scholarly journals Induction of Immune Tolerance in Islet Transplantation Using Apoptotic Donor Leukocytes

2021 ◽  
Vol 10 (22) ◽  
pp. 5306
Author(s):  
Naoya Sato ◽  
Shigeru Marubashi
Keyword(s):  
Islet Transplantation ◽  
T Cell Activation ◽  
Immune Tolerance ◽  
Chronic Rejection ◽  
Cell Activation ◽  
Tolerance Induction ◽  
Effective Treatment Option ◽  
Transplant Tolerance ◽  
Primate Model ◽  
Maintenance Immunosuppression

Allogeneic islet transplantation has become an effective treatment option for severe Type 1 diabetes with intractable impaired awareness due to hypoglycemic events. Although current immunosuppressive protocols effectively prevent the acute rejection associated with initial T cell activation in recipients, chronic rejection has remained an obstacle for achieving long-term allogeneic islet engraftment. The development of donor-specific immune tolerance to the allograft is the ultimate goal given its potential ability to overcome chronic rejection and disregard the need for maintenance immunosuppression, which may be toxic to islet grafts. Recently, a breakthrough in tolerance induction during allogeneic islet transplantation using apoptotic donor lymphocytes (ADLs) in a non-human primate model had been reported. Several studies have suggested that the clonal depletion, anergy, and expansion of the antigen-specific regulatory immune network are the mechanisms for donor-specific tolerance with ADLs, which act synergistically to induce robust transplant tolerance. This achievement represents a huge step forward toward the clinical application of immune tolerance induction. We herein summarize the reported operational induction therapies in islet transplantation using the ADLs. Moreover, a few obstacles for the engraftment of transplanted islets, such as islet immunogenicity and instant blood-mediated response, which need to be resolved in the future, are also discussed.

scholarly journals Tregs and Mixed Chimerism as Approaches for Tolerance Induction in Islet Transplantation

2021 ◽  
Vol 11 ◽  
Author(s):  
Shiva Pathak ◽  
Everett H. Meyer
Keyword(s):  
Islet Transplantation ◽  
Immune Tolerance ◽  
Tolerance Induction ◽  
Mixed Chimerism ◽  
Pancreatic Islet Transplantation ◽  
Transplant Tolerance ◽  
Hematopoietic Stem ◽  
Long Term Treatment ◽  
Clinical Islet Transplantation

Pancreatic islet transplantation is a promising method for the treatment of type 1 and type 3 diabetes whereby replacement of islets may be curative. However, long-term treatment with immunosuppressive drugs (ISDs) remains essential for islet graft survival. Current ISD regimens carry significant side-effects for transplant recipients, and are also toxic to the transplanted islets. Pre-clinical efforts to induce immune tolerance to islet allografts identify ways in which the recipient immune system may be reeducated to induce a sustained transplant tolerance and even overcome autoimmune islet destruction. The goal of these efforts is to induce tolerance to transplanted islets with minimal to no long-term immunosuppression. Two most promising cell-based therapeutic strategies for inducing immune tolerance include T regulatory cells (Tregs) and donor and recipient hematopoietic mixed chimerism. Here, we review preclinical studies which utilize Tregs for tolerance induction in islet transplantation. We also review myeloablative and non-myeloablative hematopoietic stem cell transplantation (HSCT) strategies in preclinical and clinical studies to induce sustained mixed chimerism and allograft tolerance, in particular in islet transplantation. Since Tregs play a critical role in the establishment of mixed chimerism, it follows that the combination of Treg and HSCT may be synergistic. Since the success of the Edmonton protocol, the feasibility of clinical islet transplantation has been established and nascent clinical trials testing immune tolerance strategies using Tregs and/or hematopoietic mixed chimerism are underway or being formulated.

scholarly journals Cyclosporine A, in Contrast to Rapamycin, Affects the Ability of Dendritic Cells to Induce Immune Tolerance Mechanisms

2021 ◽  
Vol 69 (1) ◽  
Author(s):  
Maja Machcińska ◽  
Monika Kotur ◽  
Aleksandra Jankowska ◽  
Marta Maruszewska-Cheruiyot ◽  
Artur Łaski ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell Activation ◽  
Immune Tolerance ◽  
Cyclosporine A ◽  
Cell Activation ◽  
Immunosuppressive Agents ◽  
Immunosuppressive Drugs ◽  
Transplant Tolerance ◽  
Phagocytic Capacity ◽  
Immature Dendritic Cells

