scholarly journals B7-H4 Pathway in Islet Transplantation andβ-Cell Replacement Therapies

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Xiaojie Wang ◽  
Jianqiang Hao ◽  
Daniel L. Metzger ◽  
Ziliang Ao ◽  
Mark Meloche ◽  
...  
Keyword(s):  
T Cell ◽  
Islet Transplantation ◽  
Autoimmune Diabetes ◽  
Islet Cell Transplantation ◽  
T Cell Homeostasis ◽  
Allograft Survival ◽  
Cell Replacement ◽  
Nonobese Diabetic ◽  
Alloreactive T Cell ◽  
Donor Specific Tolerance

Type 1 diabetes (T1D) is a chronic autoimmune disease and characterized by absolute insulin deficiency.β-cell replacement by islet cell transplantation has been established as a feasible treatment option for T1D. The two main obstacles after islet transplantation are alloreactive T-cell-mediated graft rejection and recurrence of autoimmune diabetes mellitus in recipients. T cells play a central role in determining the outcome of both autoimmune responses and allograft survival. B7-H4, a newly identified B7 homolog, plays a key role in maintaining T-cell homeostasis by reducing T-cell proliferation and cytokine production. The relationship between B7-H4 and allograft survival/autoimmunity has been investigated recently in both islet transplantation and the nonobese diabetic (NOD) mouse models. B7-H4 protects allograft survival and generates donor-specific tolerance. It also prevents the development of autoimmune diabetes. More importantly, B7-H4 plays an indispensable role in alloimmunity in the absence of the classic CD28/CTLA-4 : B7 pathway, suggesting a synergistic/additive effect with other agents such as CTLA-4 on inhibition of unwanted immune responses.

scholarly journals Resilience of T cell-intrinsic dysfunction in transplantation tolerance

2019 ◽  
Vol 116 (47) ◽  
pp. 23682-23690 ◽  
Author(s):  
Michelle L. Miller ◽  
Christine M. McIntosh ◽  
Ying Wang ◽  
Luqiu Chen ◽  
Peter Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cardiac Transplantation ◽  
T Cell Memory ◽  
Cell Dysfunction ◽  
Antigen Persistence ◽  
T Cell Dysfunction ◽  
Alloreactive T Cell ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Following antigen stimulation, naïve T cells differentiate into memory cells that mediate antigen clearance more efficiently upon repeat encounter. Donor-specific tolerance can be achieved in a subset of transplant recipients, but some of these grafts are rejected after years of stability, often following infections. Whether T cell memory can develop from a tolerant state and whether these formerly tolerant patients develop antidonor memory is not known. Using a mouse model of cardiac transplantation in which donor-specific tolerance is induced with costimulation blockade (CoB) plus donor-specific transfusion (DST), we have previously shown that systemic infection with Listeria monocytogenes (Lm) months after transplantation can erode or transiently abrogate established tolerance. In this study, we tracked donor-reactive T cells to investigate whether memory can be induced when alloreactive T cells are activated in the setting of tolerance. We show alloreactive T cells persist after induction of cardiac transplantation tolerance, but fail to acquire a memory phenotype despite becoming antigen experienced. Instead, donor-reactive T cells develop T cell-intrinsic dysfunction evidenced when removed from the tolerant environment. Notably, Lm infection after tolerance did not rescue alloreactive T cell memory differentiation or functionality. CoB and antigen persistence were sufficient together but not separately to achieve alloreactive T cell dysfunction, and conventional immunosuppression could substitute for CoB. Antigen persistence was required, as early but not late surgical allograft removal precluded the acquisition of T cell dysfunction. Our results demonstrate transplant tolerance-associated T cell-intrinsic dysfunction that is resistant to memory development even after Lm-mediated disruption of tolerance.

