scholarly journals Tolerance Induction Strategies in Vascularized Composite Allotransplantation: Mixed Chimerism and Novel Developments

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
David A. Leonard ◽  
Duncan A. McGrouther ◽  
Josef M. Kurtz ◽  
Curtis L. Cetrulo
Keyword(s):  
Solid Organ Transplantation ◽  
Tolerance Induction ◽  
Small Animal ◽  
Preclinical Study ◽  
Mixed Chimerism ◽  
Specific Reference ◽  
Solid Organ ◽  
Vascularized Composite Allotransplantation ◽  
Transplant Tolerance ◽  
Transplanted Organs

Since the start of the clinical vascularized composite allotransplantation (VCA) era over a decade ago this field has witnessed significant developments in both basic and translational research. Transplant tolerance, defined as rejection-free acceptance of transplanted organs or tissues without long-term immunosuppression, holds the potential to revolutionize the field of VCA by removing the need for life-long immunosuppression. While tolerance of organ and vascularized composite transplants may be induced in small animal models by a variety of protocols, only mixed-chimerism-based protocols have successfully bridged the gap to preclinical study and to clinical trial in solid organ transplantation to date. In this paper we review the mixed-chimerism approach to tolerance induction, with specific reference to the field of VCA transplantation, and provide an overview of some novel cellular therapies as potential adjuvants to mixed chimerism in the development of tolerance induction protocols for clinical vascularized composite allotransplantation.

scholarly journals The Need for Inducing Tolerance in Vascularized Composite Allotransplantation

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Kadiyala V. Ravindra ◽  
Hong Xu ◽  
Larry D. Bozulic ◽  
David D. Song ◽  
Suzanne T. Ildstad
Keyword(s):  
Solid Organ Transplantation ◽  
Tolerance Induction ◽  
Mixed Chimerism ◽  
Future Research ◽  
Solid Organ ◽  
Vascularized Composite Allotransplantation ◽  
Split Tolerance ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Successful hand and face transplantation in the last decade has firmly established the field of vascularized composite allotransplantation (VCA). The experience in VCA has thus far been very similar to solid organ transplantation in terms of the morbidity associated with long-term immunosuppression. The unique immunological features of VCA such as split tolerance and resistance to chronic rejection are being investigated. Simultaneously there has been laboratory work studying tolerogenic protocols in animal VCA models. In order to optimize VCA outcomes, translational studies are needed to develop less toxic immunosuppression and possibly achieve donor-specific tolerance. This article reviews the immunology, animal models, mixed chimerism & tolerance induction in VCA and the direction of future research to enable better understanding and wider application of VCA.

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 The self-peptide repertoire plays a critical role in transplant tolerance induction

2020 ◽  
Author(s):  
Eric T. Son ◽  
Pouya Faridi ◽  
Moumita Paul-Heng ◽  
Mario Leong ◽  
Kieran English ◽  
...  
Keyword(s):  
T Cells ◽  
Critical Role ◽  
Tolerance Induction ◽  
Genetically Engineered ◽  
Solid Organ ◽  
Transplant Tolerance ◽  
Mhc I ◽  
Definitive Evidence ◽  
Antigen Presentation Pathway ◽  
Presentation Pathway

AbstractWhile direct allorecognition underpins both solid organ allograft rejection and tolerance induction, the specific molecular targets of most directly-alloreactive CD8+T cells have not been defined. In this study, we used a combination of genetically-engineered MHC I constructs, mice with a hepatocyte-specific mutation in the class I antigen-presentation pathway and immunopeptidomic analysis to provide definitive evidence for the contribution of the peptide cargo of allogeneic MHC I molecules to transplant tolerance induction. We established a systematic approach for the discovery of directly-recognised pMHC epitopes, and identified 17 strongly immunogenic H-2Kb-associated peptides recognised by CD8+T cells from B10.BR (H-2k) mice, 13 of which were also recognised by BALB/c (H-2d) mice. As few as five different tetramers used together were able to identify almost 40% of alloreactive T cells within a polyclonal population, suggesting that there are immunodominant allogeneic MHC-peptide complexes that can account for a large proportion of the alloresponse.

