scholarly journals Chimerism-Based Experimental Models for Tolerance Induction in Vascularized Composite Allografts: Cleveland Clinic Research Experience

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Maria Siemionow ◽  
Aleksandra Klimczak
Keyword(s):  
Current Knowledge ◽  
Cleveland Clinic ◽  
Experimental Studies ◽  
Tolerance Induction ◽  
Experimental Models ◽  
Successful Outcome ◽  
Large Animal ◽  
Research Experience ◽  
Widespread Application ◽  
Large Animal Models

The preclinical experimental models of vascularized composite allografts (VCAs) have been rapidly developed for the assessment of immunomodulatory protocols for clinical application. Recently, researchers have focused on immunomodulatory protocols which overcome the immunologic barrier between the allogeneic donor and recipient and may lead to tolerance induction. In order to test the feasibility of chimerism induction, experimental VCAs have been performed in different models including rodents, large animals, and nonhuman primates. These models differ in the complexity of transplanted tissue and in their responses to immunomodulatory protocols. In most applications, VCA contains multiple-tissue components; however, each individual component of CTA possesses unique immunologic characteristics that ultimately contribute to the chimerism induction and successful outcome of the VCA. Heterogenic character and complexity of tissue components in different VCA models determine the quality and robustness of donor-specific chimerism. As introduced in experimental studies, variable immunomodulatory options have been studied to achieve tolerance to VCA in rodents and large animal models allowing for widespread application in clinic. In this paper, based on our own experience, we have analyzed the current knowledge of tolerance-inducing strategies via chimerism induction in VCA experimental models in the context of immunomodulatory protocols and VCA complexity and their relevance and applicability to clinical practice.

Immunodepletive anti-α/β-TCR antibody in transplantation of composite tissue allografts: Cleveland Clinic research experience

Immunotherapy ◽  
2009 ◽  
Vol 1 (4) ◽  
pp. 585-598
Author(s):  
Maria Siemionow ◽  
Aleksandra Klimczak
Keyword(s):  
T Cell ◽  
Cleveland Clinic ◽  
Experimental Studies ◽  
Tolerance Induction ◽  
Selective Inhibition ◽  
Experimental Models ◽  
Research Experience ◽  
Antilymphocyte Serum ◽  
Composite Tissue ◽  
Clinical Transplantation

The immunologic characteristics of composite tissue allografts (CTA), which contain skin, lymphoid elements and bone with bone marrow, raise new challenges for transplant immunologists. Owing to the heterogeneity of transplanted tissues in limb or face transplant models, researchers are focusing on the new tolerance-inducing strategies facilitating CTA acceptance. A number of immunosuppressive protocols have been designed to develop tolerance in experimental models; however, only a few protocols have been introduced to clinical transplantation. In this review, based on own experiences, we discuss the major strategies for tolerance induction in limb and face allograft models in experimental studies. This review is focused on tolerance induction strategies by establishment of donor-specific chimerism using different immunomodulatory protocols, including nonselective T-cell depletion with polyclonal antibody antilymphocyte serum and selective inhibition of αβ-T-cell receptors on the alloreactive T cells.

scholarly journals Clinical and preclinical tolerance protocols for vascularized composite allograft transplantation

2021 ◽  
Vol 48 (6) ◽  
pp. 703-713
Author(s):  
Jerry Huanda Yang ◽  
Ariel C. Johnson ◽  
Salih Colakoglu ◽  
Christene A. Huang ◽  
David Woodbridge Mathes
Keyword(s):  
Radiation Treatment ◽  
Immunosuppressive Treatment ◽  
Tolerance Induction ◽  
Human Leukocyte ◽  
Donor Cell ◽  
Large Animal ◽  
Valuable Insight ◽  
Widespread Application ◽  
Large Animal Models ◽  
Vascularized Composite Allograft

The field of vascularized composite allografts (VCAs) has undergone significant advancement in recent decades, and VCAs are increasingly common and accepted in the clinical setting, bringing hope of functional recovery to patients with debilitating injuries. A major obstacle facing the widespread application of VCAs is the side effect profile associated with the current immunosuppressive regimen, which can cause a wide array of complications such as infection, malignancy, and even death. Significant concerns remain regarding whether the treatment outweighs the risk. The potential solution to this dilemma would be achieving VCA tolerance, which would allow recipients to receive allografts without significant immunosuppression and its sequelae. Promising tolerance protocols are being studied in kidney transplantation; four major trials have attempted to withdraw immunosuppressive treatment with various successes. The common theme in all four trials is the use of radiation treatment and donor cell transplantation. The knowledge gained from these trials can provide valuable insight into the development of a VCA tolerance protocol. Despite similarities, VCAs present additional barriers compared to kidney allografts regarding tolerance induction. VCA donors are likely to be deceased, which limits the time for significant pre-conditioning. VCA donors are also more likely to be human leukocyte antigen–mismatched, which means that tolerance must be induced across major immunological barriers. This review also explores adjunct therapies studied in large animal models that could be the missing element in establishing a safe and stable tolerance induction method.

