Clopidogrel Anergy and Monitored

Clopidogrel Anergy2003 Germany Müller et at 105 patients with stable coronary artery disease using clopidogrel for PCI,about5%of patients showed no response to the drug,which is defined as platelets in the 20μmol/L ADP under the action of its aggregation only on the basis of the inhibition rate of 10%or less.These people postoperative thrombosis,showing the drug has resisters,and postoperative thrombosis related.2004 SchrPat the current

Dysregulation of Circular Antigen-Specific T Cells Anergy in Autoimmune Vitiligo

Background: Vitiligo is an autoimmune disorder related to melanocyte loss;however, the exact interplay between antigen-specific autoimmunity and local oxidative stress remains unclear. Recently, the migration ability and number of Foxp3-expressing regulatory T cells (Tregs) in lesional skin was found to be reduced in vitiligo patients. Objectives: We aimed to clarify the T cell anergy status of melanocytes by focusing on the impaired equivalence of peripheral melanocyte-specific cytotoxic T cells and functional Tregs in patients with progressive vitiligo. Materials and methods: Ten progressive vitiligo patients and 10 age-matched healthy individuals were enrolled in this study. We analyzed the number of functional Tregs in progressive vitiligo patients and compared the findings with those of controls. Next, to assess the suppressive activity of Tregs on melanocyte-specific T lymphocytes, we strictly purified the functional Tregs fraction and Melan-A-specific CD8+ T cells and co-cultured these cells with each other. The number of Melan-A-specific CD8+ T cells was then counted by FACS. In addition, the expression of the representative exhaustion markers PD-1 and CTLA-4 on functional Tregs was assessed in vitiligo patients and normal controls. Results: The number of functional Tregs itself was not significantly decreased in the blood of vitiligo patients compared to healthy controls. However, the cytotoxic T cell (CTL) proliferation was significantly decreased after cultivation with Tregs from healthy individuals (p < 0.01), and this decrease in CTLs was less marked after cultivation with Tregs from vitiligo patients. Conclusions: We demonstrated a reduced suppressive function of activated Tregs on Melan-A-specific CTLs in the circulating cells of vitiligo patients compared with healthy controls. This result suggests that T cell anergy with Tregs dysfunction may participate in the immune response to melanocytes in vitiligo patients.

Cytokines in the BALB/c mouse testis in various conditions

Aim: To investigate whether testosterone, estrogens, vasectomy, experimental cryptorchidism, varicocele or agingwould induce changes in the cytokine environment of the mouse testis. Methods: In adult male BALB/c mice,testosterone implants, estradiol benzoate, vasectomy, unilateral cryptorchidism, unilateral varicocele were adminis-tered/performed. The mice were followed up for different periods of time and were then sacrificed with testes incisedfor examination. The control mice received the vehicle or sham-operation. Results: IL-10 was present in Leydigcells of nearly every testis and IL-10 + macrophages in 39% of testes. IL-6 was found in the testes of intact adultmice, mice treated with testosterone for 70 days, cryptorchid testes and sham-operated testes. Conclusion: Resultssuggest that IL-10 might be involved in the generation of the immunologically privileged microenvironment in the testis.(Asian J Androl 2001 Mar; 3: 9-19)

Natural epitope variants of the hepatitis C virus impair cytotoxic T lymphocyte activity

AIM:To understand how interactions between hepatitis C virus(HCV) and the host's immune system might lead to viral persistence or effective elimination of HCV.METHODS:Nucleotides 3519-3935 of the non-structural 3(NS3) region were amplified by using reverse transcription polymerase chain reaction(PCR).PCR products of the HCV NS3 regions were integrated into a PCR T7TOPO TA vector and then sequenced in both directions using an automated DNA sequencer.Relative major histocompatibility complex binding levels of wild-type and variant peptides were performed by fluorescence polarization-based peptide competition assays.Peptides with wild type and variant sequences of NS3 were synthesized locally using F-moc chemistry and purified by high-performance liquid chromatography.Specific cytotoxic T lymphocytes(CTLs) clones toward HCV NS3 wild-type peptides were generated through limiting dilution cloning.The CTL clones specifically recognizing HCV NS3 wild-type peptides were tested by tetramer staining and flow cytometry.Cytolytic activity of CTL clones was measured using target cells labeled with the fluorescence enhancing ligand,DELFIA EuTDA.RESULTS:The pattern of natural variants within three human leukocyte antigen(HLA)-A2-restricted NS3 epitopes has been examined in one patient with chronic HCV infection at 12,28 and 63 mo post-infection.Results obtained may provide convincing evidence of immune selection pressure for all epitopes investigated.Statistical analysis of the extensive sequence variation found within these NS3 epitopes favors a Darwinian selection model of variant viruses.Mutations within the epitopes coincided with the decline of CTL responses,and peptide-binding studies suggested a signif icant impact of the mutation on T cell recognition rather than peptide presentation by HLA molecules.While most variants were either not recognized or elicited low responses,such could antagonize CTL responses to target cells pulsed with wild-type peptides.CONCLUSION:Cross-recognition of CTL epitopes from wild-type and naturally-occurring HCV variants may lead to impaired immune responses and ultimately contribute to viral persistence.

