| 1. |
- Dimayuga, Paul C, et al.
(författare)
-
T Cell Modulation of Intimal Thickening After Vascular Injury. The Bimodal Role of IFN-{gamma} in Immune Deficiency.
- 2005
-
Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 25:Oct 13, s. 2528-2534
-
Tidskriftsartikel (refereegranskat)abstract
- Background - Immune deficiency results in exuberant intimal thickening after arterial injury. The mechanisms involved are not well defined. We investigated the role of T cells and IFN-gamma in the response to injury in normal and immune-deficient Rag-1KO mice. Methods and Results - Carotid arterial injury was induced in wild-type (WT), Rag-1KO mice, and Rag-1KO mice reconstituted with T cell-enriched splenocytes. The exuberant intimal thickening in Rag-1KO mice compared with WT mice 21 days after injury was reduced by T cell transfer (P < 0.01). Exogenous IFN-gamma starting on the day of injury inhibited intimal thickening in Rag-1KO mice. However, antibody neutralization of endogenous IFN-gamma in Rag-1KO mice starting 7 days after injury decreased intimal thickening, indicating that late presence of IFN-gamma promoted intimal thickening in Rag-1KO mice. Results further suggest that the effect of late IFN-gamma in Rag-1KO mice is mediated in part by increased IRF-1 and iNOS expression, coupled with low SOCS1 expression. Conclusion - T cells inhibit intimal thickening in the early stages of the response to injury through basal IFN-gamma secretion. In the Rag-1KO mice, late IFN-gamma expression promotes intimal thickening. These findings add novel insight to conditions of immune deficiency that affect intimal thickening.
|
|
| 2. |
- Dimayuga, Paul, et al.
(författare)
-
Inhibitory effect on arterial injury-induced neointimal formation by adoptive B-cell transfer in Rag-1 knockout mice.
- 2002
-
Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1524-4636 .- 1079-5642. ; 22:4, s. 644-649
-
Tidskriftsartikel (refereegranskat)abstract
- We investigated the effect of B-cell reconstitution in immune-deficient Rag-1 knockout (KO) mice subjected to arterial injury. After 21 days, injury induced a 4- to 5-fold increase in neointimal formation in Rag-1 KO mice fed normal chow compared with wild-type (WT) mice (0.020+/-0.0160 [n=8] versus 0.0049+/-0.0022 [n=8] mm(2), respectively; P<0.05) and in western-type diet-fed Rag-1 KO mice compared with WT mice (0.0312+/-0.0174 [n=7] versus 0.0050+/-0.0028 [n=6] mm(2), respectively; P<0.05). To investigate the role of B cells in response to injury, Rag-1 KO mice were reconstituted with B cells derived from the spleens of WT mice, with donors and recipients on the same diet. Reconstitution of Rag-1 KO mice with B cells from WT mice (both fed normal chow) reduced neointimal formation compared with the effect in unreconstituted Rag-1 KO mice (0.0076+/-0.0039 [n=9] versus 0.020+/-0.0160 [n=8] mm(2), respectively; P<0.05). Reconstitution of Rag-1 KO mice with B cells from WT mice (both fed a western diet) reduced neointimal formation compared the effect in Rag-1 KO mice (0.0087+/-0.0037 [n=8] versus 0.0312+/-0.0174 [n=7] mm(2), respectively; P<0.05). Injured carotid arteries from reconstituted Rag-1 KO mice had detectable IgM and IgG, indicating viable transfer of B cells. The results suggest that B cells modulate the response to arterial injury.