scholarly journals Large Animal Models of Vascularized Composite Allotransplantation: A Review of Immune Strategies to Improve Allograft Outcomes

2021 ◽  
Vol 12 ◽  
Author(s):  
Abraham J. Matar ◽  
Rebecca L. Crepeau ◽  
Gerhard S. Mundinger ◽  
Curtis L. Cetrulo ◽  
Radbeh Torabi
Keyword(s):  
Animal Models ◽  
Ex Vivo ◽  
Solid Organ Transplantation ◽  
Tolerance Induction ◽  
Large Animal ◽  
Solid Organ ◽  
Large Animal Models ◽  
Large Animals ◽  
And Function ◽  
Made In

Over the past twenty years, significant technical strides have been made in the area of vascularized composite tissue allotransplantation (VCA). As in solid organ transplantation, the allogeneic immune response remains a significant barrier to long-term VCA survival and function. Strategies to overcome acute and chronic rejection, minimize immunosuppression and prolong VCA survival have important clinical implications. Historically, large animals have provided a valuable model for testing the clinical translatability of immune modulating approaches in transplantation, including tolerance induction, co-stimulation blockade, cellular therapies, and ex vivo perfusion. Recently, significant advancements have been made in these arenas utilizing large animal VCA models. In this comprehensive review, we highlight recent immune strategies undertaken to improve VCA outcomes with a focus on relevant preclinical large animal models.

scholarly journals Large animal models of stroke and traumatic brain injury as translational tools

2018 ◽  
Vol 315 (2) ◽  
pp. R165-R190 ◽  
Author(s):  
Annabel J. Sorby-Adams ◽  
Robert Vink ◽  
Renée J. Turner
Keyword(s):  
Traumatic Brain Injury ◽  
Ischemic Stroke ◽  
Brain Injury ◽  
Animal Models ◽  
Animal Species ◽  
Experimental Models ◽  
Clinical Translation ◽  
Large Animal ◽  
Large Animal Models ◽  
Significant Burden

Acute central nervous system injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide. Studies in animal models have greatly enhanced our understanding of the complex pathophysiology that underlies TBI and stroke and enabled the preclinical screening of over 1,000 novel therapeutic agents. Despite this, the translation of novel therapeutics from experimental models to clinical therapies has been extremely poor. One potential explanation for this poor clinical translation is the choice of experimental model, given that the majority of preclinical TBI and ischemic stroke studies have been conducted in small animals, such as rodents, which have small lissencephalic brains. However, the use of large animal species such as nonhuman primates, sheep, and pigs, which have large gyrencephalic human-like brains, may provide an avenue to improve clinical translation due to similarities in neuroanatomical structure when compared with widely adopted rodent models. This purpose of this review is to provide an overview of large animal models of TBI and ischemic stroke, including the surgical considerations, key benefits, and limitations of each approach.

scholarly journals Chronic Thromboembolic Pulmonary Hypertension – What Have We Learned From Large Animal Models

2021 ◽  
Vol 8 ◽  
Author(s):  
Kelly Stam ◽  
Sebastian Clauss ◽  
Yannick J. H. J. Taverne ◽  
Daphne Merkus
Keyword(s):  
Pulmonary Hypertension ◽  
Animal Models ◽  
Current Knowledge ◽  
Pulmonary Arteries ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Large Animal ◽  
Large Animal Models ◽  
Microvascular Remodeling ◽  
Thromboembolic Pulmonary Hypertension ◽  
The Right

Chronic thrombo-embolic pulmonary hypertension (CTEPH) develops in a subset of patients after acute pulmonary embolism. In CTEPH, pulmonary vascular resistance, which is initially elevated due to the obstructions in the larger pulmonary arteries, is further increased by pulmonary microvascular remodeling. The increased afterload of the right ventricle (RV) leads to RV dilation and hypertrophy. This RV remodeling predisposes to arrhythmogenesis and RV failure. Yet, mechanisms involved in pulmonary microvascular remodeling, processes underlying the RV structural and functional adaptability in CTEPH as well as determinants of the susceptibility to arrhythmias such as atrial fibrillation in the context of CTEPH remain incompletely understood. Several large animal models with critical clinical features of human CTEPH and subsequent RV remodeling have relatively recently been developed in swine, sheep, and dogs. In this review we will discuss the current knowledge on the processes underlying development and progression of CTEPH, and on how animal models can help enlarge understanding of these processes.

