28 results on '"Mohiuddin, Muhammad"'
Search Results
2. Research opportunities and ethical considerations for heart and lung xenotransplantation research: A report from the National Heart, Lung, and Blood Institute workshop.
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Khush KK, Bernat JL, Pierson RN 3rd, Silverman HJ, Parent B, Glazier AK, Adams AB, Fishman JA, Gusmano M, Hawthorne WJ, Homan ME, Hurst DJ, Latham S, Park CG, Maschke KJ, Mohiuddin MM, Montgomery RA, Odim J, Pentz RD, Reichart B, Savulescu J, Wolpe PR, Wong RP, and Fenton KN
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- Humans, Animals, United States, National Heart, Lung, and Blood Institute (U.S.), Biomedical Research ethics, Tissue Donors supply & distribution, Tissue Donors ethics, Transplantation, Heterologous ethics, Lung Transplantation ethics, Heart Transplantation ethics
- Abstract
Xenotransplantation offers the potential to meet the critical need for heart and lung transplantation presently constrained by the current human donor organ supply. Much was learned over the past decades regarding gene editing to prevent the immune activation and inflammation that cause early organ injury, and strategies for maintenance of immunosuppression to promote longer-term xenograft survival. However, many scientific questions remain regarding further requirements for genetic modification of donor organs, appropriate contexts for xenotransplantation research (including nonhuman primates, recently deceased humans, and living human recipients), and risk of xenozoonotic disease transmission. Related ethical questions include the appropriate selection of clinical trial participants, challenges with obtaining informed consent, animal rights and welfare considerations, and cost. Research involving recently deceased humans has also emerged as a potentially novel way to understand how xeno-organs will impact the human body. Clinical xenotransplantation and research involving decedents also raise ethical questions and will require consensus regarding regulatory oversight and protocol review. These considerations and the related opportunities for xenotransplantation research were discussed in a workshop sponsored by the National Heart, Lung, and Blood Institute, and are summarized in this meeting report., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Kiran K. Khush: recipient of NHLBI research grant on donor heart evaluation for transplantation (R01HL125303). Brendan Parent: recipient of Applebaum Foundation grant to study ethics of xenotransplantation. Karen J. Maschke and Michael Gusmano: recipients of NCATS research grant on ethical translation of xenotransplantation clinical trials (1R01TR003844-0). The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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3. A Standardized Approach to Orthotopic (Life-supporting) Porcine Cardiac Xenotransplantation in a Nonhuman Primate Model.
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Goerlich CE, Griffith BP, Shah A, Treffalls JA, Zhang T, Lewis B, Tatarov I, Hershfeld A, Sentz F, Braileanu G, Ayares D, Singh AK, and Mohiuddin MM
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- Humans, Animals, Swine, Transplantation, Heterologous methods, Primates, Heterografts, Heart, Animals, Genetically Modified, Graft Rejection prevention & control, Heart Transplantation adverse effects, Heart Transplantation methods
- Abstract
Cardiac xenotransplantation from swine has been proposed to "bridge the gap" in supply for heart failure patients requiring transplantation. Recent preclinical success using genetically modified pig donors in baboon recipients has demonstrated survival greater than 6 mo, with a modern understanding of xenotransplantation immunobiology and continued experience with large animal models of cardiac xenotransplantation. As a direct result of this expertise, the Food and Drug Administration approved the first in-human transplantation of a genetically engineered cardiac xenograft through an expanded access application for a single patient. This clinical case demonstrated the feasibility of xenotransplantation. Although this human study demonstrated proof-of-principle application of cardiac xenotransplantation, further regulatory oversight by the Food and Drug Administration may be required with preclinical trials in large animal models of xenotransplantation with long-term survival before approval of a more formalized clinical trial. Here we detail our surgical approach to pig-to-primate large animal models of orthotopic cardiac xenotransplantation, and the postoperative care of the primate recipient, both in the immediate postoperative period and in the months thereafter. We also detail xenograft surveillance methods and common issues that arise in the postoperative period specific to this model and ways to overcome them. These studies require multidisciplinary teams and expertise in orthotopic transplantation (cardiac surgery, anesthesia, and cardiopulmonary bypass), immunology, genetic engineering, and experience in handling large animal donors and recipients, which are described here. This article serves to reduce the barriers to entry into a field with ever-growing enthusiasm, but demands expertise knowledge and experience to be successful., Competing Interests: D.A. is employed by Revivicor, Inc., a subsidiary of United Therapeutics. United Therapeutics was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. The other authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
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4. Partial heart xenotransplantation: A research protocol in non-human primates.
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Rajab TK, Goerlich CE, Forbess JM, Griffith BP, and Mohiuddin MM
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- Animals, Transplantation, Heterologous methods, Primates, Graft Rejection, Organ Transplantation methods, Heart Transplantation, Transplants
- Abstract
Partial heart transplantation is a new type of transplant that delivers growing heart valve replacements for babies. Partial heart transplantation differs from orthotopic heart transplantation because only the part of the heart containing the heart valve is transplanted. It also differs from homograft valve replacement because viability of the graft is preserved by tissue matching, minimizing donor ischemia times, and recipient immunosuppression. This preserves partial heart transplant viability and allows the grafts to fulfill biological functions such as growth and self-repair. These advantages over conventional heart valve prostheses are balanced by similar disadvantages as other organ transplants, most importantly limitations in donor graft availability. Prodigious progress in xenotransplantation promises to solve this problem by providing an unlimited source of donor grafts. In order to study partial heart xenotransplantation, a suitable large animal model is important. Here we describe our research protocol for partial heart xenotransplantation in nonhuman primates., (© 2023 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)
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- 2023
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5. Graft dysfunction in compassionate use of genetically engineered pig-to-human cardiac xenotransplantation: a case report.