|
|
| 3. |
- Dimayuga, Paul
(författare)
-
The inflammatory response to arterial injury
- 2001
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atherosclerosis as a disease is postulated to stem from a response to injury of the arterial wall by various stimuli. The inflammatory response is proposed to mediate intimal formation after injury. One pathway of cellular response to injury is through transcription factor NF-kB. We show that balloon injury of rat arteries leads to increased NF-kB activity and ICAM-1 expression, associated with increased medial cell proliferation early (3 days) and neointima formation (14 days) subsequently. Administration of high-dose aspirin, a known anti-inflammatory agent, reduced NF-kB activation, ICAM-1 expression, medial cell proliferation and neointimal formation. Studies on signal transduction that lead to activation of inflammatory genes have focused on the kinase-phosphatase balance mediating signaling pathways. Phosphorylation of specific residues of the transcription factors AP-1 and NF-kB is a critical step in their activation. Protein phosphatase 2A (PP2A) activity was reduced after injury, associated with AP-1 and NF-kB activation. Phosphatase activator octreotide inhibited the injury-induced PP2A inactivation associated with reduced AP-1 and NF-kB activity, and medial SMC proliferation. The effect of hypercholesterolemia on the inflammatory response to periadventitial cuff induced arterial injury was investigated in wild type and apoE deficient mice. Increased serum lipid levels resulted in increased arterial cholesterol content which augmented VCAM-1 expression. This resulted in increased presence of monocyte/macrophage in the wall of the injured artery and increased neointimal formation. Administration of a monoclonal VCAM-1 antibody reduced monocyte accumulation and intimal formation. Furthermore, antibody treatment partially reduced SMC migration in a model of in vitro injury. HDL has been shown to modulate the inflammatory response. Injured hypercholesterolemic apoE deficient mice fed cholesterol diet and treated with reconstituted HDL had reduced presence of MDA-modified LDL in the media after injury. There was also a reduction in VCAM-1 expression, monocyte/macrophage infiltration and reduced neointima formation. Various studies have indicated a complex role of the immune system in the response to injury and atherogenesis. Serum IFN-g was depressed after injury in chow-fed mice. Atherogenic diet also led to depressed serum IFN-g. Injury to immune-deficient RAG-1 KO mice resulted in robust neointimal formation. Reconstitution with T cells from atherogenic diet-fed mice had modest results but direct administration of rIFN-g inhibited neointimal formation. Reconstitution with B cells also inhibited neointimal formation. The systemic effect of arterial injury has not been scrutinized yet. It was hypothesized that injury would affect pre-existing plaques in other arteries of apoE KO mice. Carotid arterial injury had an anti-inflammatory effect on pre-existing plaques in aortic arch of apoE KO mice. This was characterized by less macrophage and lipid presence compared to controls. The injury also had a stabilizing effect on pre-existing plaques as indicated by more connective tissue stain. Plaque sizes were unchanged. The study affirms the inflammatory response to injury at various levels. In addition, new insights into the immune mechanism involved in arterial injury are also presented.
|
|
| 4. |
|
|
| 5. |
- Nordin Fredrikson, Gunilla, et al.
(författare)
-
Inhibition of Atherosclerosis in ApoE-Null Mice by Immunization with ApoB-100 Peptide Sequences.
- 2003
-
Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : The Assoc.. - 1524-4636 .- 1079-5642. ; 23:5, s. 879-884
-
Tidskriftsartikel (refereegranskat)abstract
- Objective - LDL oxidation is believed to play an important role in the development of atherosclerosis, and oxidized LDL particles have been shown to become targets for the immune system. Immunization of animals with oxidized LDL results in reduction of atherosclerosis, suggesting an atheroprotective effect of this immune response. Methods and Results - Using a polypeptide library covering the complete sequence of apoB-100, a large number of native and malondialdehyde-modified peptide sequences in apoB-100 that are recognized by antibodies in human plasma were identified. We report here that immunization with apoB-100 peptide sequences, against which high levels of IgG and IgM antibodies are present in healthy human controls, reduce atherosclerosis in apoE-null mice by about 60%. Immunizations with these peptides were also found to increase the collagen content of subvalvular lesions. Conclusions - These studies have identified peptide sequences in apoB-100 that induce immune responses, which inhibits atherosclerosis. This suggests a way of developing an immunization therapy for coronary heart disease.
|
|
| 6. |
- Shah, Prediman K, et al.
(författare)
-
Vaccine for Atherosclerosis.
- 2014
-
Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 64:25, s. 2779-2791
-
Forskningsöversikt (refereegranskat)abstract
- Atherosclerosis is an immune-mediated inflammatory disease of the arterial wall, with both the innate and adaptive immune systems responding to many endogenous and exogenous antigens. Both proatherogenic as well as atheroprotective roles have been identified for the immune system in atherosclerosis. Hence, it is conceivable that an immunomodulatory strategy via active immunization against many of these antigens could potentially alter the natural history of atherosclerosis. This review discusses: 1) the complex role of important components of the innate and adaptive immune systems in atherogenesis; 2) the nature of many antigens that have been tested successfully in vaccine formulations to reduce atherosclerosis in pre-clinical experimental models; and 3) the potential opportunities and challenges for clinical application of vaccination for atherosclerosis in the future.
|
|
| 7. |
|
|