Frequency and Absolute Number of FoxP3^+ Regulatory T Cells Correlate with Disease Progression of Chronic HIV-1 Infection

CD4^＋CD25^＋ Regulatory T cells （Treg） have been found to down-regulate immune activation in HIV-1 infection. However, whether the depletion of Treg benefits to the disease status of HIV infection remains undefined. To address this issue, we enumerated the Treg absolute counts and frequency in 75 antiviral-naive HIV-1-infected individuals in this study. It was found that HIV-infected patients displayed a significant decline in Treg absolute counts but a significant increase in Treg frequency. In addition, with disease progression indicated by CD4 T-cell absolute counts, circulating Treg frequency gradually increased; while Treg absolute counts were gradually decreased, suggesting that the alteration of Treg number closely correlated with disease progression in HIV infection Functional analysis further showed that Treg efficiently inhibit both CD4 and CD8 T cell proliferation in vitro. Thus, our findings indicates that Treg actively participate in pathogenesis of chronic HIV infection, influencing the disease progression.

Adaptive immune response during hepatitis C virus infection

Hepatitis C virus(HCV)infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma.HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control.Liver damage and disease progression during HCV infection are driven by both viral and host factors.Specifically,adaptive immune response carries out an essential task in controllingnon-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery.HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion.To impair HCV-specific T cell reactivity,HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro-and antiapoptotic proteins.In this review,the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.

New era in cancer immunotherapy: Twenty years to the discovery of monoclonal antibodies harnessing the immune system to eradicate tumors

The better understanding of the mechanism in which the immune system responds to the developing cancer provided the outcome in a new era in cancer immunotherapy. The tumor suppressive effect on the immune system is caused by negative T cell receptor signaling that abrogate immunity against the cancer cells. Novel monoclonal antibodies that target co-inhibitory receptors on T cells block the tumor induced inhibition of the immune system and enable the immune system to eradicate the tumors. The development of such antibodies started twenty years ago by the preparation of a monoclonal antibody termed BAT. A single administration of the antibody to tumor bearing mice resulted in striking anti tumor activity that was mediated by the lymphocytes. These studies provided a basis for the new era of cancer immunotherapy. The present review summarizes twenty years to the discovery of monoclonal antibodies harnessing the immune system to eradicate tumors.

mIgM-mediated splenic marginal zone B cells targeting of folic acid for immunological evasion

Folic acid is a fully oxidized synthetic folate with high bioavailability and stability which has been extensively prescribed to prevent congenital disabilities.Here we revealed the immunosuppressive effect of folic acid by targeting splenic marginal zone B(MZB)cells.Folic acid demonstrates avid binding with the Fc domain of immunoglobulin M(IgM),targeting IgM positive MZB cells in vivo to destabilize IgM-B cell receptor(BCR)complex and block immune responses.The induced anergy of MZB cells by folic acid provides an immunological escaping window for antigens.Covalent conjugation of folic acid with therapeutic proteins and antibodies induces immunological evasion to mitigate the production of anti-drug antibodies,which is a major obstacle to the long-term treatment of biologics by reducing curative effects and/or causing adverse reactions.Folic acid acts as a safe and effective immunosuppressant via IgM-mediated MZB cells targeting to boost the clinical outcomes of biologics by inhibiting the production of anti-drug antibodies,and also holds the potential to treat other indications that adverse immune responses need to be transiently shut off.