The Experts below are selected from a list of 267 Experts worldwide ranked by ideXlab platform
Peter Stastny - One of the best experts on this subject based on the ideXlab platform.
-
Polymorphisms of Mica recognized by human alloantibodies
Immunogenetics, 2008Co-Authors: Allison Silveus, Peter StastnyAbstract:Mica antigens are polymorphic glycoproteins expressed on the surface of human endothelial cells and other cells. Antibodies against Mica have been found in transplant recipients and were found to be associated with decreased survival of kidney allografts. In the present work, we investigated the polymorphisms that are recognized by antibodies against Mica. Soluble Mica recombinant proteins representing 11 common alleles, two hybrid alleles, and two single amino acid mutated alleles were produced. Patterns of reactivity were determined with Mica bound to Luminex beads. In some studies, sera containing antibodies against Mica were absorbed by cell lines transfected with Mica*001, Mica*002, Mica*008, and Mica*009 or with untransfected cells, followed by testing of antibody reactivity against Mica proteins bound to beads. The monoclonal antibodies and sera used in this study were found to recognize up to 14 distinct Mica epitopes as demonstrated by their differential absorption/reactivity patterns. Among these, nine epitopes correlated with a single unique amino acid: one shared two signature amino acids, one shared three signature amino acids in close proximity, and three epitopes involved multiple amino acids in a nonlinear sequence. Two groups of public epitopes (Mica-G1 and Mica-G2) were characterized. Mica shared epitopes were determined by reactivity loss in single Mica antigen bead assays by absorption with Mica transfectants. Since these epitopes may be targets for antibody binding and possibly antibody-mediated allograft rejection, epitope identification may help understand the development of Mica antibodies and to identify suitable donors for sensitized transplant recipients.
-
antibodies against Mica antigens and kidney transplant rejection
The New England Journal of Medicine, 2007Co-Authors: Peter Stastny, Caner Susal, Bernd Dohler, Gerhard OpelzAbstract:Background Good HLA-A, HLA-B, and HLA-DR matches do not guarantee rejection-free renal transplantation. Some kidney transplants fail despite such matches, suggesting that other antigens might be targets for rejection. Major-histocompatibility-complex (MHC) class I–related chain A (Mica) antigens are polymorphic and can elicit antibody production. We sought to determine whether an immune response to Mica antigens might play a role in the failure of kidney allografts. Methods Pretransplantation serum samples from 1910 recipients of kidney transplants from deceased donors were tested for anti-Mica antibodies with an assay in which single Mica antigens were attached to polystyrene microspheres. Results Antibodies against Mica alleles were detected in 217 of the 1910 patients (11.4%). The presence of Mica antibodies was associated with renal-allograft rejection. The mean (±SE) 1-year graft-survival rate was 88.3±2.2% among recipients with anti-Mica antibodies as compared with 93.0±0.6% among recipients without...
-
detection of anti Mica antibodies in patients awaiting kidney transplantation during the post transplant course and in eluates from rejected kidney allografts by luminex flow cytometry
Human Immunology, 2006Co-Authors: Falko M Heinemann, Bhavna Lavingia, H Grossewilde, Guido Sireci, Zhengnan Wang, Peter StastnyAbstract:Previously we have reported on the development of antibodies against Mica alleles in kidney transplant recipients. These alloantibodies have now been determined using a new assay using Luminex beads bound to soluble recombinant Mica antigens produced in insect cells. In the present study we have analyzed sera from 85 kidney transplant recipients on the waiting list and 66 patients transplanted within the last 4 years and 59 acid eluates obtained from allograft nephrectomy specimens. Many of the patients in those groups were sensitized and some had previous transplants (waiting list: 15%; post-tx: 7.6%; eluates 22%) and their sera were found to contain anti-human leukocyte antigen (HLA) and anti-Mica antibodies. Anti-Mica antibodies were detected in 21/85 (24.7%) of the waiting list patients and in 15/66 (22.7%) of the transplanted recipients; 11 of the eluates (18.6%) were found to have Mica-specific antibodies (6 of them also had anti-HLA antibodies and 5 did not). These data suggested that immunization against mismatched Mica alleles induces development of anti-Mica antibodies. The finding of Mica allele-specific antibodies in eluates of kidney transplants suggests that anti-Mica antibodies can be involved in the pathogenesis of kidney allograft rejection. Further studies will be required to determine whether patients who produce alloantibodies against Mica alleles are at risk for transplant rejection even when no HLA antibodies are detected.
