Co-Stimulatory Molecules in Islet Xenotransplantation: CTLA4Ig Treatment in CD40 Ligand-Deficient Mice

2002 ◽  
Vol 11 (7) ◽  
pp. 715-720 ◽  
Author(s):  
Birgitta Benda ◽  
Hans-Gustaf Ljunggren ◽  
Robert Peach ◽  
Jan-Olov Sandberg ◽  
Olle Korsgren
Keyword(s):  
Pancreatic Islet ◽  
Cytotoxic T Lymphocyte ◽  
Cd40 Ligand ◽  
Xenograft Rejection ◽  
Islet Xenotransplantation ◽  
Human Igg1 ◽  
Donor Specific Tolerance ◽  
Deficient Mice

Previous work has demonstrated that short-term systemic administration of cytotoxic T lymphocyte antigen-4 (CTLA-4) Ig blocks human pancreatic islet xenograft rejection in mice and induces long-term, donor-specific tolerance, whereas studies on pig pancreatic islet rejection in mice have failed to demonstrate a role for CTLA4Ig in preventing rejection. Treatment with anti-CD40 ligand (L) monoclonal antibodies alone is somewhat effective in prolonging the survival of islet xenografts, but ineffective when applied to skin xenografts. However, simultaneous blockade of the CD28 and CD40 co-stimulatory pathways prolongs the survival of pig skin on recipient mice. To evaluate the role of CD28 and CD40 co-stimulatory pathways in pig islet-like cell cluster (ICC) xenograft rejection in mice, CD40L-deficient mice transplanted with fetal porcine ICCs were given posttransplant treatment with human (h) CTLA4Ig or a human IgG1 chimeric mAb (hL6). Xenografts were evaluated 6 or 12 days after transplantation. Fetal porcine ICC xenografts were protected from rejection in hCTLA4Ig-treated CD40L-deficient mice, whereas xenograft rejection persisted in untreated CD40L-deficient mice. Simultaneous blockade of the CD28 and CD40 co-stimulatory pathways is mandatory to inhibit ICC xenograft rejection in the pig-to-mouse model, because the CD28 and CD40 co-stimulatory pathways seem capable of efficiently substituting for one another.

scholarly journals Formaldehyde Reacts with Amino Acids and Peptides with a Potential Role in Acute Methanol Intoxication

2020 ◽  
Vol 44 (8) ◽  
pp. 880-885 ◽  
Author(s):  
David Sýkora ◽  
Jindřich Jindřich ◽  
Vladimír Král ◽  
Milan Jakubek ◽  
Ameneh Tatar ◽  
...  
Keyword(s):  
Amino Acids ◽  
High Resolution ◽  
High Resolution Mass Spectrometry ◽  
Cytotoxic T Lymphocyte ◽  
Mass Shift ◽  
Biologically Relevant ◽  
Igg1 Monoclonal Antibody ◽  
Human Igg1 ◽  
And Function

Abstract Methanol, an aliphatic alcohol widely used in the industry, causes acute and chronic intoxications associated with severe long-term health damage, including permanent visual impairment, brain damage, mainly necrosis of the basal ganglia and high mortality due to cancer. However, the role of formaldehyde, an intermediate metabolite of methanol oxidation, in methanol toxicity remains unclear. Thus, we studied the reactivity of several amino acids and peptides in the presence of formaldehyde by identifying products by direct infusion electrospray high-resolution mass spectrometry (MS) and matrix-assisted laser desorption-ionization MS. Cysteine, homocysteine and two peptides, CG and CGAG, provided cyclic products with a +12 amu mass shift with respect to the original compounds. The proposed structures of the products were confirmed by high-resolution tandem MS. Moreover, the formation of the products with +12 amu mass shift was also shown for two biologically relevant peptides, fragments of ipilimumab, which is a human IgG1 monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4. Overall, our experimental results indicate that formaldehyde reacts with some amino acids and peptides, yielding covalently modified structures. Such chemical modifications may induce undesirable changes in the properties and function of vital biomolecules (e.g., hormones, enzymes) and consequently pathogenesis.

