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1.
Characterization of the dominant autoreactive T-cell epitope in spontaneous autoimmune haemolytic anaemia of the NZB mouse 总被引:3,自引:0,他引:3
Shen CR Ward FJ Devine A Luross JA Lowrey PA Wraith DC Elson CJ Barker RN 《Journal of autoimmunity》2002,18(2):149-157
NZB mice spontaneously develop autoimmune haemolytic anaemia (AIHA) due to a T helper-dependent autoantibody response against the erythrocyte anion channel protein, Band 3. Here, we characterize the recognition of the Band 3 sequence 861-874, which carries the dominant, I-E(d)-restricted T cell epitope. The ability of N and C-terminal truncated versions of peptide 861-874 to elicit NZB splenic T-cell proliferation indicated that the core epitope spans residues 862-870. Next, a set of alanine substitution analogues was tested to determine which residues functioned either as MHC anchor or TCR contact residues. A combination of proliferation and MHC:peptide binding assays identified residues 862(L), 864(V), 865(L), and 869(K) as I-E(d) anchor residues, and 868(V) as the only TCR contact residue. The ability of the wild-type sequence 861-874 to compete with a high affinity reference peptide for binding to I-E(d) indicates that the escape of pathogenic NZB T cells from purging of the autoreactive repertoire cannot be attributed to ineffective presentation of peptide 861-874 by its restricting element. It will now be possible to design altered peptide ligands of Band 3 861-874, in order to further dissect the mechanisms responsible for the maintenance and loss of T cell tolerance to RBC autoantigens, and to modulate the immune response in AIHA. 相似文献
2.
Foxp3+ regulatory T cells (Tregs) are unique in their immunosuppressive abilities and contribution to immune regulation. However, the homeostatic processes and survival programs that maintain the Treg population remain unclear. Here, we highlight the recent study by Pierson et al.,1 which dissected the regulatory mechanisms of Treg home- ostasis and survival. 相似文献
3.
The role of interleukin (IL)-21 in influencing tumor growth or enhancing anti-tumor immunity is somewhat controversial. To further understand the potential regulatory effects of IL-21, we utilized an IL-21-secreting EG7 tumor model to demonstrate the direct effects of IL-21 on host tumor-infiltrating lymphocyte (TIL) profiles. Vector control EG7 cells (EG7-Vec) produced very low amounts of IL-21 and were highly tumorigenic. In contrast, IL-21-expressing EG7 cells, EG7-IL-21L and EG7-IL-21H, secreted relatively and extremely high levels of IL-21, respectively. Most importantly, both IL-21-expressing EG7 cells’ control of tumor growth was not due to increased proliferative ability of tumor cells, but resulted from the induction of cytotoxic cellular responses in immunocompetent mice. To identify the effects of cancer immunoediting, tumor-infiltrating lymphocyte profiles were analyzed. NK cell populations appeared to be increased in EG7-IL-21H tumor sites at days 6-8 (progression stage), though this phenomenon did not persist at days 10-12 (regression stage). However, at both days 6-8 and 10-12, a higher frequency of CD8+ T cells was observed at the tumor site in EG7-IL-21H-inoculated mice than in EG7-Vec-inoculated mice. These findings suggest that NK cell-mediated tumor rejection may efficiently drive the development of tumor-specific cytotoxic T cell responses with the help of elevated IL-21 expression. These results also suggest the therapeutic potential of IL-21. 相似文献
4.
Hall AM Ward FJ Shen CR Rowe C Bowie L Devine A Urbaniak SJ Elson CJ Barker RN 《Blood》2007,110(13):4511-4517
The mechanisms underlying apparently spontaneous autoimmune diseases, such as autoimmune hemolytic anemia (AIHA) in New Zealand Black (NZB) mice, are unknown. Here, we determine the contribution of the dominant red blood cell (RBC) autoantigen, the anion exchanger protein Band 3, to the development of NZB autoimmune responses. The approach was to prevent Band 3 expression in NZB mice by disrupting the AE1 gene. AE1(-/-) NZB mice produced RBC autoantibodies at the same levels as the wild-type strain, but they differed in recognizing antigens that correspond to glycophorins, rather than Band 3. Splenic T-helper (Th) cells from wild-type NZB mice proliferated strongly against multiple Band 3 peptides, particularly the dominant epitope within aa861-874. This helper response was severely attenuated in AE1(-/-) animals, leaving only weak proliferation to peptide aa861-874. The results demonstrate that the defect in self-tolerance in NZB AIHA is directed to the RBC type, and is not specific for, or dependent on, Band 3. However, the predisposition to RBC autoimmunity may be focused onto Band 3 by weak Th cell cross-reactivity between the helper dominant epitope and an exogenous antigen. The redundancy of the major autoantigen illustrates the requirement for specific therapy to induce dominant forms of tolerance, such as T-cell regulation. 相似文献
5.