scholarly journals Evolution of the rat hind limb transplant as an experimental model of vascularized composite allotransplantation: Approaches and advantages

2020 ◽  
Vol 8 ◽  
pp. 205031212096872
Author(s):  
Yoram Y Fleissig ◽  
Jason E Beare ◽  
Amanda J LeBlanc ◽  
Christina L Kaufman
Keyword(s):  
Upper Extremity ◽  
Hind Limb ◽  
Large Body ◽  
Surgical Techniques ◽  
Experimental Models ◽  
Tissue Loss ◽  
Large Animal ◽  
Solid Organ ◽  
Vascularized Composite Allotransplantation ◽  
Large Animal Models

As clinical experience with surgical techniques and immunosuppression in vascularized composite allotransplantation recipients has accumulated, vascularized composite allotransplantation for hand and face have become standard of care in some countries for select patients who have experienced catastrophic tissue loss. Experience to date suggests that clinical vascularized composite allotransplantation grafts undergo the same processes of allograft rejection as solid organ grafts. Nonetheless, there are some distinct differences, especially with respect to the immunologic influence of the skin and how the graft is affected by environmental and traumatic insults. Understanding the mechanisms around these similarities and differences has the potential to not only improve vascularized composite allotransplantation outcomes but also outcomes for all types of transplants and to contribute to our understanding of how complex systems of immunity and function work together. A distinct disadvantage in the study of upper extremity vascularized composite allotransplantation recipients is the low number of clinical transplants performed each year. As upper extremity transplantation is a quality of life rather than a lifesaving transplant, these numbers are not likely to increase significantly until the risks of systemic immunosuppression can be reduced. As such, experimental models of vascularized composite allotransplantation are essential to test hypotheses regarding unique characteristics of graft rejection and acceptance of vascularized composite allotransplantation allografts. Rat hind limb vascularized composite allotransplantation models have been widely used to address these questions and provide essential proof-of-concept findings which can then be extended to other experimental models, including mice and large animal models, as new concepts are translated to the clinic. Here, we review the large body of rat hind limb vascularized composite allotransplantation models in the literature, with a focus on the various surgical models that have been developed, contrasting the characteristics of the specific model and how they have been applied. We hope that this review will assist other researchers in choosing the most appropriate rat hind limb transplantation model for their scientific interests.

scholarly journals A scalable, clinically severe pig model for Duchenne muscular dystrophy

2021 ◽  
Author(s):  
Michael Stirm ◽  
Lina Marie Fonteyne ◽  
Bachuki Shashikadze ◽  
Magdalena Lindner ◽  
Maila Chirivi ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Connexin 43 ◽  
Experimental Studies ◽  
Treatment Strategies ◽  
Diagnostic Procedures ◽  
Left Ventricular ◽  
Large Animal ◽  
Large Animal Models ◽  
Disease Mechanisms

Large animal models for Duchenne muscular dystrophy (DMD) are crucial for preclinical evaluation of novel diagnostic procedures and treatment strategies. Pigs cloned from male cells lacking DMD exon 52 (DMDΔ52) resemble molecular, clinical and pathological hallmarks of DMD, but cannot be propagated by breeding due to death before sexual maturity. Therefore, female DMD+/- carriers were generated. A single founder animal had 11 litters with 29 DMDY/-, 34 DMD+/- as well as 36 male and 29 female wild-type (WT) offspring. Breeding with F1 and F2 DMD+/- carriers resulted in additional 114 DMDY/- piglets. The majority of them survived for 3-4 months, providing large cohorts for experimental studies. Pathological investigations and proteome studies of skeletal muscles and myocardium confirmed the resemblance of human disease mechanisms. Importantly, DMDY/- pigs reveal progressive fibrosis of myocardium and increased expression of connexin-43, associated with significantly reduced left ventricular fractional shortening and ejection fraction already at age 3 months. Furthermore, behavioral tests provided evidence for impaired cognitive ability of DMDY/- pigs. Our breeding cohort of DMDΔ52 pigs and standardized tissue repositories from DMDY/- pigs, DMD+/- carriers, and WT littermate controls provide important resources for studying DMD disease mechanisms and for testing novel diagnostic procedures and treatment strategies.