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Mohiuddin MM, Singh AK, Scobie L, Goerlich CE, Grazioli A, Saharia K, Crossan C, Burke A, Drachenberg C, Oguz C, Zhang T, Lewis B, Hershfeld A, Sentz F, Tatarov I, Mudd S, Braileanu G, Rice K, Paolini JF, Bondensgaard K, Vaught T, Kuravi K, Sorrells L, Dandro A, Ayares D, Lau C, and Griffith BP
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- Humans, Male, Compassionate Use Trials, Graft Rejection prevention & control, Heart, Immunoglobulins, Intravenous, Leukocytes, Mononuclear, Transplantation, Heterologous, Middle Aged, Animals, Swine, Heart Transplantation, Heart Failure surgery
- Abstract
Background: A genetically engineered pig cardiac xenotransplantation was done on Jan 7, 2022, in a non-ambulatory male patient, aged 57 years, with end-stage heart failure, and on veno-arterial extracorporeal membrane oxygenation support, who was ineligible for an allograft. This report details our current understanding of factors important to the xenotransplantation outcome., Methods: Physiological and biochemical parameters critical for the care of all heart transplant recipients were collected in extensive clinical monitoring in an intensive care unit. To ascertain the cause of xenograft dysfunction, we did extensive immunological and histopathological studies, including electron microscopy and quantification of porcine cytomegalovirus or porcine roseolovirus (PCMV/PRV) in the xenograft, recipient cells, and tissue by DNA PCR and RNA transcription. We performed intravenous immunoglobulin (IVIG) binding to donor cells and single-cell RNA sequencing of peripheral blood mononuclear cells., Findings: After successful xenotransplantation, the graft functioned well on echocardiography and sustained cardiovascular and other organ systems functions until postoperative day 47 when diastolic heart failure occurred. At postoperative day 50, the endomyocardial biopsy revealed damaged capillaries with interstitial oedema, red cell extravasation, rare thrombotic microangiopathy, and complement deposition. Increased anti-pig xenoantibodies, mainly IgG, were detected after IVIG administration for hypogammaglobulinaemia and during the first plasma exchange. Endomyocardial biopsy on postoperative day 56 showed fibrotic changes consistent with progressive myocardial stiffness. Microbial cell-free DNA testing indicated increasing titres of PCMV/PRV cell-free DNA. Post-mortem single-cell RNA sequencing showed overlapping causes., Interpretation: Hyperacute rejection was avoided. We identified potential mediators of the observed endothelial injury. First, widespread endothelial injury indicates antibody-mediated rejection. Second, IVIG bound strongly to donor endothelium, possibly causing immune activation. Finally, reactivation and replication of latent PCMV/PRV in the xenograft possibly initiated a damaging inflammatory response. The findings point to specific measures to improve xenotransplant outcomes in the future., Funding: The University of Maryland School of Medicine, and the University of Maryland Medical Center., Competing Interests: Declaration of interests DA, AD, TV, LS, and KK are employees of Revivicor, a subsidy of United Therapeutics. KB is an employee of Kiniksa Pharmaceuticals. Members of Program in Cardiac Xenotransplantation received research funding from United Therapeutics. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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6. The growth of xenotransplanted hearts can be reduced with growth hormone receptor knockout pig donors.
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Goerlich CE, Griffith B, Hanna P, Hong SN, Ayares D, Singh AK, and Mohiuddin MM
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- Animals, Humans, Animals, Genetically Modified, Graft Rejection, Heterografts, Hypertrophy, Papio, Swine, Transplantation, Heterologous, Heart Transplantation adverse effects, Receptors, Somatotropin
- Abstract
Objective: Genetically engineered pigs are thought to be an alternative organ source for patients in end-stage heart failure unable to receive a timely allograft. However, cardiac xenografts exhibit growth and diastolic heart failure within 1 month after transplantation. Grafts function for up to 6 months, but only after administration of temsirolimus and afterload-reducing agents to reduce this growth. In this study we investigated the growth and hemodynamics of growth hormone receptor (GHR) knockout xenografts, without the use of adjuncts to prevent intrinsic graft growth after transplantation., Methods: Genetically engineered pig hearts were transplanted orthotopically into weight-matched baboons between 15 and 30 kg, using continuous perfusion preservation before implantation (n = 5). Xenografts included knockout of carbohydrate antigens and knockin of human transgenes for thromboregulation, complement regulation, and inflammation reduction (grafts with intact growth hormone, n = 2). Three grafts contained the additional knockout of GHR (GHR knockout grafts; n = 3). Transthoracic echocardiograms were obtained twice monthly and comprehensively analyzed by a blinded cardiologist. Hemodynamics were measured longitudinally after transplantation., Results: All xenografts demonstrated life-supporting function after transplantation. There was no difference in intrinsic growth, measured using septal and posterior wall thickness and left ventricular mass, on transthoracic echocardiogram out to 1 month in either GHR knockout or GHR intact grafts. However, hypertrophy of the septal and posterior wall was markedly elevated by 2 months post transplantation. There was minimal hypertrophy out to 6 months in GHR knockout grafts. Physiologic mismatch was present in all grafts after transplantation, which is largely independent of growth., Conclusions: Xenografts with GHR knockout show reduced post-transplantation xenograft growth using echocardiography >6 months after transplantation, without the need for other adjuncts., (Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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7. Preclinical rationale and current pathways to support the first human clinical trials in cardiac xenotransplantation.
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Mohiuddin MM, Singh AK, and Goerlich CE
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- Animals, Humans, Transplantation, Heterologous methods, Graft Rejection, Primates, Heart Transplantation
- Abstract
Recent initiation of the first FDA-approved cardiac xenotransplantation suggests xenotransplantation could soon become a therapeutic option for patients unable to undergo allotransplantation. Until xenotransplantation is widely applied in clinical practice, consideration of benefit versus risk and approaches to management of clinical xenografts will based at least in part on observations made in experimental xenotransplantation in non-human primates. Indeed, the decision to proceed with clinical trials reflects significant progress in last few years in experimental solid organ and cellular xenotransplantation. Our laboratory at the NIH and now at University of Maryland contributed to this progress, with heterotopic cardiac xenografts surviving more than two years and life-supporting cardiac xenografts survival up to 9 months. Here we describe our contributions to the understanding of the mechanism of cardiac xenograft rejection and development of methods to overcome past hurdles, and finally we share our opinion on the remaining barriers to clinical translation. We also discuss how the first in human xenotransplants might be performed, recipients managed, and graft function monitored., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)
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- 2023
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8. The road to the first FDA-approved genetically engineered pig heart transplantation into human.