Chiu CC Lin CY Lee LY Chen YJ Kuo TF Chang JT Liao CT Wang HM Yen TC Shen CR Liao SK Cheng AJ 《Molecular cancer therapeutics》2008,7(9):2788-2797
Glucose-regulated protein 78 (Grp78) is an endoplasmic reticulum chaperone protein and is overexpressed in various cancers. However, it is unclear how significance of this molecule play an active role contributing to the oncogenic effect of head and neck cancer (HNC). To investigate the potential function of Grp78, six HNC cell lines were used. We found that Grp78 is highly expressed in all six cell lines and many of the proteins were localized in the periphery regions, implying other function of this molecule aside from endoplasmic reticulum stress response. Knockdown of Grp78 by small interfering RNA significantly reduced cell growth and colony formation to 53% to 12% compared with that of controls in all six HNC cell lines. Using in vitro wound healing and Matrigel invasion assays, we found that cell migration and invasive ability were also inhibited to 23% to 2% in all these cell lines tested. In vivo xenograft studies showed that administration of Grp78-small interfering RNA plasmid into HNC xenografts significantly inhibited both tumor growth in situ (>60% inhibition at day 34) and liver metastasis (>90% inhibition at day 20). Our study showed that Grp78 actively regulates multiple malignant phenotypes, including cell growth, migration, and invasion. Because knockdown Grp78 expression succeeds in the reduction of tumor growth and metastatic potential, this molecule may serve as a molecular target of therapeutic intervention for HNC. [Mol Cancer Ther 2008;7(9):2788-97]. 相似文献
6.
Hao-Li Liu Yau-Yau Wai Po-Hong Hsu Lee-Ang Lyu Jia-Shin Wu Chia-Rui Shen Jin-Chung Chen Tzu-Chen Yen Jiun-Jie Wang 《Journal of cerebral blood flow and metabolism》2010,30(1):177-186
Focused ultrasound has been discovered to locally and reversibly increase permeability of the blood–brain barrier (BBB). However, inappropriate sonication of the BBB may cause complications, such as hemorrhage and brain tissue damage. Tissue damage may be controlled by selecting optimal sonication parameters. In this study, we sought to investigate the feasibility of labeling cells with superparamagnetic iron oxide particles to assess the inflammatory response during focused-ultrasound-induced BBB opening. We show that infiltration of phagocytes does not occur using optimal parameters of sonication. Taken together, the results of our study support the usefulness and safety of focused-ultrasound-induced BBB opening for enhancing drug delivery to the brain. These findings may have implications for the optimization of sonication parameters. 相似文献
7.
Yih-Shiou Hwang Chia-Rui Shen Shirley H. L. Chang Chi-Chun Lai Chao-Lin Liu Kuan-Jen Chen Ken-Kuo Lin Tun-Lu Chen Ching-Hsi Hsiao 《Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie》2011,249(1):103-110
Background
Anterior segment cytomegalovirus (CMV) infection, which can be presented as anterior uveitis and corneal endotheliitis, has recently been reported in immunocompetent patients. We would like to access the validity of two presumed characteristic clinical profiles: profile 1, non-herpes simplex virus (HSV)/varicella zoster virus (VZV) corticosteroid-recalcitrant inflammatory ocular hypertensive syndrome (IOHS), and profile 2, corneal endotheliitis with specific coin-shaped keratic precipitates (KPs), that could be helpful in identifying CMV anterior segment intraocular infection. 相似文献8.
9.
Chou AS Chen HC Li CR Hsieh CH Ting LL Liao SK 《Cancer biotherapy & radiopharmaceuticals》2011,26(4):417-426
The mechanisms underlying tumor dormancy in human primary lesions and bone marrow metastases of nasopharyngeal carcinoma (NPC) are still not completely understood. The aim of this study was to determine differences in the fates of cultured primary NPC (P-NPC) cells, interferon-γ-transduced primary NPC (IFN-γ-P-NPC) cells, bone marrow metastatic NPC (BM-NPC), and IFN-γ-transduced BM-NPC (IFN-γ-BM-NPC) cells following xenotransplantation into these four groups of SCID mice through subcutaneous injection of 5×10(6) cells/site/animal (4 animals/group). The injected mice were monitored for tumor development at the sites of injection. In only the group injected with IFN-γ-P-NPC cells, the resulting nodules remained small throughout the 60-day observation period after injection, but gradually became palpably prickly. Histopathological examination revealed that these lesions invariably consisted of mostly structures of horny pearls and keratin bridges with occasional apoptotic and degenerative cells. In contrast, animals injected with nontransduced-P-NPC cells developed tumors progressively with occasional central necroses. In the two groups injected with IFN-γ-NPC-BM and NPC-BM cells, progressive growths of tumors were noted, with the latter being at slightly faster rates, whereas the xenografts of both groups showed a poorly differentiated phenotype with abundant vascularity. The study results highlight the high susceptibility of P-NPC but not BM-NPC following IFN-γ gene transfer to the induction of tumor dormancy, which is mediated via induced cell differentiation. Thus, induced cell differentiation could provide a new mechanism by which tumor dormancy is induced. 相似文献
10.
Mei-Fen Shih Yih-Dih Cheng Chia-Rui Shen Jong-Yuh Cherng 《Journal of natural medicines》2010,64(3):330-335