ABSTRACT
OBJECTIVE: To assess the effect of more intensive medical therapy on the rate of transcranial Doppler (TCD) microemboli and cardiovascular events in patients with asymptomatic carotid stenosis (ACS). DESIGN: A prospective study. SETTING: A teaching hospital. PATIENTS: Four hundred sixty-eight patients with ACS greater than 60% by Doppler peak velocity. MAIN OUTCOME MEASURES: We compared (1) the proportion of ACS patients who had microemboli on TCD, (2) cardiovascular events, (3) rate of carotid plaque progression, and (4) baseline medical therapy, before and since 2003. RESULTS: Among 468 ACS patients, 199 were enrolled between January 1, 2000, and December 31, 2002; and 269 were enrolled between January 1, 2003, and July 30, 2007. Microemboli were present in 12.6% before 2003 and 3.7% since 2003 (P < .001). The decline in microemboli coincided with better control of plasma lipids and slower progression of carotid total plaque area. Since 2003, there have been significantly fewer cardiovascular events among patients with ACS: 17.6% had stroke, death, myocardial infarction, or carotid endarterectomy for symptoms before 2003, vs 5.6% since 2003 (P < .001). The rate of carotid plaque progression in the first year of follow-up has declined from 69 mm(2) (SD, 96 mm(2)) to 23 mm(2) (SD, 86 mm(2)) (P < .001). CONCLUSIONS: Cardiovascular events and microemboli on TCD have markedly declined with more intensive medical therapy. Less than 5% of patients with ACS now stand to benefit from revascularization; patients with ACS should receive intensive medical therapy and should only be considered for revascularization if they have microemboli on TCD.
Subject(s)
Carotid Stenosis/etiology , Critical Care/methods , Intracranial Embolism/complications , Intracranial Embolism/therapy , Aged , Carotid Stenosis/mortality , Chi-Square Distribution , Confidence Intervals , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Kaplan-Meier Estimate , Lipids/blood , Male , Middle Aged , Prospective Studies , Retrospective Studies , Risk Factors , Ultrasonography, Doppler, Transcranial/methods , Viral Plaque Assay/methodsABSTRACT
The ability to control the response of B cells is of particular interest in xenotransplantation as Ab-mediated hyperacute and acute xenograft rejection are major obstacles in achieving long-term graft survival. Regulatory T cells have been proven to play a very important role in the regulation of immune responses to self or non-self Ags. Previous studies have shown that TCRalphabeta+CD3+CD4-CD8- (double-negative (DN)) T cells possess an immune regulatory function, capable of controlling antidonor T cell responses in allo- and xenotransplantation through Fas-Fas ligand interaction. In this study, we investigated the possibility that xenoreactive DNT cells suppress B cells. We found that DNT cells generated from wild-type C57BL/6 mice expressed B220 and CD25 after rat Ag stimulation. These xenoreactive B220+CD25+ DNT cells lysed activated, but not naive, B and T cells. This killing, which took place through cell-cell contact, required participation of adhesion molecules. Our results indicate that Fas ligand, TGF-beta, TNF-alpha, and TCR-MHC recognition was not involved in DNT cell-mediated syngenic cell killing, but instead this killing was mediated by perforin and granzymes. The xenoreactive DNT cells expressed high levels of granzymes in comparison to allo- or xenoreactive CD8+ T cells. Adoptive transfer of DNT cells in combination with early immune suppression by immunosuppressive analog of 15-deoxyspergualin, LF15-0195, significantly prolonged rat heart graft survival to 62.1 +/- 13.9 days in mice recipients. In conclusion, this study suggests that xenoreactive DNT cells can control B and T cell responses in perforin/granzyme-dependent mechanisms. DNT cells may be valuable in controlling B and T cell responses in xenotransplantation.
Subject(s)
Antigens, Heterophile/physiology , B-Lymphocyte Subsets/immunology , Cytotoxicity, Immunologic , Fas Ligand Protein/physiology , Granzymes/physiology , Lymphocyte Activation , Membrane Glycoproteins/physiology , Pore Forming Cytotoxic Proteins/physiology , Signal Transduction/immunology , T-Lymphocyte Subsets/immunology , fas Receptor/physiology , Adoptive Transfer , Animals , Antigens, Heterophile/administration & dosage , B-Lymphocyte Subsets/cytology , B-Lymphocyte Subsets/metabolism , Cell Communication/genetics , Cell Communication/immunology , Cell Death/genetics , Cell Death/immunology , Coculture Techniques , Cytotoxicity, Immunologic/genetics , Fas Ligand Protein/deficiency , Fas Ligand Protein/genetics , Graft Survival/genetics , Graft Survival/immunology , Heart Transplantation/immunology , Lymphocyte Activation/genetics , Membrane Glycoproteins/deficiency , Membrane Glycoproteins/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Perforin , Pore Forming Cytotoxic Proteins/deficiency , Pore Forming Cytotoxic Proteins/genetics , Rats , Rats, Inbred BN , Rats, Inbred Lew , Signal Transduction/genetics , Spleen/cytology , Spleen/immunology , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/transplantationABSTRACT
CD28 is constitutively expressed on CD4(+) cells, but its homologue CD152 is only weakly expressed after cell activation. To determine whether these 2 costimulatory molecules can be inserted into human immunodeficiency virus type 1 (HIV-1), virus was produced in CD28- and CD152-expressing Jurkat-derived cells. Both molecules were efficiently acquired by virions. Virus attachment and infectivity were more affected by CD152 than by CD28. Given that CD28/CD152-CD80/CD86 interactions play a dominant role in antigen presentation, it can thus be proposed that the association between virus-anchored host CD28/CD152 and cell-surface CD80/CD86 on target cells might have consequences for the transmission and pathogenesis of HIV-1.