scholarly journals Randomised sham-controlled double-blind trial evaluating remote ischaemic preconditioning in solid organ transplantation: a study protocol for the RIPTRANS trial

BMJ Open ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. e038340
Author(s):  
Aki Uutela ◽  
Ilkka Helanterä ◽  
Karl Lemström ◽  
Arie Passov ◽  
Simo Syrjälä ◽  
...  
Keyword(s):  
Organ Transplantation ◽  
Study Protocol ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Organ Donors ◽  
Ischaemic Preconditioning ◽  
Study Results ◽  
Remote Ischaemic Preconditioning ◽  
Brain Dead ◽  
Transplanted Organs

IntroductionRemote ischaemic preconditioning (RIPC) using a non-invasive pneumatic tourniquet is a potential method for reducing ischaemia-reperfusion injury. RIPC has been extensively studied in animal models and cardiac surgery, but scarcely in solid organ transplantation. RIPC could be an inexpensive and simple method to improve function of transplanted organs. Accordingly, we aim to study whether RIPC performed in brain-dead organ donors improves function and longevity of transplanted organs.Methods and analysesRIPTRANS is a multicentre, sham-controlled, parallel group, randomised superiority trial comparing RIPC intervention versus sham-intervention in brain-dead organ donors scheduled to donate at least one kidney. Recipients of the organs (kidney, liver, pancreas, heart, lungs) from a randomised donor will be included provided that they give written informed consent. The RIPC intervention is performed by inflating a thigh tourniquet to 300 mm Hg 4 times for 5 min. The intervention is done two times: first right after the declaration of brain death and second immediately before transferring the donor to the operating theatre. The sham group receives the tourniquet, but it is not inflated. The primary endpoint is delayed graft function (DGF) in kidney allografts. Secondary endpoints include short-term functional outcomes of transplanted organs, rejections and graft survival in various time points up to 20 years. We aim to show that RIPC reduces the incidence of DGF from 25% to 15%. According to this, the sample size is set to 500 kidney transplant recipients.Ethics and disseminationThis study has been approved by Helsinki University Hospital Ethics Committee and Helsinki University Hospital’s Institutional Review Board. The study protocol was be presented at the European Society of Organ Transplantation congress in Copenhagen 14−15 September 2019. The study results will be submitted to an international peer-reviewed scientific journal for publication.Trial registration numberNCT03855722.

Tolerance and Immunity following in Utero Transplantation of Allogeneic Fetal Liver Cells: The Cytokine Shift

2003 ◽  
Vol 12 (1) ◽  
pp. 75-82 ◽  
Author(s):  
H. Sefrioui, J. Donahue ◽  
E. A. Gilpin ◽  
A. S. Srivastava ◽  
E. Carrier
Keyword(s):  
T Cells ◽  
Fetal Liver ◽  
Solid Organ Transplantation ◽  
Tolerance Induction ◽  
Suppressor Cells ◽  
In Utero ◽  
Third Party ◽  
Solid Organ ◽  
In Utero Transplantation ◽  
Ifn Γ

Although in utero transplantation (IUT) has resulted in donor-specific tolerance to postnatal solid organ transplantation, the mechanisms of this tolerance remain poorly understood. Our recent findings demonstrate that under specific conditions prenatal injection of allogeneic cells may lead to allosensitization instead of tolerance. These laboratory observations were supported by clinical findings as well, and therefore suggested that, depending on the conditions of prenatal transplantation, tolerance or immunity may develop. The present study explored the role of CD4 cells, cytokines, and I-E superantigen in developing tolerance vs. immunity after in utero transplantation. Sixteen animals survived IUT (40–60% survival rate) and were free from any signs of graft-versus-host disease (GVHD). Mice were considered tolerant when their antidonor and antihost CTL responses were similar, sensitized when antidonor responses were significantly higher than antihost and anti-third-party responses, and nontolerant when antidonor responses in transplanted and control mice were similar. The TH1 → TH2 shift was associated with tolerance and TH2 → TH1 shift with allosensitization. Our results showed that tolerant BALB/c (H-2d, I-E+) → C57BL/6 (H-2b, I-E–) (2/7) mice showed higher IL-4 (p < 0.05) in antidonor MLR, and partial deletion of recipient I-E-reactive T cells (CD3Vβ11) (p < 0.045). On the other hand, nontolerant animals (5/7) demonstrated high production of IFN-γ (p < 0.05) without deletion of CD3Vβ11 T cells. In C57CBL/6 (H-2b, I-E–) → C3H (H-2k, I-E+) mice CD3Vβ11 T cells do not play any role in tolerance induction because they are deleted in the C3H background. Tolerant mice (4/9) showed an overproduction of IL-4 (p < 0.05) in antidonor MLR whereas allosensitized animals (5/9) demonstrated high level of IFN-γ (p < 0.05). Suppressor cells seem to play no role in tolerant C57BL/6 → C3H as demonstrated by suppressor assay. Hence, a shift from TH1 → TH2 or TH2 → TH1 cytokines may determine whether tolerance or immunity develops.