scholarly journals Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile

2010 ◽  
Vol 207 (2) ◽  
pp. 391-404 ◽  
Author(s):  
Esther Lutgens ◽  
Dirk Lievens ◽  
Linda Beckers ◽  
Erwin Wijnands ◽  
Oliver Soehnlein ◽  
...  
Keyword(s):  
Immune Responses ◽  
Inflammatory Diseases ◽  
Tumor Necrosis Factor Receptor ◽  
Cd40 Ligand ◽  
Therapeutic Effects ◽  
Signaling Axis ◽  
Plaque Phenotype ◽  
Necrosis Factor

The CD40–CD40 ligand (CD40L) signaling axis plays an important role in immunological pathways. Consequently, this dyad is involved in chronic inflammatory diseases, including atherosclerosis. Inhibition of CD40L in apolipoprotein E (Apoe)–deficient (Apoe−/−) mice not only reduced atherosclerosis but also conferred a clinically favorable plaque phenotype that was low in inflammation and high in fibrosis. Blockade of CD40L may not be therapeutically feasible, as long-term inhibition will compromise systemic immune responses. Conceivably, more targeted intervention strategies in CD40 signaling will have less deleterious side effects. We report that deficiency in hematopoietic CD40 reduces atherosclerosis and induces features of plaque stability. To elucidate the role of CD40–tumor necrosis factor receptor-associated factor (TRAF) signaling in atherosclerosis, we examined disease progression in mice deficient in CD40 and its associated signaling intermediates. Absence of CD40-TRAF6 but not CD40-TRAF2/3/5 signaling abolishes atherosclerosis and confers plaque fibrosis in Apoe−/− mice. Mice with defective CD40-TRAF6 signaling display a reduced blood count of Ly6Chigh monocytes, an impaired recruitment of Ly6C+ monocytes to the arterial wall, and polarization of macrophages toward an antiinflammatory regulatory M2 signature. These data unveil a role for CD40–TRAF6, but not CD40–TRAF2/3/5, interactions in atherosclerosis and establish that targeting specific components of the CD40–CD40L pathway harbors the potential to achieve therapeutic effects in atherosclerosis.

Stimulation of osteoprotegerin production is responsible for osteosclerosis in mice overexpressing TPO

Blood ◽  
2003 ◽  
Vol 101 (8) ◽  
pp. 2983-2989 ◽  
Author(s):  
Hédia Chagraoui ◽  
Micheline Tulliez ◽  
Tarek Smayra ◽  
Emiko Komura ◽  
Stéphane Giraudier ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Wild Type ◽  
Myeloproliferative Syndrome ◽  
Bone Trabeculae ◽  
Deficient Mice ◽  
Tgf Β1

Abstract Myelofibrosis and osteosclerosis are prominent features arising in mice overexpressing thrombopoietin (TPO). The pivotal role of transforming growth factor β1 (TGF-β1) in the pathogenesis of myelofibrosis has been documented, but the mechanisms mediating osteosclerosis remain unclear. Here, we used mice deficient in osteoprotegerin (OPG), a secreted inhibitor of bone resorption, to determine whether osteosclerosis occurs through a deregulation of osteoclastogenesis. Marrow cells from opg-deficient mice (opg−/−) or wild-type (WT) littermates were infected with a retrovirus encoding TPO and engrafted into anopg−/− or WT background for long-term reconstitution. The 4 combinations of graft/host (WT/WT,opg−/−/opg−/−,opg−/−/WT, and WT/opg−/−) were studied. Elevation of TPO and TGF-β1 levels in plasma was similar in the 4 experimental groups and all the mice developed a similar myeloproliferative syndrome associated with severe myelofibrosis. Osteosclerosis developed in WT hosts engrafted with WT or opg−/− hematopoietic cells and was associated with increased OPG levels in plasma and decreased osteoclastogenesis. In contrast,opg−/− hosts exhibited an osteoporotic phenotype and a growth of bone trabeculae was rarely seen. These findings suggest that osteosclerosis in mice with TPO overexpression occurs predominantly via an up-regulation of OPG in host stromal cells leading to disruption of osteoclastogenesis.

