Abstract 93: Natural CD4+CD25+ Regulatory T Cells Control the Development and Complications of Abdominal Aortic Aneurysm in Mice
Hafid Ait‐OufellaYu WangOlivier HerbinStéphane PotteauxSimon BourcierLudivine LauransBruno EspositoAlain TedguiZiad Mallat
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Abdominal aortic aneurysm (AAA) is characterized by a prominent inflammatory cell infiltrate and local destruction of extracellular matrix. Following the acute phase, the inflammatory infiltrate is predominately composed of T lymphocytes and macrophages. We have previously reported that inhibition of Th1 or Th2 cell responses had no effect on the development or the complications of experimental murine AAA. We hypothesized that another subset of T cell, natural Treg cells (Tregs), plays a role in the pathophysiology of AAA. Male C57Bl/6 mice were infused with Angiotensin II (1μg/kg/mn) for 28 days using osmotic pumps. A control group received non-immune isotype-matched IgG antibody (n=20) and a group received anti-CD25 antibody (n=20) every 10 days that depleted more than 95% of Tregs in lymphoid organs. Treg depletion induced AAA rupture (15% vs 0%, P<0.05) and more severe AAA stages compared to control mice (P<0.01). Histological analysis showed an increase of elastin degradation (mean layer number 2.5 vs 5.6, P=0.01) and an increase of T cell accumulation in the adventitia of Treg-depleted mice (2816 vs 330 μm2, P<0.01). CD28 or B7 deficiency leads to a profound reduction in Treg cells. We infused Angiotensin II into C57Bl/6 CD28+/+ (n=17), CD28 -/- mice (n=11) or B7 -/- mice (n=16). CD28 or B7 deficiency did not alter the pressor response to Angiotensin II. CD28 and B7 deficiency induced an increase of AAA incidence compared to control mice, respectively 68%, 72%, and 10%, P<0.001. Moreover, CD28 and B7 deficiency induced 20% of AAA rupture whereas no rupture was observed in control mice. In another set of experiments, transfer of Tregs (3x106 cells) into CD28 -/- mice abolished AAA rupture (0% vs 15%, P<0.05) and significantly reduced AAA severity (P<0.01). Moreover, Treg transfer decreased elastin degradation (mean layer number 3.7 vs 2.5, P=0.04) and T cell infiltration in the adventitia (390 vs 2747 μm2, P<0.01). Conclusion: We have shown for the first time that natural regulatory T cell protected against AAA development and rupture.Keywords:
Adventitia
Pathophysiology
Summary: In the present work, two important negative regulators of T cell responses in rats were examined. At the molecular level, rat CTLA-4, a receptor important for deactivating T cell responses, was examined for the expression pattern and in vitro functions. For this purpose, anti-rat CTLA-4 mAbs were generated. Consistent with the studies in mice and humans, rat CTLA-4 was detectable only in CD25+CD4+ regulatory T cells in unstimulated rats, and was upregulated in all activated T cells. Cross-linking rat CTLA-4 led to the deactivation of anti-TCR- and anti-CD28 stimulated (costimulation) T cell responses such as reduction in activation marker expression, proliferation, and cytokine IL-2 production. Although T cells stimulated with the superagonistic anti-CD28 antibody alone without TCR engagement also increased their CTLA-4 expression, a delayed kinetics of CTLA-4 upregulation was found in cells stimulated in this way. The physiological relevance of this finding needs further investigation. At the cellular level, rat CD25+CD4+ regulatory T cells were examined here in detail. Using rat anti-CTLA-4 mAbs, the phenotype of CD25+CD4+ regulatory T cells was investigated. Identical to the mouse and human Treg phenotype, rat CD25+CD4+ T cells constitutively expressed CTLA-4, were predominantly CD45RC low, and expressed high level of CD62L (L-selectin). CD25+CD4+ cells proliferated poorly and were unable to produce IL-2 upon engagement of the TCR and CD28. Furthermore, rat CD25+CD4+ cells produced high amounts of anti-inflammatory cytokine IL-10 upon stimulation. Importantly, freshly isolated CD25+CD4+ T cells from naive rats exhibited suppressor activities in the in vitro suppressor assays. In vitro, CD25+CD4+ regulatory T cells proliferated vigorously upon superagonistic anti-CD28 stimulation and became very potent suppressor cells. In vivo, a single injection of CD28 superagonist into rats induced transient accumulation and activation of CD25+CD4+ regulatory T cells. These findings suggest firstly that efficient expansion of CD25+CD4+ cells without losing their suppressive effects (even enhance their suppressive activities) can be achieved with the superagonistic anti- CD28 antibody in vitro. Secondly, the induction of disproportional expansion of CD25+CD4+ cells by a single injection of superagonistic anti-CD28 antibody in vivo implies that superagonistic anti-CD28 antibody may be a promising candidate in treating autoimmune diseases by causing a transient increase of activated CD25+CD4+ T cells and thus tipping ongoing autoimmune responses toward selftolerance.