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Singh AK, Griffith BP, Goerlich CE, Ayares D, and Mohiuddin MM
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- Animals, Animals, Genetically Modified, Graft Rejection, Humans, Male, Papio, Primates, Swine, Transplantation, Heterologous, United States, United States Food and Drug Administration, Graft Survival, Heart Transplantation
- Abstract
We have been testing genetically engineered (GE) pig hearts and optimizing immunosuppression (IS) in non-human primates (NHPs) since 2005. We demonstrate how we translated this preclinical investigation into a US Food and Drug Administration (FDA)-approved clinical cardiac xenotransplantation. First, genetically engineered (GE) pig hearts were transplanted into the abdomen of NHP along with IS, which included anti-CD20 and anti-CD40-based co-stimulation blockade antibodies. We reported 945 days of survival of three gene GE pig hearts in NHPs. Building on this proof-of-concept, we tested 3-10 gene-modified GE pig hearts (in order to improve the immunocompatibility of the xenograft further) in a life-supporting orthotopic model, but had limited success due to perioperative cardiac xenograft dysfunction (PCXD). With novel non-ischemic continuous perfusion preservation (NICP), using the XVIVO Heart solution (XHS), life-supporting survival was extended to 9 months. We approached the FDA under an application for "Expanded Access" (EA), to transplant a GE pig heart in a patient with end-stage non-ischemic cardiomyopathy. He was without other therapeutic options and dependent on VA-ECMO. A team of FDA reviewers reviewed our preclinical research experience and data and allowed us to proceed. This clinical cardiac xenotransplantation was performed, and the patient survived for 60 days, demonstrating the translational preclinical investigation of cardiac xenotransplantation from bench to bedside. The ultimate etiology of graft failure is currently a topic of investigation and lessons learned will progress the field forward., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2022
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9. Recent advances in porcine cardiac xenotransplantation: from aortic valve replacement to heart transplantation.
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Kavarana S, Kwon JH, Zilinskas K, Kang L, Turek JW, Mohiuddin MM, and Rajab TK
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- Adult, Animals, Aortic Valve, Humans, Swine, Transplantation, Heterologous, Heart Failure surgery, Heart Transplantation, Heart-Assist Devices
- Abstract
Introduction: Cardiac xenotransplantation presents significant potential to the field of heart failure by addressing the high demand for donor organs. The availability of xenograft hearts would substantially augment the number of life-saving organs available to patients and may ultimately liberalize eligibility criteria for transplantation., Areas Covered: In this review, we will discuss the need for cardiac xenotransplantation and the history of research and clinical practice in this field. Specifically, we address immunologic concepts and clinical lessons learned from heart valve replacement using xenogeneic tissues, the advancement of xenotransplantation using organs from genetically modified animals, and the progression of this research to the first-in-man pig-to-human heart transplantation., Expert Opinion: Cardiac xenotransplantation holds tremendous promise, but the indications for this new treatment in adults will need to be clearly defined because mechanical support with ventricular assist devices and total artificial hearts are increasingly successful alternatives in heart failure. Cardiac xenotransplantation will also serve as temporary bridge to allotransplantation in babies with complex congenital heart disease who are too small for the currently available mechanical assist devices and total artificial hearts. Moreover, xenotransplantation of the part of the heart containing a heart valve could deliver growing heart valve implants for babies with severe heart valve dysfunction.
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- 2022
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10. Xenotransplantation Is the Future of Pediatric Cardiac Surgery.
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Rajab TK, Mohiuddin MM, and Kavarana MN
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- Child, Forecasting, Graft Rejection, Humans, Transplantation, Heterologous, Heart Transplantation
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- 2022
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11. Genetically Modified Porcine-to-Human Cardiac Xenotransplantation.
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Griffith BP, Goerlich CE, Singh AK, Rothblatt M, Lau CL, Shah A, Lorber M, Grazioli A, Saharia KK, Hong SN, Joseph SM, Ayares D, and Mohiuddin MM
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- Animals, Extracorporeal Membrane Oxygenation, Heart, Humans, Immunosuppression Therapy, Swine, Animals, Genetically Modified genetics, Heart Transplantation methods, Heterografts, Transplantation, Heterologous methods
- Abstract
A 57-year-old man with nonischemic cardiomyopathy who was dependent on venoarterial extracorporeal membrane oxygenation (ECMO) and was not a candidate for standard therapeutics, including a traditional allograft, received a heart from a genetically modified pig source animal that had 10 individual gene edits. Immunosuppression was based on CD40 blockade. The patient was weaned from ECMO, and the xenograft functioned normally without apparent rejection. Sudden diastolic thickening and failure of the xenograft occurred on day 49 after transplantation, and life support was withdrawn on day 60. On autopsy, the xenograft was found to be edematous, having nearly doubled in weight. Histologic examination revealed scattered myocyte necrosis, interstitial edema, and red-cell extravasation, without evidence of microvascular thrombosis - findings that were not consistent with typical rejection. Studies are under way to identify the mechanisms responsible for these changes. (Funded by the University of Maryland Medical Center and School of Medicine.)., (Copyright © 2022 Massachusetts Medical Society.)
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- 2022
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12. Progressive genetic modifications of porcine cardiac xenografts extend survival to 9 months.
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Mohiuddin MM, Goerlich CE, Singh AK, Zhang T, Tatarov I, Lewis B, Sentz F, Hershfeld A, Braileanu G, Odonkor P, Strauss E, Williams B, Burke A, Hittman J, Bhutta A, Tabatabai A, Gupta A, Vaught T, Sorrells L, Kuravi K, Dandro A, Eyestone W, Kaczorowski DJ, Ayares D, and Griffith BP
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- Animals, Animals, Genetically Modified, Graft Survival, Heterografts, Humans, Immunosuppressive Agents, Papio, Swine, Transplantation, Heterologous, Graft Rejection, Heart Transplantation
- Abstract
We report orthotopic (life-supporting) survival of genetically engineered porcine cardiac xenografts (with six gene modifications) for almost 9 months in baboon recipients. This work builds on our previously reported heterotopic cardiac xenograft (three gene modifications) survival up to 945 days with an anti-CD40 monoclonal antibody-based immunosuppression. In this current study, life-supporting xenografts containing multiple human complement regulatory, thromboregulatory, and anti-inflammatory proteins, in addition to growth hormone receptor knockout (KO) and carbohydrate antigen KOs, were transplanted in the baboons. Selective "multi-gene" xenografts demonstrate survival greater than 8 months without the requirement of adjunctive medications and without evidence of abnormal xenograft thickness or rejection. These data demonstrate that selective "multi-gene" modifications improve cardiac xenograft survival significantly and may be foundational for paving the way to bridge transplantation in humans., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2022
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13. Cardiac Xenotransplantation: Progress in Preclinical Models and Prospects for Clinical Translation.
