Tolerogenic therapies in transplantation

Page, Eugenia K.; Dar, Wasim; Knechtle, Stuart J.

doi:10.3389/fimmu.2012.00198

Cited by 64 publications

(54 citation statements)

References 180 publications

(198 reference statements)

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“…An important component of immune defenses against bacteria is a repertoire of germline “natural antibodies” that have affinity for non-protein bacterial epitopes such as carbohydrates. 16,17 These antibodies are produced in the absence of T-cell stimulation early in the course of infection, with the best-characterized Gram-positive responses against cell wall epitopes such as poly-N-acetylglucosamine (PNAG) and capsular polysaccharide (CP) teichoic acids from Staphylococcus species 18,19 and Streptococcus pneumoniae . 20 In addition, CPs are an important component of several bacterial vaccines, 21 and opsonizing antibodies targeting polysaccharides have been investigated as therapeutic agents for Burkholderia dolosa 22 and S. aureus .…”

Section: Introductionmentioning

confidence: 99%

Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

Fong¹,

Kajihara²,

Chen³

et al. 2018

mAbs

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Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a growing health threat worldwide. Efforts to identify novel antibodies that target S. aureus cell surface antigens are a promising direction in the development of antibiotics that can halt MRSA infection. We biochemically and structurally characterized three patient-derived MRSA-targeting antibodies that bind to wall teichoic acid (WTA), which is a polyanionic surface glycopolymer. In S. aureus, WTA exists in both α- and β-forms, based on the stereochemistry of attachment of a N-acetylglucosamine residue to the repeating phosphoribitol sugar unit. We identified a panel of antibodies cloned from human patients that specifically recognize the α or β form of WTA, and can bind with high affinity to pathogenic wild-type strains of S. aureus bacteria. To investigate how the β-WTA specific antibodies interact with their target epitope, we determined the X-ray crystal structures of the three β-WTA specific antibodies, 4462, 4497, and 6078 (Protein Data Bank IDs 6DWI, 6DWA, and 6DW2, respectively), bound to a synthetic WTA epitope. These structures reveal that all three of these antibodies, while utilizing distinct antibody complementarity-determining region sequences and conformations to interact with β-WTA, fulfill two recognition principles: binding to the β-GlcNAc pyranose core and triangulation of WTA phosphate residues with polar contacts. These studies reveal the molecular basis for targeting a unique S. aureus cell surface epitope and highlight the power of human patient-based antibody discovery techniques for finding novel pathogen-targeting therapeutics.

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Section: Introductionmentioning

confidence: 99%

Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

Fong¹,

Kajihara²,

Chen³

et al. 2018

mAbs

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“…There was an elevated incidence of early acute rejection, but several patients were able to wean down to low-dose single agent. Additional cell types with tolerogenic properties include mesenchymal stromal cells (English and Wood 2013) and tolerogenic dendritic cells (Page et al 2012). These cell types have been shown effective in animal models and are also entering into clinical testing.…”

Section: Other Possibilitiesmentioning

confidence: 99%

“…A number of additional cellular therapy approaches with promising results in preclinical studies are entering into clinical trial (reviewed in Page et al 2012;Tang and Bluestone 2013). Tolerogenic macrophage, dendritic cells, and mesenchymal stromal cells have all shown promise in transplant models.…”

Section: Other Possibilitiesmentioning

confidence: 99%

Tolerance--Is It Worth It?

Finger

Strom

Matas

2013

Cold Spring Harbor Perspectives in Medicine

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We are entering an exciting time in the study of immunologic tolerance. Several cellular and molecular strategies have been developed that show promise in nonhuman transplant models and these approaches are just now appearing in clinical trials. Tolerance strategies that prevent immune rejection and obviate the need for immunosuppressive medications (with inherent risk of cancer, infection, and organ toxicity) would improve both graft and patient survival. Each tolerance protocol brings its own set of associated risks. As the results of these trials become available, we must continue to evaluate their successes and failures. The balance of these outcomes will help us answer the question: "Tolerance-Is it worth it?"WHAT IS TOLERANCE?

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“…Conditioning with total lymphoid irradiation and ATG promoted increased proportions of CD4+ CD25+ regulatory T cells and chimerism in 15 patients. 8 patients had successful withdrawal of immunosuppression for 1-3 years but 4 had recurrent disease or rejection and were unable to withdraw [28][29][30][31].…”

Section: Total Lymphoid Elimination Protocolsmentioning

confidence: 99%

Current State of Tolerance: The Holy Grail

Rathore¹

2017

Arch Clin Nephrol

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Research in Tolerance and Chimerism by Transplant immunologists for over half a century is akin to the pursuit of the Holy Grail. Animal experiments for inducing tolerance may not have been successful initially but in that process, our knowledge of the fascinating immune system has been greatly enriched. Understanding of innate and adaptive immune systems has paved the way for development of potent immunosuppression. However, achieving clinical or operational tolerance long term in renal transplant recipients in the absence of immunosuppression is the ultimate goal for clinicians. Reduction in immunosuppression will lower morbidity and mortality associated with heavy burden of immunosuppression. This review article will be of particular interest to clinicians involved in delivering care to renal transplant recipients. We have elucidated mechanisms of self-tolerance through central and peripheral tolerance, evolution of tolerogenic strategies, difference between macro and micro-chimerism, overview of successful protocols for inducing tolerance and recent work in the development of expanding regulatory cell lines. It is most encouraging to note progress using cellular therapies as reported by Immune Tolerance Network and by Transplant Research & Immunology group at Oxford. We may not be far from achieving clinical tolerance albeit with minimal if not completely immunosuppression free regimens in the longer term. Review Article Tolerance in TransplantationThe highest result of education is toleranceHelen Keller [1], Tolerance is derived from 'tolero' in Latin, which means to endure. Achieving transplant tolerance has been the subject of research for over half a century and our current understanding of tolerance has evolved during that time. It is by no means complete and the search for true tolerance continues.Tolerance is the ability of a foreign tissue or organ to survive in a host without immunosuppression. It can be described as donor specifi c non-reactivity in experimental models [2]. "Clinical operational tolerance" is described as a well-functioning graft lacking histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges including infections [3,4].In contrast, "Immunological tolerance" is no detectable immune reaction towards the allograft in absence of immunosuppression. It is a state of permanent and specifi c immunological acceptance of the allograft by the host immune system in the absence of immunosuppression. Self-toleranceThe concept of tolerance towards transplanted organs is best understood through learning about self-tolerance. The lymphoid system, which consists of T and B-lymphocytes, controls the immune system protecting the host from foreign pathogens. In the developmental pathway of the lymphoid system, T cells and B cells undergo education and maturation in the central lymphoid organs; the thymus and bone marrow. During this maturation process, T and B cells learn to differentiate between s...

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Tolerogenic therapies in transplantation

Cited by 64 publications

References 180 publications

Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

Tolerance--Is It Worth It?

Current State of Tolerance: The Holy Grail

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