AbstractFollowing organ transplantation, it is essential that immune tolerance is induced in the graft recipient to reduce the risk of rejection and avoid complications associated with the long-term use of immunosuppressive drugs. Immature dendritic cells (DCs) are considered to promote transplant tolerance and may minimize the risk of graft rejection. The aim of the study was to evaluate the effects of immunosuppressive agents: rapamycin (Rapa) and cyclosporine A (CsA) on generation of human tolerogenic DCs (tolDCs) and also to evaluate the ability of these cells to induce mechanisms of immune tolerance. tolDCs were generated in the environment of Rapa or CsA. Next, we evaluated the effects of these agents on surface phenotypes (CD11c, MHC II, CD40, CD80, CD83, CD86, CCR7, TLR2, TLR4), cytokine production (IL-4, IL-6, IL-10, IL-12p70, TGF-β), phagocytic capacity and resistant to lipopolysaccharide activation of these DCs. Moreover, we assessed ability of such tolDCs to induce T cell activation and apoptosis, Treg differentiation and production of Th1- and Th2-characteristic cytokine profile. Data obtained in this study demonstrate that rapamycin is effective at generating maturation-resistant tolDCs, however, does not change the ability of these cells to induce mechanisms of immune tolerance. In contrast, CsA affects the ability of these cells to induce mechanisms of immune tolerance, but is not efficient at generating maturation-resistant tolDCs.

scholarly journals Molecular Profiling of Acute and Chronic Rejections of Renal Allografts

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Hřibová Petra ◽  
Honsová Eva ◽  
Brabcová Irena ◽  
Hrubá Petra ◽  
Viklický Ondřej
Keyword(s):  
Immune Response ◽  
T Cell ◽  
T Cell Activation ◽  
Chronic Rejection ◽  
Cell Activation ◽  
Expression Patterns ◽  
B Cell Activation ◽  
Graft Dysfunction ◽  
Gene Expressions ◽  
Lower Expression

Both antibody mediated (AMR) and T-cell mediated (TCMR) rejections either acute or chronic represent the main reason for late graft dysfunction. In this study we aimed to evaluate differences in the intrarenal expression patterns of immune system related genes in acute and chronic rejections. Graft biopsies were performed and evaluated according to Banff classification. Using the TaqMan Low Density Array, the intrarenal expressions of 376 genes relating to immune response (B-cell activation, T-cell activation, chemokines, growth factors, immune regulators, and apoptosis) were analyzed in the four rejection categories: chronic AMR, chronic TCMR, acute AMR, and acute TCMR. The set of genes significantly upregulated in acute TCMR as compared to acute AMR was identified, while no difference in gene expressions between chronic rejections groups was found. In comparison with functioning grafts, grafts that failed within the next 24 months after the chronic rejection morphological confirmation presented at biopsy already established severe graft injury (low eGFR, higher proteinuria), longer followup, higher expression of CDC20, CXCL6, DIABLO, GABRP, KIAA0101, ME2, MMP7, NFATC4, and TGFB3 mRNA, and lower expression of CCL19 and TRADD mRNA. In conclusion, both Banff 2007 chronic rejection categories did not differ in intrarenal expression of 376 selected genes associated with immune response.

scholarly journals Tim-3 Relieves Experimental Autoimmune Encephalomyelitis by Suppressing MHC-II

2022 ◽  
Vol 12 ◽  
Author(s):  
Lili Tang ◽  
Ge Li ◽  
Yang Zheng ◽  
Chunmei Hou ◽  
Yang Gao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
T Cell Activation ◽  
Immune Tolerance ◽  
Cell Activation ◽  
Autoimmune Encephalomyelitis ◽  
Mhc Ii ◽  
Experimental Autoimmune

Tim-3, an immune checkpoint inhibitor, is widely expressed on the immune cells and contributes to immune tolerance. However, the mechanisms by which Tim-3 induces immune tolerance remain to be determined. Major histocompatibility complex II (MHC-II) plays a key role in antigen presentation and CD4+T cell activation. Dysregulated expressions of Tim-3 and MHC-II are associated with the pathogenesis of many autoimmune diseases including multiple sclerosis. Here we demonstrated that, by suppressing MHC-II expression in macrophages via the STAT1/CIITA pathway, Tim-3 inhibits MHC-II-mediated autoantigen presentation and CD4+T cell activation. As a result, overexpression or blockade of Tim-3 signaling in mice with experimental autoimmune encephalomyelitis (EAE) inhibited or increased MHC-II expression respectively and finally altered clinical outcomes. We thus identified a new mechanism by which Tim-3 induces immune tolerance in vivo and regulating the Tim-3-MHC-II signaling pathway is expected to provide a new solution for multiple sclerosis treatment.

scholarly journals Regulation and Function of the CD3γ DxxxLL Motif: A Binding Site for Adaptor Protein-1 and Adaptor Protein-2 in Vitro

1997 ◽  
Vol 138 (2) ◽  
pp. 271-281 ◽  
Author(s):  
Jes Dietrich ◽  
Jesper Kastrup ◽  
Bodil L. Nielsen ◽  
Niels Ødum ◽  
Carsten Geisler
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tolerance Induction ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Cell Receptor ◽  
Coated Vesicle