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Singh AK, Goerlich CE, Shah AM, Zhang T, Tatarov I, Ayares D, Horvath KA, and Mohiuddin MM
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- Animals, Graft Rejection genetics, Heterografts, Humans, Swine, Tissue Donors, Transplantation, Heterologous, Heart Transplantation, Primates
- Abstract
Survival of pig cardiac xenografts in a non-human primate (NHP) model has improved significantly over the last 4 years with the introduction of costimulation blockade based immunosuppression (IS) and genetically engineered (GE) pig donors. The longest survival of a cardiac xenograft in the heterotopic (HHTx) position was almost 3 years and only rejected when IS was stopped. Recent reports of cardiac xenograft survival in a life-sustaining orthotopic (OHTx) position for 6 months is a significant step forward. Despite these achievements, there are still several barriers to the clinical success of xenotransplantation (XTx). This includes the possible transmission of porcine pathogens with pig donors and continued xenograft growth after XTx. Both these concerns, and issues with additional incompatibilities, have been addressed recently with the genetic modification of pigs. This review discusses the spectrum of issues related to cardiac xenotransplantation, recent progress in preclinical models, and its feasibility for clinical translation., Competing Interests: Author DA was employed by the company Revivicor Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Singh, Goerlich, Shah, Zhang, Tatarov, Ayares, Horvath and Mohiuddin.)
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- 2022
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14. Blood Cardioplegia Induction, Perfusion Storage and Graft Dysfunction in Cardiac Xenotransplantation.
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Goerlich CE, Griffith B, Singh AK, Abdullah M, Singireddy S, Kolesnik I, Lewis B, Sentz F, Tatarov I, Hershfeld A, Zhang T, Strauss E, Odonkor P, Williams B, Tabatabai A, Bhutta A, Ayares D, Kaczorowski DJ, and Mohiuddin MM
- Subjects
- Animals, Heart Arrest, Induced methods, Heterografts, Papio, Perfusion, Swine, Transplantation, Heterologous, Heart Transplantation
- Abstract
Background: Perioperative cardiac xenograft dysfunction (PCXD) describes a rapidly developing loss of cardiac function after xenotransplantation. PCXD occurs despite genetic modifications to increase compatibility of the heart. We report on the incidence of PCXD using static preservation in ice slush following crystalloid or blood-based cardioplegia versus continuous cold perfusion with XVIVO
© heart solution (XHS) based cardioplegia., Methods: Baboons were weight matched to genetically engineered swine heart donors. Cardioplegia volume was 30 cc/kg by donor weight, with del Nido cardioplegia and the addition of 25% by volume of donor whole blood. Continuous perfusion was performed using an XVIVO© Perfusion system with XHS to which baboon RBCs were added., Results: PCXD was observed in 5/8 that were preserved with crystalloid cardioplegia followed by traditional cold, static storage on ice. By comparison, when blood cardioplegia was used followed by cold, static storage, PCXD occurred in 1/3 hearts and only in 1/5 hearts that were induced with XHS blood cardioplegia followed by continuous perfusion. Survival averaged 17 hours in those with traditional preservation and storage, followed by 11.47 days and 15.03 days using blood cardioplegia and XHS+continuous preservation, respectively. Traditional preservation resulted in more inotropic support and higher average peak serum lactate 14.3±1.7 mmol/L compared to blood cardioplegia 3.6±3.0 mmol/L and continuous perfusion 3.5±1.5 mmol/L., Conclusion: Blood cardioplegia induction, alone or followed by XHS perfusion storage, reduced the incidence of PCXD and improved graft function and survival, relative to traditional crystalloid cardioplegia-slush storage alone., Competing Interests: DA is employed by Revivicor, Inc., a subsidiary of United Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Goerlich, Griffith, Singh, Abdullah, Singireddy, Kolesnik, Lewis, Sentz, Tatarov, Hershfeld, Zhang, Strauss, Odonkor, Williams, Tabatabai, Bhutta, Ayares, Kaczorowski and Mohiuddin.)- Published
- 2021
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15. Heterotopic Porcine Cardiac Xenotransplantation in the Intra-Abdominal Position in a Non-Human Primate Model.
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Goerlich CE, DiChiacchio L, Zhang T, Singh AK, Lewis B, Tatarov I, Hershfeld A, Sentz F, Ayares D, Corcoran P, Horvath K, and Mohiuddin MM
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- Abdomen surgery, Animals, Female, Graft Rejection prevention & control, Immunosuppressive Agents therapeutic use, Male, Models, Animal, Papio, Swine, Tissue Donors, Graft Survival physiology, Heart Transplantation methods, Transplantation, Heterologous methods, Transplantation, Heterotopic methods
- Abstract
Heterotopic cardiac transplantation in the intra-abdominal position in a large animal model has been essential in the progression of the field of cardiac transplantation. Our group has over 10 years of experience in cardiac xenotransplantation with pig to baboon models, the longest xenograft of which survived over 900 days, with rejection only after reducing immunosuppression. This article aims to clarify our approach to this model in order to allow others to share success in long-term survival. Here, we demonstrate the approach to implantation of a cardiac graft into the intra-abdominal position in a baboon recipient for the study of transplantation and briefly highlight our model's ability to provide insight into not only xenotransplantation but across disciplines. We include details that have provided us with consistent success in this model; performance of the anastomoses, de-airing of the graft, implantation of a long-term telemetry device for invasive graft monitoring, and ideal geometric positioning of the heart and telemetry device in the limited space of the recipient abdomen. We additionally detail surveillance techniques to assess long-term graft function.
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- 2020
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16. Early Experience With Preclinical Perioperative Cardiac Xenograft Dysfunction in a Single Program.