scholarly journals Mixed chimerism

2001 ◽  
Vol 356 (1409) ◽  
pp. 707-726 ◽  
Author(s):  
Megan Sykes ◽  
David H. Sachs
Keyword(s):  
Lymphocyte Subsets ◽  
Tolerance Induction ◽  
Mixed Chimerism ◽  
Large Animal ◽  
Rodent Models ◽  
Cell Type ◽  
Potential Toxicity ◽  
Large Animal Models ◽  
Conditioning Regimens ◽  
Made In

Induction of mixed chimerism has the potential to overcome the current limitations of transplantation, namely chronic rejection, complications of immunosuppressive therapy and the need for xenografts to overcome the current shortage of allogeneic organs. Successful achievement of mixed chimerism had been shown to tolerize T cells, B cells and possibly natural killer cells, the lymphocyte subsets that pose major barriers to allogeneic and xenogeneic transplants. Current understanding of the mechanisms involved in tolerization of each cell type is reviewed. Considerable advances have been made in reducing the potential toxicity of conditioning regimens required for the induction of mixed chimerism in rodent models, and translation of these strategies to large animal models and in a patient are important advances toward more widespread clinical application of the mixed chimerism approach for tolerance induction.

scholarly journals Cellular Senescence in the Kidney

2019 ◽  
Vol 30 (5) ◽  
pp. 726-736 ◽  
Author(s):  
Marie-Helena Docherty ◽  
Eoin D. O’Sullivan ◽  
Joseph V. Bonventre ◽  
David A. Ferenbach
Keyword(s):  
Kidney Development ◽  
Current Knowledge ◽  
Experimental Studies ◽  
Human Kidney ◽  
Experimental Models ◽  
Cell Manipulation ◽  
Future Research ◽  
Transplant Failure ◽  
Secretory Phenotype

Senescent cells have undergone permanent growth arrest, adopt an altered secretory phenotype, and accumulate in the kidney and other organs with ageing and injury. Senescence has diverse physiologic roles and experimental studies support its importance in nephrogenesis, successful tissue repair, and in opposing malignant transformation. However, recent murine studies have shown that depletion of chronically senescent cells extends healthy lifespan and delays age-associated disease—implicating senescence and the senescence-associated secretory phenotype as drivers of organ dysfunction. Great interest is therefore focused on the manipulation of senescence as a novel therapeutic target in kidney disease. In this review, we examine current knowledge and areas of ongoing uncertainty regarding senescence in the human kidney and experimental models. We summarize evidence supporting the role of senescence in normal kidney development and homeostasis but also senescence-induced maladaptive repair, renal fibrosis, and transplant failure. Recent studies using senescent cell manipulation and depletion as novel therapies to treat renal disease are discussed, and we explore unanswered questions for future research.

scholarly journals A Versatile Hermetically Sealed Microelectronic Implant for Peripheral Nerve Stimulation Applications

2021 ◽  
Vol 15 ◽  
Author(s):  
Dai Jiang ◽  
Fangqi Liu ◽  
Henry T. Lancashire ◽  
Timothy A. Perkins ◽  
Matthew Schormans ◽  
...  
Keyword(s):  
High Speed ◽  
Experimental Studies ◽  
Accelerated Aging ◽  
Cmos Technology ◽  
Electrical Performance ◽  
Radio Link ◽  
Large Animal ◽  
Large Animal Models ◽  
Aging Conditions

This article presents a versatile neurostimulation platform featuring a fully implantable multi-channel neural stimulator for chronic experimental studies with freely moving large animal models involving peripheral nerves. The implant is hermetically sealed in a ceramic enclosure and encapsulated in medical grade silicone rubber, and then underwent active tests at accelerated aging conditions at 100°C for 15 consecutive days. The stimulator microelectronics are implemented in a 0.6-μm CMOS technology, with a crosstalk reduction scheme to minimize cross-channel interference, and high-speed power and data telemetry for battery-less operation. A wearable transmitter equipped with a Bluetooth Low Energy radio link, and a custom graphical user interface provide real-time, remotely controlled stimulation. Three parallel stimulators provide independent stimulation on three channels, where each stimulator supports six stimulating sites and two return sites through multiplexing, hence the implant can facilitate stimulation at up to 36 different electrode pairs. The design of the electronics, method of hermetic packaging and electrical performance as well as in vitro testing with electrodes in saline are presented.

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