scholarly journals Oridonin Prolongs the Survival of Mouse Cardiac Allografts by Attenuating the NF-κB/NLRP3 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoxiao Du ◽  
Weitao Que ◽  
Xin Hu ◽  
Xiao Yu ◽  
Wen-Zhi Guo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Organ Transplantation ◽  
Mrna Level ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Transplant Tolerance ◽  
Term Survival ◽  
Cardiac Allografts ◽  
Ifn Γ

BackgroundOridonin (Ori), the main bioactive ingredient of the natural anti-inflammatory herb Rabdosia rubescens, could be a covalent inhibitor of the NLRP3 inflammasome. Solid organ transplantation provides a life-saving optional therapy for patients with end-stage organ dysfunction. The long-term survival of solid organ transplantation remains restricted because of the possibility of rejection and the toxicity, infection, cardiovascular disease, and malignancy related to immunosuppressive (IS) drugs. However, the pathogenic mechanisms involved remain unclear. The ideal IS drugs to prevent allograft rejection have not been identified. Here, we investigated whether Ori could prolong the in vivo survival of completely mismatched cardiac allografts.MethodsThe cardiac transplantation models were conducted among three groups of mice from C57BL/6NCrSlc (B6/N) or C3H/HeNSlc (C3H) to C3H: the syngeneic and the allogeneic group, whose recipients were treated with vehicle of Ori, and the Ori treatment group, in which the recipients were transplanted hearts from MHC-I mismatched donors and treated with different dosages of Ori from post-operative day (POD) 0 to 7. Then, we investigated the effect of Ori on bone marrow-derived dendritic cell (BMDC) and allogeneic mixed lymphocyte reaction in vitro.ResultsOri with 3, 10, and 15 mg/kg Ori could prolong the survival (MST = 22.8, 49.2, and 65.3 days, respectively). We found that infiltrating CD8+ T cells and macrophages were decreased, and regulatory T cells (Tregs) were expanded in allografts on POD7. The mRNA level of IL-1β and IFN-γ of allografts was downregulated. Mechanistically, Ori-treated BMDCs suppressed T-cell proliferation and IFN-γ+CD4+ T-cell differentiation, along with the expansion of Tregs and IL-10+CD4+ T cells. Ori inhibited NOD, LRR-, and pyrin domain-containing protein 3 (NLRP3) expression; attenuated NF-κB and IκBα phosphorylation in LPS-activated BMDCs; downregulated NLRP3, Caspase-1, IL-1β, IL-18, and IFN-γ; and upregulated IL-10 expression.ConclusionsOur findings highlight the potential of Ori as a novel and natural IS agent to improve transplant tolerance. Ori could exert IS activity through decreasing IL-1β and IL-18 production and Th1 differentiation and proliferation and expanding Tregs via inhibiting the NF-κB/NLRP3 signaling pathway.