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DiChiacchio L, Singh AK, Lewis B, Zhang T, Hardy N, Pasrija C, Morales D, Odonkor P, Strauss E, Williams B, Deatrick KB, Kaczorowski DJ, Ayares D, Griffith BP, Bartlett ST, and Mohiuddin MM
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- Animals, Biopsy, Disease Models, Animal, Female, Graft Rejection diagnosis, Graft Rejection drug therapy, Graft Survival, Male, Papio, Perioperative Period, Swine, Transplantation, Heterologous, Graft Rejection physiopathology, Heart Transplantation adverse effects, Immunosuppression Therapy methods, Immunosuppressive Agents therapeutic use
- Abstract
Background: Perioperative cardiac xenograft dysfunction (PCXD) was described by McGregor and colleagues as a major barrier to the translation of heterotopic cardiac xenotransplantation into the orthotopic position. It is characterized by graft dysfunction in the absence of rejection within 24 to 48 hours of transplantation. We describe our experience with PCXD at a single program., Methods: Orthotopic transplantation of genetically engineered pig hearts was performed in 6 healthy baboons. The immunosuppression regimen included induction by anti-CD20 monoclonal antibodies (mAb), thymoglobulin, cobra venom factor, and anti-CD40 mAb, and maintenance with anti-CD40 mAb, mycophenolate mofetil, and tapering doses of steroids. Telemetry was used to assess graft function. Extracorporeal membrane oxygenation was used to support 1 recipient. A full human clinical transplantation team was involved in these experiments and the procedure was performed by skilled transplantation surgeons., Results: A maximal survival of 40 hours was achieved in these experiments. The surgical procedures were uneventful, and all hearts were weaned from cardiopulmonary bypass without issue. Support with inotropes and vasopressors was generally required after separation from cardiopulmonary bypass. The cardiac xenografts performed well immediately, but within the first several hours they required increasing support and ultimately resulted in arrest despite maximal interventions. All hearts were explanted immediately; histology showed no signs of rejection., Conclusions: Despite excellent surgical technique, uneventful weaning from cardiopulmonary bypass, and adequate initial function, orthotopic cardiac xenografts slowly fail within 24 to 48 hours without evidence of rejection. Modification of preservation techniques and minimizing donor organ ischemic time may be able to ameliorate PCXD., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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17. Consideration of appropriate clinical applications for cardiac xenotransplantation.
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Chan JL, Miller JG, Singh AK, Horvath KA, Corcoran PC, and Mohiuddin MM
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- Animals, Heart Transplantation methods, Humans, Prognosis, Graft Survival, Heart Failure surgery, Heart Transplantation trends, Patient Selection, Transplantation, Heterologous methods
- Abstract
The field of cardiac xenotransplantation has entered an exciting era due to recent advances in the field. Although several hurdles remain, the use of rapidly evolving transgenic technology has the potential to address current allogeneic donor pool constraints and mechanical circulatory system device limitations. The success of xenotransplantation will undoubtedly be dependent on specific patient selection criteria. Defining these particular indications for xenotransplantation is important as we approach the possibility of clinical applications., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2018
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18. Circulating cell-free DNA as a biomarker of tissue injury: Assessment in a cardiac xenotransplantation model.
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Agbor-Enoh S, Chan JL, Singh A, Tunc I, Gorham S, Zhu J, Pirooznia M, Corcoran PC, Thomas ML, Lewis BGT, Jang MK, Ayares DL, Horvath KA, Mohiuddin MM, and Valantine H
- Subjects
- Acute Disease, Animals, Follow-Up Studies, Graft Rejection immunology, Half-Life, Organisms, Genetically Modified, Papio, Swine, Transplantation, Heterotopic, Troponin blood, Biomarkers blood, Cell-Free Nucleic Acids blood, Heart Transplantation adverse effects, Transplantation, Heterologous adverse effects
- Abstract
Background: Observational studies suggest that cell-free DNA (cfDNA) is a biomarker of tissue injury in a range of conditions including organ transplantation. However, the lack of model systems to study cfDNA and its relevance to tissue injury has limited the advancements in this field. We hypothesized that the predictable course of acute humoral xenograft rejection (AHXR) in organ transplants from genetically engineered donors provides an ideal system for assessing circulating cfDNA as a marker of tissue injury., Methods: Genetically modified pig donor hearts were heterotopically transplanted into baboons (n = 7). Cell-free DNA was extracted from pre-transplant and post-transplant baboon plasma samples for shotgun sequencing. After alignment of sequence reads to pig and baboon reference sequences, we computed the percentage of xenograft-derived cfDNA (xdcfDNA) relative to recipient by counting uniquely aligned pig and baboon sequence reads., Results: The xdcfDNA percentage was high early post-transplantation and decayed exponentially to low stable levels (baseline); the decay half-life was 3.0 days. Post-transplantation baseline xdcfDNA levels were higher for transplant recipients that subsequently developed graft loss than in the 1 animal that did not reject the graft (3.2% vs 0.5%). Elevations in xdcfDNA percentage coincided with increased troponin and clinical evidence of rejection. Importantly, elevations in xdcfDNA percentage preceded clinical signs of rejection or increases in troponin levels., Conclusion: Cross-species xdcfDNA kinetics in relation to acute rejection are similar to the patterns in human allografts. These observations in a xenotransplantation model support the body of evidence suggesting that circulating cfDNA is a marker of tissue injury., (Copyright © 2018. Published by Elsevier Inc.)
- Published
- 2018
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19. CD4+CD25 Hi FoxP3+ regulatory T cells in long-term cardiac xenotransplantation.
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Singh AK, Chan JL, Seavey CN, Corcoran PC, Hoyt RF Jr, Lewis BGT, Thomas ML, Ayares DL, Horvath KA, and Mohiuddin MM
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- Animals, Animals, Genetically Modified, Forkhead Transcription Factors immunology, Graft Rejection drug therapy, Graft Rejection immunology, Graft Survival immunology, Immune Tolerance, Immunosuppression Therapy methods, Immunosuppressive Agents pharmacology, Papio, Swine, Heart Transplantation methods, Heterografts immunology, T-Lymphocytes, Regulatory immunology, Time, Transplantation, Heterologous methods
- Abstract
Background: CD4+CD25
Hi FoxP3+ T (Treg) cells are a small subset of CD4+ T cells that have been shown to exhibit immunoregulatory function. Although the absolute number of Treg cells in peripheral blood lymphocytes (PBL) is very small, they play an important role in suppressing immune reactivity. Several studies have demonstrated that the number of Treg cells, rather than their intrinsic suppressive capacity, may contribute to determining the long-term fate of transplanted grafts. In this study, we analyzed Treg cells in PBL of long-term baboon recipients who have received genetically modified cardiac xenografts from pig donors., Methods: Heterotopic cardiac xenotransplantation was performed on baboons using hearts obtained from GTKO.hCD46 (n = 8) and GTKO.hCD46.TBM (n = 5) genetically modified pigs. Modified immunosuppression regimen included antithymocyte globulin (ATG), anti-CD20, mycophenolate mofetil (MMF), cobra venom factor (CVF), and costimulation blockade (anti-CD154/anti-CD40 monoclonal antibody). FACS analysis was performed on PBLs labeled with anti-human CD4, CD25, and FoxP3 monoclonal antibodies (mAb) to analyze the percentage of Treg cells in six baboons that survived longer than 2 months (range: 42-945 days) after receiving a pig cardiac xenograft., Results: Total WBC count was low due to immunosuppression in baboons who received cardiac xenograft from GTKO.hCD46 and GTKO.hCD46.hTBM donor pigs. However, absolute numbers of CD4+CD25Hi FoxP3 Treg cells in PBLs of long-term xenograft cardiac xenograft surviving baboon recipients were found to be increased (15.13 ± 1.50 vs 7.38 ± 2.92; P < .018) as compared to naïve or pre-transplant baboons. Xenograft rejection in these animals was correlated with decreased numbers of regulatory T cells., Conclusion: Our results suggest that regulatory T (Treg) cells may contribute to preventing or delaying xenograft rejection by controlling the activation and expansion of donor-reactive T cells, thereby masking the antidonor immune response, leading to long-term survival of cardiac xenografts., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)- Published