Anti-α/β T cell receptor monoclonal antibody provides an efficient therapy for autoimmune diabetes in nonobese diabetic (NOD) mice

1991 ◽  
Vol 21 (5) ◽  
pp. 1163-1169 ◽  
Author(s):  
Pascal Sempé ◽  
Pierre Bédossa ◽  
Marie-Francoise Richard ◽  
Maria-Carme Villà ◽  
Jean-Francois Bach ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
T Cell Receptor ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Nonobese Diabetic ◽  
Receptor Monoclonal Antibody

The Programmed Death-1 (pd-1) Pathway Regulates Peripheral T Cell Tolerance During Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice

2007 ◽  
Vol 123 ◽  
pp. S27 ◽  
Author(s):  
Brian T. Fife ◽  
Indira Guleria ◽  
Melanie Bupp ◽  
Qizhi Tang ◽  
Todd Eagar ◽  
...  
Keyword(s):  
T Cell ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Nonobese Diabetic ◽  
Programmed Death ◽  
Programmed Death 1

scholarly journals Homeostatic T Cell Proliferation after Islet Transplantation

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Paolo Monti ◽  
Lorenzo Piemonti
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Islet Transplantation ◽  
T Cell Proliferation ◽  
Pancreatic Islet Transplantation ◽  
Therapeutic Approaches ◽  
Cell Responses ◽  
New Therapeutic Approaches ◽  
Alloreactive T Cell

Pancreatic islet transplantation in patients with type 1 diabetes mellitus is performed under immunosuppression to avoid alloreactive T cell responses and to control the reactivation of autoreactive memory T cells. However, lymphopenia associated with immunosuppression and T cell depletion can induce a paradoxical expansion of lymphocyte subsets under the influence of homeostatic proliferation. Homeostatic T cell proliferation is mainly driven by the IL-7/IL-7 receptor axis, a molecular pathway which is not affected by standard immune-suppressive drugs and, consequently, represents a novel potential target for immuno-modulatory strategies. In this review, we will discuss how homeostatic T cell proliferation can support autoimmunity recurrence after islet transplantation and how it can be targeted by new therapeutic approaches.

scholarly journals Development of Type 1 Diabetes Mellitus in Nonobese Diabetic Mice Follows Changes in Thymocyte and Peripheral T Lymphocyte Transcriptional Activity

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Thais A. Fornari ◽  
Paula B. Donate ◽  
Claudia Macedo ◽  
Elza T. Sakamoto-Hojo ◽  
Eduardo A. Donadi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Transcriptional Activity ◽  
Cell Activation ◽  
Autoimmune Diabetes ◽  
Immune Reactivity ◽  
Diabetic Mice ◽  
Nonobese Diabetic

As early as one month of age, nonobese diabetic (NOD) mice feature pancreatic infiltration of autoreactive T lymphocytes, which destruct insulin-producing beta cells, producing autoimmune diabetes mellitus (T1D) within eight months. Thus, we hypothesized that during the development of T1D, the transcriptional modulation of immune reactivity genes may occur as thymocytes mature into peripheral T lymphocytes. The transcriptome of thymocytes and peripheral CD3+T lymphocytes from prediabetic or diabetic mice analyzed through microarray hybridizations identified 2,771 differentially expressed genes. Hierarchical clustering grouped mice according to age/T1D onset and genes according to their transcription profiling. The transcriptional activity of thymocytes developing into peripheral T lymphocytes revealed sequential participation of genes involved with CD4+/CD8+T-cell differentiation (Themis), tolerance induction by Tregs (Foxp3), and apoptosis (Fasl) soon after T-cell activation (IL4), while the emergence of T1D coincided with the expression of cytotoxicity (Crtam) and inflammatory response genes (Tlr) by peripheral T lymphocytes.

scholarly journals Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses

2016 ◽  
Vol 213 (3) ◽  
pp. 415-431 ◽  
Author(s):  
Colleen M. Lau ◽  
Simone A. Nish ◽  
Nir Yogev ◽  
Ari Waisman ◽  
Steven L. Reiner ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Expression Profiles ◽  
T Cell Responses ◽  
Graft Versus Host Reaction ◽  
T Cell Homeostasis ◽  
Cell Responses ◽  
Activating Mutation ◽  
A Cell ◽  
Alloreactive T Cell