Several receptors are downregulated by internalization after ligand binding. Regulation of T cell receptor (TCR) expression is an important step in T cell activation, desensitization, and tolerance induction. One way T cells regulate TCR expression is by phosphorylation/dephosphorylation of the TCR subunit clusters of differentiation (CD)3γ. Thus, phosphorylation of CD3γ serine 126 (S126) causes a downregulation of the TCR. In this study, we have analyzed the CD3γ internalization motif in three different systems in parallel: in the context of the complete multimeric TCR; in monomeric CD4/CD3γ chimeras; and in vitro by binding CD3γ peptides to clathrin-coated vesicle adaptor proteins (APs). We find that the CD3γ D127xxxLL131/132 sequence represents one united motif for binding of both AP-1 and AP-2, and that this motif functions as an active sorting motif in monomeric CD4/ CD3γ molecules independently of S126. An acidic amino acid is required at position 127 and a leucine (L) is required at position 131, whereas the requirements for position 132 are more relaxed. The spacing between aspartic acid 127 (D127) and L131 is crucial for the function of the motif in vivo and for AP binding in vitro. Furthermore, we provide evidence indicating that phosphorylation of CD3γ S126 in the context of the complete TCR induces a conformational change that exposes the DxxxLL sequence for AP binding. Exposure of the DxxxLL motif causes an increase in the TCR internalization rate and we demonstrate that this leads to an impairment of TCR signaling. On the basis of the present results, we propose the existence of at least three different types of L-based receptor sorting motifs.

T cell activation and thymic tolerance induction require different adhesion intensities of the CD8 co-receptor

1992 ◽  
Vol 4 (10) ◽  
pp. 1169-1174 ◽  
Author(s):  
Martina Knobloch ◽  
Günther Schönrich ◽  
Johannes Schenkel ◽  
Marie Malissen ◽  
Bernard Malissen ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tolerance Induction

T Cell Activation Is Not a Prerequisite for Peripheral Tolerance Induction to Mls 1a

1994 ◽  
Vol 154 (2) ◽  
pp. 380-392 ◽  
Author(s):  
Gerald T. Todd ◽  
Timothy P. Lukacsko ◽  
Robert L. Fairchild
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tolerance Induction ◽  
Peripheral Tolerance

scholarly journals Murine B7-2, an alternative CTLA4 counter-receptor that costimulates T cell proliferation and interleukin 2 production.

1993 ◽  
Vol 178 (6) ◽  
pp. 2185-2192 ◽  
Author(s):  
G J Freeman ◽  
F Borriello ◽  
R J Hodes ◽  
H Reiser ◽  
J G Gribben ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Tolerance Induction ◽  
T Cell Proliferation ◽  
Antigen Presenting ◽  
Supergene Family ◽  
Costimulatory Pathway

The B7-1 molecule, expressed on antigen presenting cells (APC), provides a crucial costimulatory signal for T cell activation. Recent studies demonstrate the existence of alternative, non-B7-1 CTLA4 counter-receptors in mice and humans. Here, we describe the molecular cloning and demonstrate costimulatory function of the murine B7-2 (mB7-2) gene. Murine B7-2 cDNA encodes a member of the Ig supergene family that binds CTLA4-Ig and stains with the GL1 but not anti-mB7-1 mAb. Murine B7-2 costimulates the proliferation and interleukin 2 production of CD4+ T cells and this costimulation can be inhibited by either CTLA4-Ig or GL1 mAb. Identification of the B7-2 molecule will permit further manipulation of the B7:CD28/CTLA4 costimulatory pathway which has been shown to be involved in the prevention of tolerance, induction of tumor immunity, and most recently, in the pathogenesis of autoimmunity.

scholarly journals VISTA regulates microglia homeostasis and myelin phagocytosis, and is associated with MS lesion pathology

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Malte Borggrewe ◽  
Susanne M. Kooistra ◽  
Evelyn M. Wesseling ◽  
Fenja L. Gierschek ◽  
Maaike L. Brummer ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tolerance Induction ◽  
Autoimmune Encephalomyelitis ◽  
Expression Of Genes ◽  
The Central Nervous System ◽  
Immunoglobulin Domain ◽  
Microglia Morphology

AbstractV-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator (NCR) that is involved in T-cell quiescence, inhibition of T-cell activation, and in myeloid cells regulates cytokine production, chemotaxis, phagocytosis, and tolerance induction. In the central nervous system (CNS), VISTA is expressed by microglia, the resident macrophage of the parenchyma, and expression is decreased during neuroinflammation; however, the function of VISTA in microglia is unknown. Here, we extensively analyzed VISTA expression in different MS lesion stages and characterized the function of VISTA in the CNS by deleting VISTA in microglia. VISTA is differentially expressed in distinct MS lesion stages. In mice, VISTA deletion in Cx3Cr1-expressing cells induced a more amoeboid microglia morphology, indicating an immune-activated phenotype. Expression of genes associated with cell cycle and immune-activation was increased in VISTA KO microglia. In response to LPS and during experimental autoimmune encephalomyelitis (EAE), VISTA KO and WT microglia shared similar transcriptional profiles and VISTA deletion did not affect EAE disease progression or microglia responses. VISTA KO in microglia in vitro decreased the uptake of myelin. This study demonstrates that VISTA is involved in microglia function, which likely affects healthy CNS homeostasis and neuroinflammation.

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