- 2018
- Full Text
- View/download PDF
20. Heart xenotransplantation.
- Author
-
Chan JL and Mohiuddin MM
- Subjects
- Animals, Humans, Graft Survival, Heart Transplantation methods, Immunosuppression Therapy methods, Transplantation, Heterologous methods
- Abstract
Purpose of Review: Cardiac xenotransplantation has entered an exciting era, marked by numerous considerable advances in the field, and continues to be of great interest because of its potential ability in ameliorating the current constraints of limited allograft availability. This review aims to examine recent progress in this rapidly changing discipline., Recent Findings: Although several hurdles remain, the use of rapidly evolving transgenic technology, in combination with novel immunosuppression regimens, has the potential to address current allogenic donor pool constraints and mechanical circulatory system device limitations. Furthermore, innovative uses of biomarker tools, such as miRNA, serve as a method for improved monitoring of xenograft status. These tools may allow for more targeted immunosuppressive strategies as well as earlier interventions to mitigate xenograft rejection. Finally, coinciding with these remarkable advances, preliminary consideration of the clinical application for cardiac xenotransplantation has begun, particularly regarding specific patient criteria for these initial clinical trials., Summary: The studies in this review highlight efforts in multiple disciplines to optimize perioperative and postxenotransplant outcomes. In examining these individual topics, this article reflects the exciting and ongoing progress in the field of cardiac xenotransplantation.
- Published
- 2017
- Full Text
- View/download PDF
21. Encouraging experience using multi-transgenic xenografts in a pig-to-baboon cardiac xenotransplantation model.
- Author
-
Chan JL, Singh AK, Corcoran PC, Thomas ML, Lewis BG, Ayares DL, Vaught T, Horvath KA, and Mohiuddin MM
- Subjects
- Animals, Animals, Genetically Modified genetics, Animals, Genetically Modified immunology, Graft Survival immunology, Immunosuppression Therapy methods, Papio metabolism, Papio hamadryas, Swine, Transplantation, Heterotopic methods, Graft Rejection immunology, Heart Transplantation methods, Heterografts immunology, Immunosuppressive Agents pharmacology, Transplantation, Heterologous methods
- Abstract
Background: Innovations in transgenic technology have facilitated improved xenograft survival. Additional gene expression appears to be necessary to overcome the remaining immune and biologic incompatibilities. We report for the first time the novel use of six-gene modifications within a pig-to-baboon cardiac xenotransplantation model., Methods: Baboons (8-15 kg) underwent heterotopic cardiac transplantation using xenografts obtained from genetically engineered pigs. Along with previously described modifications (GTKO, hCD46), additional expression of human transgenes for thromboregulation (endothelial protein C receptor, tissue factor pathway inhibitor, thrombomodulin), complement inhibition (decay accelerating factor), and cellular immune suppression (hCD39, hCD47) was used. Immunosuppression consisted of targeted T-cell and B-cell depletion and conventional anti-rejection agents., Results: Heterotopic cardiac transplantations were performed without complication. Flow cytometry and immunohistochemistry on donor biopsies confirmed transgenic phenotype. In contrast to the prior three-gene generation, significant coagulopathy or consumptive thrombocytopenia has not been observed in the six-gene cohort. As a result, these recipients have experienced decreased bleeding-related complications. Pro-inflammatory responses also appear to be mitigated based on cytokine analysis. Baboons survived the critical 30-day post-operative period when mortality has historically been highest, with no evidence of graft rejection., Conclusions: The inclusion of additional human genes in genetically engineered pigs appears to confer superior xenograft outcomes. Introduction of these genes has not been associated with adverse outcomes. This multifactorial approach to genetic engineering furthers the prospect of long-term cardiac xenograft survival and subsequent clinical application., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
- Full Text
- View/download PDF
22. Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft.
- Author
-
Mohiuddin MM, Singh AK, Corcoran PC, Thomas Iii ML, Clark T, Lewis BG, Hoyt RF, Eckhaus M, Pierson Iii RN, Belli AJ, Wolf E, Klymiuk N, Phelps C, Reimann KA, Ayares D, and Horvath KA
- Subjects
- Animals, Animals, Genetically Modified, Antilymphocyte Serum pharmacology, CD40 Antigens antagonists & inhibitors, CD40 Antigens genetics, CD40 Antigens immunology, Female, Galactosyltransferases deficiency, Galactosyltransferases genetics, Galactosyltransferases immunology, Gene Expression, Humans, Male, Membrane Cofactor Protein genetics, Membrane Cofactor Protein immunology, Mycophenolic Acid analogs & derivatives, Mycophenolic Acid pharmacology, Papio, Rituximab pharmacology, Swine, Thrombomodulin genetics, Thrombomodulin immunology, Transgenes, Transplantation, Heterologous, Antibodies pharmacology, Graft Survival drug effects, Heart Transplantation, Immunologic Factors pharmacology, Immunotherapy methods
- Abstract
Preventing xenograft rejection is one of the greatest challenges of transplantation medicine. Here, we describe a reproducible, long-term survival of cardiac xenografts from alpha 1-3 galactosyltransferase gene knockout pigs, which express human complement regulatory protein CD46 and human thrombomodulin (GTKO.hCD46.hTBM), that were transplanted into baboons. Our immunomodulatory drug regimen includes induction with anti-thymocyte globulin and αCD20 antibody, followed by maintenance with mycophenolate mofetil and an intensively dosed αCD40 (2C10R4) antibody. Median (298 days) and longest (945 days) graft survival in five consecutive recipients using this regimen is significantly prolonged over our recently established survival benchmarks (180 and 500 days, respectively). Remarkably, the reduction of αCD40 antibody dose on day 100 or after 1 year resulted in recrudescence of anti-pig antibody and graft failure. In conclusion, genetic modifications (GTKO.hCD46.hTBM) combined with the treatment regimen tested here consistently prevent humoral rejection and systemic coagulation pathway dysregulation, sustaining long-term cardiac xenograft survival beyond 900 days.