scholarly journals Role of Interleukin-23-Dependent Antifungal Immune Responses in Dendritic Cell-Vaccinated Mice

2011 ◽  
Vol 79 (9) ◽  
pp. 3778-3783 ◽  
Author(s):  
Mingquan Zheng ◽  
Rekha R. Rapaka ◽  
Amy C. Yu ◽  
Judd E. Shellito ◽  
Jay K. Kolls
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Recombinant Adenovirus ◽  
Cd40 Ligand ◽  
Antibody Responses ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Interleukin 23 ◽  
Deficient Mice

ABSTRACTCD40 ligand (CD40L) transduction of antigen-pulsed dendritic cells (DCs) can result in antigen-specific humoral immune responses even in CD4+T-cell-depleted settings. Here, we show that CD40L transduction of DCs results in the induction of interleukin-12p40 (IL-12p40), IL-12p70, and IL-23. Using DCs that were deficient in IL-12p40, IL-12p35, or IL-23p19, we show that these molecules are dispensable for primary IgG1 responses toPneumocystis, but IgG2c was dependent on IL-12p40 and IL-23p19 but not IL-12p35. Antigen-specific recall responses in CD4-deficient mice were critically dependent on IL-12p40 and IL-23p19 expression in DCs and were not affected by the lack of IL-12p35. To confirm that this defect in recall was due to IL-23, transduction of IL-12p40−/−DCs with a recombinant adenovirus expressing functional IL-23 restored recall responses in DC-vaccinated CD4-deficient mice. These data show that DC-produced IL-23 is critical for vaccine-induced antigen-specific IgG2c and recall antibody responses in the setting of CD4+T-cell depletion.

scholarly journals Asymmetric Recovery in Cerebellar-Deficient Mice Following Unilateral Labyrinthectomy

2008 ◽  
Vol 100 (2) ◽  
pp. 945-958 ◽  
Author(s):  
M. Beraneck ◽  
J. L. McKee ◽  
M. Aleisa ◽  
K. E. Cullen
Keyword(s):  
Head Rotation ◽  
Motor Deficits ◽  
Wild Type ◽  
Gaze Stabilization ◽  
Unilateral Labyrinthectomy ◽  
Head Rotations ◽  
Sinusoidal Rotations ◽  
Deficient Mice

The term “vestibular compensation” refers to the resolution of motor deficits resulting from a peripheral vestibular lesion. We investigated the role of the cerebellum in the compensation process by characterizing the vestibuloocular reflex (VOR) evoked by head rotations at frequencies and velocities similar to those in natural behaviors in wild-type ( WT) versus cerebellar-deficient Lurcher ( Lc/+) mice. We found that during exploratory activity, normal mice produce head rotations largely consisting of frequencies ≤4 Hz and velocities and accelerations as large as 400°/s and 5,000°/s2, respectively. Accordingly, the VOR was characterized using sinusoidal rotations (0.2–4 Hz) as well as transient impulses (∼400°/s; ∼2,000°/s2). Before lesions, WT and Lc/+ mice produced similar VOR responses to sinusoidal rotation. Lc/+ mice, however, had significantly reduced gains for transient stimuli. After unilateral labyrinthectomy, VOR recovery followed a similar course for WT and Lc/+ groups during the first week: gain was reduced by 80% for ipsilesionally directed head rotations on day 1 and improved for both strains to values of ∼0.4 by day 5. Moreover, responses evoked by contralesionally directed rotations returned to prelesion in both strains within this period. However, unlike WT, which showed improving responses to ipsilesionally directed rotations, recovery plateaued after first week for Lc/+ mice. Our results show that despite nearly normal recovery in the acute phase, long-term compensation is compromised in Lc/+. We conclude that cerebellar pathways are critical for long-term restoration of VOR during head rotation toward the lesioned side, while noncerebellar pathways are sufficient to restore proper gaze stabilization during contralesionally directed movements.