A common genetic alteration in acute myeloid leukemia is the internal tandem duplication (ITD) in FLT3, the receptor for cytokine FLT3 ligand (FLT3L). Constitutively active FLT3-ITD promotes the expansion of transformed progenitors, but also has pleiotropic effects on hematopoiesis. We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration. Pre-leukemic mice with the Flt3ITD knock-in allele manifested an expansion of classical DCs (cDCs) and plasmacytoid DCs. The expansion originated in DC progenitors, was cell intrinsic, and was further enhanced in Flt3ITD/ITD mice. The mutation caused the down-regulation of Flt3 on the surface of DCs and reduced their responsiveness to Flt3L. Both canonical Batf3-dependent CD8+ cDCs and noncanonical CD8+ cDCs were expanded and showed specific alterations in their expression profiles. Flt3ITD mice showed enhanced capacity to support T cell proliferation, including a cell-extrinsic expansion of regulatory T (T reg) cells. Accordingly, these mice restricted alloreactive T cell responses during graft-versus-host reaction, but failed to control autoimmunity without T reg cells. Thus, the FLT3-ITD mutation directly affects DC development, indirectly modulating T cell homeostasis and supporting T reg cell expansion. We hypothesize that this effect of FLT3-ITD might subvert immunosurveillance and promote leukemogenesis in a cell-extrinsic manner.

scholarly journals Impaired Plasma Membrane Targeting of Grb2–Murine Son of Sevenless (mSOS) Complex and Differential Activation of the Fyn–T Cell Receptor (TCR)-ζ–Cbl Pathway Mediate T Cell Hyporesponsiveness in Autoimmune Nonobese Diabetic Mice

1997 ◽  
Vol 186 (6) ◽  
pp. 887-897 ◽  
Author(s):  
Konstantin Salojin ◽  
Jian Zhang ◽  
Mark Cameron ◽  
Bruce Gill ◽  
Guillermo Arreaza ◽  
...  
Keyword(s):  
T Cells ◽  
Plasma Membrane ◽  
T Cell ◽  
Mapk Pathway ◽  
Autoimmune Diabetes ◽  
Ras Signaling ◽  
Differential Activation ◽  
Nonobese Diabetic ◽  
Ras Activation ◽  
Son Of Sevenless

Nonobese diabetic (NOD) mouse thymocytes are hyporesponsive to T cell antigen receptor (TCR)-mediated stimulation of proliferation, and this T cell hyporesponsiveness may be causal to the onset of autoimmune diabetes in NOD mice. We previously showed that TCR-induced NOD T cell hyporesponsiveness is associated with a block in Ras activation and defective signaling along the PKC/Ras/MAPK pathway. Here, we report that several sequential changes in TCR-proximal signaling events may mediate this block in Ras activation. We demonstrate that NOD T cell hyporesponsiveness is associated with the (a) enhanced TCR-β–associated Fyn kinase activity and the differential activation of the Fyn–TCR-ζ–Cbl pathway, which may account for the impaired recruitment of ZAP70 to membrane-bound TCR-ζ; (b) relative inability of the murine son of sevenless (mSOS) Ras GDP releasing factor activity to translocate from the cytoplasm to the plasma membrane; and (c) exclusion of mSOS and PLC-γ1 from the TCR-ζ–associated Grb2/pp36–38/ZAP70 signaling complex. Our data suggest that altered tyrosine phosphorylation and targeting of the Grb2/pp36–38/ZAP70 complex to the plasma membrane and cytoskeleton and the deficient association of mSOS with this Grb2-containing complex may block the downstream activation of Ras and Ras-mediated amplification of TCR/CD3-mediated signals in hyporesponsive NOD T cells. These findings implicate mSOS as an important mediator of downregulation of Ras signaling in hyporesponsive NOD T cells.

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