- Published
- 2016
- Full Text
- View/download PDF
23. Current status of pig heart xenotransplantation.
- Author
-
Mohiuddin MM, Reichart B, Byrne GW, and McGregor CGA
- Subjects
- Animals, Immunosuppression Therapy methods, Swine immunology, Graft Survival immunology, Heart Transplantation methods, Papio immunology, Swine genetics, Transplantation, Heterologous methods
- Abstract
Significant progress in understanding and overcoming cardiac xenograft rejection using a clinically relevant large animal pig-to-baboon model has accelerated in recent years. This advancement is based on improved immune suppression, which attained more effective regulation of B lymphocytes and possibly newer donor genetics. These improvements have enhanced heterotopic cardiac xenograft survival from a few weeks to over 2 years, achieved intrathoracic heterotopic cardiac xenograft survival of 50 days and orthotopic survival of 57 days. This encouraging progress has rekindled interest in xenotransplantation research and refocused efforts on preclinical orthotopic cardiac xenotransplantation., (Copyright © 2015 IJS Publishing Group Limited. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
24. Genetically engineered pigs and target-specific immunomodulation provide significant graft survival and hope for clinical cardiac xenotransplantation.
- Author
-
Mohiuddin MM, Singh AK, Corcoran PC, Hoyt RF, Thomas ML 3rd, Ayares D, and Horvath KA
- Subjects
- Animals, Animals, Genetically Modified, Animals, Newborn, Drug Therapy, Combination, Galactosyltransferases genetics, Galactosyltransferases immunology, Graft Rejection genetics, Graft Rejection immunology, Graft Rejection metabolism, Humans, Immunosuppressive Agents pharmacology, Membrane Cofactor Protein genetics, Membrane Cofactor Protein immunology, Myocardial Contraction, Papio, Swine, Thrombomodulin genetics, Thrombomodulin immunology, Time Factors, Transplantation, Heterologous, Ventricular Function, Left, Ventricular Pressure, Galactosyltransferases deficiency, Graft Rejection prevention & control, Graft Survival drug effects, Heart Transplantation adverse effects, Membrane Cofactor Protein metabolism, Thrombomodulin metabolism
- Abstract
Objectives: Cardiac transplantation and available mechanical alternatives are the only possible solutions for end-stage cardiac disease. Unfortunately, because of the limited supply of human organs, xenotransplantation may be the ideal method to overcome this shortage. We have recently seen significant prolongation of heterotopic cardiac xenograft survival from 3 to 12 months and beyond., Methods: Hearts from genetically engineered piglets that were alpha 1-3 galactosidase transferase knockout and expressed the human complement regulatory gene, CD46 (groups A-C), and the human thrombomodulin gene (group D) were heterotropically transplanted in baboons treated with antithymocyte globulin, cobra venom factor, anti-CD20 antibody, and costimulation blockade (anti-CD154 antibody [clone 5C8]) in group A, anti-CD40 antibody (clone 3A8; 20 mg/kg) in group B, clone 2C10R4 (25 mg/kg) in group C, or clone 2C10R4 (50 mg/kg) in group D, along with conventional nonspecific immunosuppressive agents., Results: Group A grafts (n = 8) survived for an average of 70 days, with the longest survival of 236 days. Some animals in this group (n = 3) developed microvascular thrombosis due to platelet activation and consumption, which resulted in spontaneous hemorrhage. The median survival time was 21 days in group B (n = 3), 80 days in group C (n = 6), and more than 200 days in group D (n = 5). Three grafts in group D are still contracting well, with the longest ongoing graft survival surpassing the 1-year mark., Conclusions: Genetically engineered pig hearts (GTKOhTg.hCD46.hTBM) with modified targeted immunosuppression (anti-CD40 monoclonal antibody) achieved long-term cardiac xenograft survival. This potentially paves the way for clinical xenotransplantation if similar survival can be reproduced in an orthotopic transplantation model., (Copyright © 2014 The American Association for Thoracic Surgery. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
25. Cutting edge: transplant tolerance induced by anti-CD45RB requires B lymphocytes.
- Author
-
Deng S, Moore DJ, Huang X, Lian MM, Mohiuddin M, Velededeoglu E, Lee MK 4th, Sonawane S, Kim J, Wang J, Chen H, Corfe SA, Paige C, Shlomchik M, Caton A, and Markmann JF
- Subjects
- Animals, Antibodies, Monoclonal physiology, B-Lymphocyte Subsets cytology, B-Lymphocyte Subsets transplantation, Cell Communication genetics, Cell Communication immunology, Cell Proliferation, Immunophenotyping, Leukocyte Common Antigens biosynthesis, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Transplantation Tolerance genetics, Antibodies, Monoclonal administration & dosage, B-Lymphocyte Subsets immunology, Heart Transplantation immunology, Leukocyte Common Antigens immunology, Transplantation Tolerance immunology
- Abstract
Selective interference with the CD45RB isoform by mAb (anti-CD45RB) reliably induces donor-specific tolerance. Although previous studies suggest participation of regulatory T cells, a mechanistic understanding of anti-CD45RB-induced tolerance is lacking. We report herein the unexpected finding that tolerance induced by this agent is not established in B cell-deficient mice but can be recovered by preemptive B lymphocyte transfer to B cell-deficient hosts. Using B cells from genetically modified donors to reconstitute B cell-deficient recipients, we evaluate the role of B lymphocyte-expressed CD45RB, T cell costimulatory molecules, and the production of Abs in this novel tolerance mechanism. Our data document an Ab-induced tolerance regimen that is uniquely B lymphocyte-dependent and suggest mechanistic contributions to tolerance development from the B cell compartment through interactions with T cells.