Mature dendritic cells can enhance CD8+ cell noncytotoxic anti-HIV responses: the role of IL-15

Blood ◽  
2004 ◽  
Vol 103 (7) ◽  
pp. 2699-2704 ◽  
Author(s):  
JoAnn Castelli ◽  
Elaine K. Thomas ◽  
Michel Gilliet ◽  
Yong-Jun Liu ◽  
Jay A. Levy
Keyword(s):  
Dendritic Cells ◽  
Cd40 Ligand ◽  
Substantial Effect ◽  
Clinical State ◽  
Cd8 Cells ◽  
Interleukin 15 ◽  
Cd8 Cell ◽  
Anti Hiv

Abstract The CD8+ cell noncytotoxic anti-HIV response (CNAR) is associated with a long-term healthy clinical state in HIV-infected individuals. Over time CNAR is reduced concomitant with progression to disease. In studies to evaluate whether the interaction between CD8+ cells and dendritic cells (DCs) could increase CNAR, CD8+ cells from individuals who showed a decrease in this antiviral activity were cocultured with monocyte-derived dendritic cells matured with CD40 ligand. After coculture with these mature DCs, the CD8+ cells showed an increase in CNAR greater than that observed with CD8+ cells costimulated with CD3/CD28 antibodies. This antiviral response appeared to be mediated primarily by production of interleukin-15 (IL-15) by the mature DCs. Purified IL-15 also enhanced CNAR, whereas IL-12 showed no substantial effect. These studies provide another potential approach by which the immune system in HIV infection could be restored by cytokine therapy, particularly IL-15 administration. (Blood. 2004;103:2699-2704)

scholarly journals Control of appetite, blood glucose, and blood pressure during melanocortin-4 receptor activation in normoglycemic and diabetic NPY-deficient mice

2018 ◽  
Vol 314 (4) ◽  
pp. R533-R539 ◽  
Author(s):  
Alexandre A. da Silva ◽  
J. Nathan Freeman ◽  
John E. Hall ◽  
Jussara M. do Carmo
Keyword(s):  
Food Intake ◽  
Recovery Period ◽  
Receptor Activation ◽  
Metabolic Functions ◽  
Melanocortin 4 Receptor ◽  
The Central Nervous System ◽  
Deficient Mice ◽  
Antidiabetic Effects

Although central melanocortin 4 receptor (MC4R) blockade abolishes the central nervous system (CNS)-mediated anorexogenic, antidiabetic, and cardiovascular actions of leptin, chronic MC4R stimulation fails to completely mimic the effects of leptin. Because neuropeptide Y (NPY) and MC4R exert opposite effects on cardiovascular and metabolic functions, we tested the role of NPY in offsetting the long-term actions of MC4R activation. Wild-type (WT) and NPY-deficient (NPY−/−) mice were implanted with telemetry probes for measuring mean arterial pressure (MAP) and heart rate (HR) 24 h/day. After the mice recovered from surgery and stable baseline measurements, the MC3/4R agonist melanotan II (MTII, 120 μg·kg−1·day−1 iv) was infused for 7 days followed by a recovery period. No major differences between groups were observed at baseline except for slightly higher food intake and HR in NPY−/− mice (4.3 ± 0.2 vs. 3.4 ± 0.2 g/day and 567 ± 14 vs. 522 ± 13 beats/min). Chronic MTII infusion reduced food intake in both groups while causing transient increases in MAP and HR only in WT mice (peaks of 11 ± 3 mmHg and 126 ± 13 beats/min). To examine whether NPY deficiency would amplify the antidiabetic effects of MC4R activation, diabetes was induced with streptozotocin (STZ) 1 wk before baseline measurements were taken, and the same experimental protocol was followed. In WT and NPY−/− mice, STZ-induced diabetes led to similar hyperphagia, hyperglycemia, and weight loss, which were not reversed by chronic MTII treatment. Our results demonstrate that chronic MC4R activation, even in NPY-deficient mice, does not mimic chronic antidiabetic, cardiovascular, or metabolic actions of leptin, and that NPY is not essential for hyperphagia or cardiovascular changes associated with diabetes.

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