis, xenozoonosis) should be performed in collaboration with an expert data safety review panel and the appropriate public health and competent authorities. It should be considered an obligation of performance of xenotransplantation trials to report outcomes, including any infectious disease transmissions, in the scientific literature. Repositories of samples from source animals and from recipients prior to, and following xenograft transplantation are essential to the investigation of possible infectious disease events. Concerns over any potential hazards associated with xenotransplantation may overshadow potential benefits. Careful microbiological screening of source animals used as xenotransplant donors may enhance the safety of transplantation beyond that of allotransplant procedures. Xenogeneic tissues may be relatively resistant to infection by some human pathogens. Moreover, xenotransplantation may be made available at the time when patients require organ replacement on a clinical basis. Insights gained in studies of the microbiology and immunology of xenotransplantation will benefit transplant recipients in the future. This document summarizes approaches to disease surveillance in individual recipients of nonhuman tissues.Publication Viral Infection InducesDe NovoLesions of Coronary Allograft Vasculopathy Through a Natural Killer Cell-Dependent Pathway(Wiley-Blackwell, 2009) Graham, Jay A.; Wilkinson, R. A.; Hirohashi, Tsutomu; Chase, Catharine M.; Colvin, Robert; Madsen, Joren; Fishman, Jay; Russell, PaulViral infections including those due to cytomegalovirus (CMV) have been associated with accelerated cardiac allograft vasculopathy (CAV) in clinical trials and some animal models. Evidence demonstrating a direct causal relationship between such infections and de novo formation of coronary vascular lesions is lacking. Heterotopic murine cardiac transplants were performed in a parental to F1 combination in animals lacking both T- and B-lymphocytes (RAG−/−). Coronary vasculopathy developed almost exclusively in the presence of recipient infection with lymphocytic choriomeningitis virus (LCMV) but not in uninfected controls. This process was also dependent upon the presence of NK cells as depletion of NK cells abrogated the process. These data show that a viral infection in its native host, and not previously implicated in the production of CAV, can contribute to the development of advanced coronary vascular lesions in cardiac allotransplants in mice. These data also suggest that virus-induced CAV can develop via an NK-cell dependent pathway in the absence of T- and B-lymphocytes.Publication Results of Gal-Knockout Porcine Thymokidney Xenografts(Wiley-Blackwell, 2009) Griesemer, Adam D.; Hirakata, Atsushi; Shimizu, Akira; Moran, Shannon; Tena, A.; Iwaki, Hideyuki; Ishikawa, Yoshinori; Schule, Patrick; Arn, J. Scott; Robson, Simon; Fishman, Jay; Sykes, Megan; Sachs, David; Yamada, KazuhikoClinical transplantation for the treatment of end-stage organ disease is limited by a shortage of donor organs. Successful xenotransplantation could immediately overcome this limitation. The development of homozygous α1,3-galactosyltransferase knockout (GalT-KO) pigs removed hyperacute rejection as the major immunologic hurdle to xenotransplantation. Nevertheless, GalT- KO organs stimulate robust immunologic responses that are not prevented by immunosuppressive drugs. Murine studies show that recipient thymopoiesis in thymic xenografts induces xenotolerance. We transplanted life-supporting composite thymokidneys prepared in GalT-KO miniature swine to baboons in an attempt to induce tolerance in a pre-clinical xenotransplant model. Here, we report the results of 7 xenogenic thymokidney transplants using a steroid-free immunosuppressive regimen that eliminated whole body irradiation in all but 1 recipient. The regimen resulted in average recipient survival of over 50 days. This was associated with donor- specific unresponsiveness in vitro and early baboon thymopoiesis in the porcine thymus tissue of these grafts, suggesting the development of T cell tolerance. The kidney grafts had no signs of cellular infiltration or deposition of IgG, and no grafts were lost due to rejection. These results show that xenogeneic thymus transplantation can support early human thymopoiesis, which in turn may induce T cell tolerance to solid organ xenografts.Publication Current status of xenotransplantation and prospects for clinical application(Wiley-Blackwell, 2009) Pierson, Richard N.; Dorling, Anthony; Ayares, David; Rees, Michael Kenneth; Seebach, Jörg D.; Fishman, Jay; Hering, Bernhard J.; Cooper, David K. C.Xenotransplantation is one promising approach to bridge the gap between available human cells, tissues, and organs and the needs of patients with diabetes or end-stage organ failure. Based on recent progress using genetically-modified source pigs, improving results with conventional and experimental immunosuppression, and expanded understanding of residual physiologic hurdles, xenotransplantation appears likely to be evaluated in clinical trials in the near future for some select applications. This review offers a comprehensive overview of known mechanisms of xenograft injury, a contemporary assessment of preclinical progress and residual barriers, and our opinions regarding where breakthroughs are likely to occur.
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