- Published
- 2007
- Full Text
- View/download PDF
26. Mouse-heart grafts expressing an incompatible carbohydrate antigen. II. Transition from accommodation to tolerance.
- Author
-
Ogawa H, Mohiuddin MM, Yin DP, Shen J, Chong AS, and Galili U
- Subjects
- Adoptive Transfer, Animals, B-Lymphocytes cytology, B-Lymphocytes immunology, B-Lymphocytes transplantation, Cell Differentiation, Immune Tolerance, Immunization, Immunologic Memory, Kidney immunology, Kidney metabolism, Membranes immunology, Membranes metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Swine, Time Factors, Epitopes, Galactosyltransferases immunology, Heart Transplantation, Histocompatibility, Myocardium metabolism
- Abstract
Background: Immune response to incompatible ABO antigens on allografts may result in rejection, accommodation, or immune tolerance. Our objective has been to develop a model for studying these three types of immune response to incompatible carbohydrate antigen in alpha1,3-galactosyltransferase knockout (KO) mice. KO mice lack the alpha-gal epitope and can produce the anti-Gal antibody against it after immunization with pig kidney membranes (PKM) that express this epitope., Methods: KO mice were transplanted with syngeneic wild-type (WT) heart expressing alpha-gal epitopes. Subsequently, the mice were lethally irradiated and received lymphocytes including memory anti-Gal B cells from PKM immunized KO mice. Immune response to incompatible alpha-gal epitopes on the graft was determined by transplanted-heart function and by production of anti-Gal after PKM immunizations., Results: Anti-Gal B cells exposed for 1 to 2 weeks to alpha-gal epitopes of WT hearts differentiate into cells producing noncytolytic accommodating antibodies. Exposure for longer periods (2-4 weeks) induces a transition from accommodation into tolerance, indicated by the inability of mice to produce anti-Gal antibodies despite repeated PKM immunizations. WT hearts in accommodating and in tolerized mice continue to function for months., Conclusions: In the absence of T-cell help, anticarbohydrate B cells exposed to incompatible carbohydrate antigens of transplanted organs differentiate first into cells capable of producing accommodating antibodies, but, after prolonged exposure, these B cells gradually become tolerized. These findings suggest that prolonged T-cell suppression in recipients of ABO-incompatible allografts may result in a similar induction of tolerance to incompatible blood-group antigens.
- Published
- 2004
- Full Text
- View/download PDF
27. Antibody-mediated accommodation of heart grafts expressing an incompatible carbohydrate antigen.
- Author
-
Mohiuddin MM, Ogawa H, Yin DP, Shen J, and Galili U
- Subjects
- Adoptive Transfer, Animals, B-Lymphocytes immunology, Carbohydrate Sequence, Epitopes immunology, Female, Graft Rejection immunology, Immunoglobulin G immunology, Immunologic Memory, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Multiple Myeloma, Tumor Cells, Cultured, Galactose immunology, Galactosyltransferases genetics, Heart Transplantation immunology
- Abstract
Background: Accommodation in patients transplanted with ABO incompatible allografts describes a state in which antibodies are produced against the incompatible blood group carbohydrate antigen; however, the graft is not rejected. The present study describes an experimental model for antibody-mediated accommodation of organs expressing incompatible carbohydrate antigens., Methods: The model includes alpha1,3galactosyltransferase knockout mice that lack the alpha-gal epitope (Galalpha1-3Galbeta1-4GlcNAc-R), transplanted heterotopically with wild-type (WT) hearts expressing this epitope. The mice are irradiated and receive memory anti-Gal B cells by adoptive transfer. Immunization of these mice with pig-kidney membranes induces the production of large amounts of anti-Gal, which binds specifically to alpha-gal epitopes., Results: Under the described accommodation protocol, transplanted mice produce anti-Gal that binds to alpha-gal epitopes on endothelial cells of the grafted WT heart; however, the WT hearts continued to function for months. Second WT hearts transplanted into accommodating, anti-Gal producing mice, were not rejected. Anti-Gal in accommodating mice was not cytolytic, whereas anti-Gal in rejecting mice readily induced complement-mediated lysis of cells expressing alpha-gal epitopes. In addition, accommodating mice displayed a preferential increase in the anti-Gal immunoglobulin (Ig)G2b subclass., Conclusions: The immune system may be manipulated to accommodate grafts expressing incompatible carbohydrate antigens by preferential production of noncytolytic anticarbohydrate antibodies.
- Published
- 2003
- Full Text
- View/download PDF
28. CD4+CD25HiFoxP3+ regulatory T cells in long‐term cardiac xenotransplantation.
- Author
-
Singh, Avneesh K., Chan, Joshua L., Seavey, Caleb N., Corcoran, Philip C., Hoyt, Jr, Robert F., Lewis, Billeta G. T., Thomas, Marvin L., Ayares, David L., Horvath, Keith A., and Mohiuddin, Muhammad M.
- Subjects
T cells ,IMMUNOSUPPRESSION ,COBRA venom factor ,XENOGRAFTS ,HEART transplantation - Abstract
Abstract: Background: CD4+CD25
Hi FoxP3+ T (Treg) cells are a small subset of CD4+ T cells that have been shown to exhibit immunoregulatory function. Although the absolute number of Treg cells in peripheral blood lymphocytes (PBL) is very small, they play an important role in suppressing immune reactivity. Several studies have demonstrated that the number of Treg cells, rather than their intrinsic suppressive capacity, may contribute to determining the long‐term fate of transplanted grafts. In this study, we analyzed Treg cells in PBL of long‐term baboon recipients who have received genetically modified cardiac xenografts from pig donors. Methods: Heterotopic cardiac xenotransplantation was performed on baboons using hearts obtained from GTKO.hCD46 (n = 8) and GTKO.hCD46.TBM (n = 5) genetically modified pigs. Modified immunosuppression regimen included antithymocyte globulin (ATG), anti‐CD20, mycophenolate mofetil (MMF), cobra venom factor (CVF), and costimulation blockade (anti‐CD154/anti‐CD40 monoclonal antibody). FACS analysis was performed on PBLs labeled with anti‐human CD4, CD25, and FoxP3 monoclonal antibodies (mAb) to analyze the percentage of Treg cells in six baboons that survived longer than 2 months (range: 42‐945 days) after receiving a pig cardiac xenograft. Results: Total WBC count was low due to immunosuppression in baboons who received cardiac xenograft from GTKO.hCD46 and GTKO.hCD46.hTBM donor pigs. However, absolute numbers of CD4+CD25Hi FoxP3 Treg cells in PBLs of long‐term xenograft cardiac xenograft surviving baboon recipients were found to be increased (15.13 ± 1.50 vs 7.38 ± 2.92;P < .018) as compared to naïve or pre‐transplant baboons. Xenograft rejection in these animals was correlated with decreased numbers of regulatory T cells. Conclusion: Our results suggest that regulatory T (Treg) cells may contribute to preventing or delaying xenograft rejection by controlling the activation and expansion of donor‐reactive T cells, thereby masking the antidonor immune response, leading to long‐term survival of cardiac xenografts. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
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