CTLA-4
ZAP70
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The aim of the present study was to investigate the effect of removal of the adventitia on vascular remodeling and vasoconstriction of the carotid artery in New Zealand rabbit. Adventitia of carotid artery was removed mechanically. The histology, morphology and reactivity of the carotid artery was observed by immunohistochemistry and measurement of carotid ring tension immediately, 1 week and 2 weeks after removal of the adventitia. No damage of intima and media was observed after removing the adventitia. Removal of the adventitia caused a remarkable proliferation of the vascular media and formed the neointima. Compared with the control ring, norepinephrine (NE)-induced vasocontraction in adventitia -denuded carotid artery was significantly reduced immediately and 1 week after the operation (P0.05). Adventitia removal promoted the neointima formation and decreased vasoconstriction of the carotid artery, indicating that the adventitia is involved in the regulation of vascular remodeling and vasoconstriction.
Adventitia
Neointima
Tunica intima
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Objective To investigate the relationship between adventitia activation and collagen metablosim in rat via the observation of the changes of the adventitial angiotension I-converting enzyme(ACE)activity in the spontancous hypertensive rats(SHR)and Wistar rats,and the possible mechanism of blood vessel remodeling and functional regulation of adventitia.Methods Ten 20 weeks old male spontancous hypertensive rats were used for the experiment group and ten 20 week old male Wistar rat were used for the control group.Blood pressure and heart beat of the rats were measured by tail-cuff method every week.Pathomorphology of the main artery was studied and blood vessel collagen content and ACE activity were determined by spectrophotometer.Results ACE activity of the adventitia of the SHR was significantly higher than that of Wistar rats,and the adventitialy ACE activity was correlated with adventitial collagen level(r=0.65).Conclusion The adventitia of the spontenous hypertensive rat was activated;ACE activity was increased and related to the increase of adventitial collagen.The activation of adventitia in the hypertensive blood vessel remodeling is important.
Adventitia
Cuff
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Aim To develop a new animal model for the investigation of adventitial function in atherosclerosis.Methods One carotid artery adventitia of rabbit with 2 mg/mL typeII collagenase was digested,then adventitia with microforceps was removed,and the contralateral carotid artery was used as control.HE staining and immunohistochemistry were performed to assure adventitia was removed,and to assess intimal change after adventitial removal.Results It is feasible to remove vascular adventitia with collagenase digestion and mechanical dissection.Removal of adventitia of rabbit carotid artery induced neointima development in 2 weeks.Cells in neointima were secreating smooth muscle cells.The other sides were normal.Conclusions The method we used to remove artery adventitia is effective.Normal adventitia is necessary for normal vessel structure.
Adventitia
Neointima
Cervical Artery
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Adventitia
Coronary arteries
Infiltration (HVAC)
Coronary atherosclerosis
Arterial wall
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AIM: To study the pathogenesis of atherosclerotic lesions which were closely related to the adventitial inflammation of coronary artery (CA) in apolipoprotein E gene knockout (apoE-/-) mice. METHODS: The hearts of apoE-/- mice were cut consecutively. Three kinds of CA samples (① Infiltration of inflammatory cells at CA adventitia, without lesion; ② Infiltration of inflammatory cells at CA adventitia, with the top of extending lesion directly from aorta; ③ Infiltration of inflammatory cells at CA adventitia, with mature lesion) were chosen to represent the three stages of atherosclerotic lesion formation. HE staining, Movat staining, immunohistochemical staining and electron transmission microscopy were used respectively to identify the types of the inflammatory cells infiltrated at adventitia of coronary artery. RESULTS: The constituent ratio of macrophages which infiltrated in the CA adventitia without atherosclerotic lesions, of neutrophils which were involved in the CA adventitia with young atherosclerotic lesions and of lymphocytes in the CA adventitia with mature lesions, were 60.00%, 57.65% and 66.67%, which were higher than those in the other two groups, respectively (P0.01). CONCLUSION: It was showed that CA adventitial inflammation might be an early event inducing the formation of atherosclerotic lesions. The CA adventitia undergoes a process from acute to chronic inflammation during the formation of atherosclerotic lesions.