Transplantation Principles

2020 ◽  
Author(s):  
Maria Siemionow ◽  
Fatih Zor
Keyword(s):  
Transplant Rejection ◽  
Solid Organ Transplantation ◽  
Surgical Techniques ◽  
Immunosuppressive Drugs ◽  
Organ Shortage ◽  
Solid Organ ◽  
Major Advance ◽  
Vascularized Composite Allotransplantation ◽  
Comprehensive Overview ◽  
Keywords Transplantation

Transplantation is a truly multidisciplinary specialty where a surgical procedure requires inputs from both, the specialists of the specific organ e.g. nephrologist for kidney transplant or hepatologist for liver transplant, as well as from experts of other specialties such as immunology, infectious diseases etc. It is also a rapidly grooving field with the advances in surgical techniques, immunological knowledge and pharmacology. A recent, major advance in the field of transplantation is the emergence of new procedure of vascularized composite allotransplantation, which includes transplantation of non-lifesaving organs such as face, hands, abdominal wall or uterus. Additionally, organ shortage in transplantation yielded a new area of research such as xenotransplantation and regenerative medicine. The specialty of transplantation may be difficult to comprehend for those entering the field; thus, the goal of this chapter is to provide a comprehensive overview of the most important aspects of transplantation. This review contains 2 figures, 3 tables, and 67 references. Keywords: transplantation, solid organ transplantation (SOT), vascularized composite allotransplantation (VCA), transplant immunology, allorecognition, acute rejection, chronic transplant rejection, principles of transplantation, transplantation terminology, immunosuppressive drugs

scholarly journals Regulatory T cells: tolerance induction in solid organ transplantation

2017 ◽  
Vol 189 (2) ◽  
pp. 197-210 ◽  
Author(s):  
T. Vaikunthanathan ◽  
N. Safinia ◽  
D. Boardman ◽  
R. I. Lechler ◽  
G. Lombardi
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Organ Transplantation ◽  
Solid Organ Transplantation ◽  
Tolerance Induction ◽  
Solid Organ

scholarly journals A Large-Scale Bank of Organ Donor Bone Marrow and Matched Mesenchymal Stem Cells for Promoting Immunomodulation and Transplant Tolerance

2021 ◽  
Vol 12 ◽  
Author(s):  
Brian H. Johnstone ◽  
Franka Messner ◽  
Gerald Brandacher ◽  
Erik J. Woods
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Living Donor ◽  
Progenitor Cell ◽  
Large Scale ◽  
Organ Donor ◽  
Mixed Chimerism ◽  
Solid Organ ◽  
Transplant Tolerance ◽  
Hematopoietic Stem

Induction of immune tolerance for solid organ and vascular composite allografts is the Holy Grail for transplantation medicine. This would obviate the need for life-long immunosuppression which is associated with serious adverse outcomes, such as infections, cancers, and renal failure. Currently the most promising means of tolerance induction is through establishing a mixed chimeric state by transplantation of donor hematopoietic stem cells; however, with the exception of living donor renal transplantation, the mixed chimerism approach has not achieved durable immune tolerance on a large scale in preclinical or clinical trials with other solid organs or vascular composite allotransplants (VCA). Ossium Health has established a bank of cryopreserved bone marrow (BM), termed “hematopoietic progenitor cell (HPC), Marrow,” recovered from deceased organ donor vertebral bodies. This new source for hematopoietic cell transplant will be a valuable resource for treating hematological malignancies as well as for inducing transplant tolerance. In addition, we have discovered and developed a large source of mesenchymal stem (stromal) cells (MSC) tightly associated with the vertebral body bone fragment byproduct of the HPC, Marrow recovery process. Thus, these vertebral bone adherent MSC (vBA-MSC) are matched to the banked BM obtained from each donor, as opposed to third-party MSC, which enhances safety and potentially efficacy. Isolation and characterization of vBA-MSC from over 30 donors has demonstrated that the cells are no different than traditional BM-MSC; however, their abundance is &gt;1,000-fold higher than obtainable from living donor BM aspirates. Based on our own unpublished data as well as reports published by others, MSC facilitate chimerism, especially at limiting hematopoietic stem and progenitor cell (HSPC) numbers and increase safety by controlling and/or preventing graft-vs.-host-disease (GvHD). Thus, vBA-MSC have the potential to facilitate mixed chimerism, promote complementary peripheral immunomodulatory functions and increase safety of BM infusions. Both HPC, Marrow and vBA-MSC have potential use in current VCA and solid organ transplant (SOT) tolerance clinical protocols that are amenable to “delayed tolerance.” Current trials with HPC, Marrow are planned with subsequent phases to include vBA-MSC for tolerance of both VCA and SOT.

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