Adventitia
Infiltration (HVAC)
Pathogenesis
Cellular infiltration
Apolipoprotein E
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Ag receptor stimulation of preactivated T cells causes rapid cell death in an IL-2- and Fas-dependent manner. This phenomenon, known as activation-induced cell death (AICD), plays a pivotal role in the removal of Ag-reactive T cells after initial expansion. In this study, we report a novel form of T cell apoptosis that is distinct from classic AICD. When peripheral T cells were activated with anti-CD3 and anti-CD28 Abs precoated onto plastic plates, CD4(+)CD25(-) and CD8 T cells initially expanded but underwent massive apoptosis after 4 d. Unlike classic AICD, this type of T cell apoptosis pathway requires engagement of CD28 and expression of p53, a tumor-suppressor gene. The most striking feature of this form of apoptosis was regulatory T cell resistance. Under the same stimulating conditions, CD4(+)CD25(+) T cells grew continuously beyond 4 d. Consequently, when the entire CD4 population was cultured with plate-bound anti-CD3 plus anti-CD28 Ab, CD4(+)CD25(+)FoxP3(+) regulatory T cells outgrew nonregulatory T cells and expanded >7000-fold after 11 d. The data presented herein demonstrate a novel process of Ag-induced T cell death by sustained TCR and CD28 engagement and represent a simple and efficient procedure for the expansion of regulatory T cells in vitro.
Regulatory T cell
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Objective To study the expressions of CD25 in CD4+ T cells and CD28 in CD8+ T cells in the peripheral blood of HIV/AIDS. Methods CD25 in CD4+ T cells and CD28 in CD8+ T cells in the peripheral blood of 35 HIV/AIDS and 41 normal control were detected by flow cytometr. Results It shows that in patients with HIV/AIDS and the normal subjects,the expression percent of CD25 in CD4+T cells(27.51±4.23)%,(44.41±9.17)%、CD4+25+T cells(2.00±1.42)%,(16.62±4.60)%、CD4+25-T cells(5.16±3.37)%,(21.03±6.19)%、CD28 in CD8+T cells(25.12±6.33)%,(44.24±8.61)%, CD8+28-T cells(36.85±8.98)%,(13.33±4.58)%had significantly different (P0.01);CD8+28+T cells(12.31±4.14)%,(10.51±3.71)%had no significantly different (P0.05). Conclusions The low expression of CD25 in CD4+ T cells and CD28 in CD8+ T cells in HIV infection patients was closely associated with Immunodeficiency by HIV infection, the increase of CD8+28-T cells help to promote HIV/AIDS patients with inflammatory response and immune activation.
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The aim of the present study was to investigate the effect of removal of the adventitia on vascular remodeling and vasoconstriction of the carotid artery in New Zealand rabbit. Adventitia of carotid artery was removed mechanically. The histology, morphology and reactivity of the carotid artery was observed by immunohistochemistry and measurement of carotid ring tension immediately, 1 week and 2 weeks after removal of the adventitia. No damage of intima and media was observed after removing the adventitia. Removal of the adventitia caused a remarkable proliferation of the vascular media and formed the neointima. Compared with the control ring, norepinephrine (NE)-induced vasocontraction in adventitia-denuded carotid artery was significantly reduced immediately and 1 week after the operation (P<0.05). Adventitia removal promoted the neointima formation and decreased vasoconstriction of the carotid artery, indicating that the adventitia is involved in the regulation of vascular remodeling and vasoconstriction.
Adventitia
Neointima
Tunica intima
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10 rabbits underwent a cholesterol feeding. 10 rabbits were used as control animals. After 12 weeks in the tissue extract of the intima-media-complex of the aorta as well as in the serum the total lipids and the total cholesterol were determined. On histological preparations the thickness of the adventitia of the aorta was measured. In comparison to the control group the animals fed with cholesterol showed a significant increase of the lipid values in the serum and the aorta as well as of the thickness of the adventitia. However, no connections could be proved between the parameters of the serum lipids and the morphological changes of the adventitia.
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