-
Characterization of a novel Mica allele, Mica*047
Tissue Antigens, 2002Co-Authors: Yanzheng Zhang, A. M. Lázaro, Fariba Mirbaha, Bhavna Lavingia, Robert Vorhaben, Peter StastnyAbstract:We report the identification of a novel Mica allele, Mica*047. It was initially detected because of an unusual hybridization pattern with sequence-specific oligonucleotides (SSOP) in a normal subject of Caucasian origin. Cloning and sequencing of both strands, and comparison of the sequence with previously defined Mica alleles, revealed that the new allele is similar to Mica*041 except for one nucleotide substitution at position 811 (C→G). It appears that this new allele could have been generated by an interallelic sequence exchange between Mica*011 and Mica*041 1 .
-
identification of Mica as a new polymorphic alloantigen recognized by antibodies in sera of organ transplant recipients
Human Immunology, 2000Co-Authors: Norberto W Zwirner, Fariba Mirbaha, C Y Marcos, Peter StastnyAbstract:Abstract MHC class I-related chain A (Mica) is an HLA-related, polymorphic gene the product of which may be recognized by a subpopulation of intestinal γδ T cells and may play a role in the activation of a subpopulation of natural killer cells. Using anti-Mica specific rabbit sera we previously demonstrated that freshly isolated monocytes, keratinocytes, fibroblasts, and endothelial cells express Mica. To analyze whether Mica may be a target for specific antibodies in sera of transplanted patients, we produced three recombinant Mica proteins consisting of the α1, α2, and α3 domains, and used them in an enzyme-linked immunosorbent assay. We found that several patients had specific antibodies against Mica. Most of them were detected in serum samples collected at different times after organ rejection. Although this finding raises the question of how these patients became immunized, the fact that the polymorphic, HLA-like Mica molecule, expressed at the cell surface of endothelial cells, is recognized by specific antibodies in sera of transplanted patients, suggests the Mica may be a target molecule in allograft rejection.
Alexander Steinle - One of the best experts on this subject based on the ideXlab platform.
-
Mica nkg2d mediated immunogene therapy of experimental gliomas
Cancer Research, 2003Co-Authors: Manuel A Friese, Michael Platten, Stefan Z Lutz, Ulrike Naumann, Steffen Aulwurm, Felix Bischof, H J Buhring, J Dichgans, Hansgeorg Rammensee, Alexander SteinleAbstract:The failure of conventional cancer therapy renders glioblastoma an attractive target for immunotherapy. Tumor cells expressing ligands of the activating immunoreceptor NKG2D stimulate tumor immunity mediated by natural killer (NK), γδ T, and CD8 + T cells. We report that human glioma cells express the NKG2D ligands Mica, MICB, and members of the UL16-binding protein family constitutively. However, glioma cells resist NK cell cytolysis because of high MHC class I antigen expression. Plasmid-mediated or adenovirus-mediated overexpression of Mica in glioma cells enhances their sensitivity to NK and T-cell responses in vitro and markedly delays the growth of s.c. and intracerebral LN-229 human glioma cell xenografts in nude mice and of SMA-560 gliomas in syngeneic VMDk mice. Glioma cells forming progressive tumors after implantation of stably Mica-transfected human LN-229 cells lost Mica expression, indicating a strong selection against Mica expression in vivo . Rejection of Mica-expressing SMA-560 cells in VMDk mice resulted in protective immunity to a subsequent challenge with wild-type tumor cells. Finally, the growth of syngeneic intracerebral SMA-560 tumors is inhibited by peripheral vaccination with adenovirus-mediated, Mica-infected irradiated tumor cells, and vaccination results in immune cell activation in the NK and T-cell compartments in vivo . These data commend Mica immunogene therapy as a novel experimental treatment for human malignant gliomas.
-
cutting edge down regulation of Mica on human tumors by proteolytic shedding
Journal of Immunology, 2002Co-Authors: Helmut R Salih, Hansgeorg Rammensee, Alexander SteinleAbstract:The immunoreceptor NKG2D stimulates tumor immunity through activation of CD8 T cells and NK cells. Its ligand Mica has been shown to be broadly expressed on human tumors of epithelial origin. Mica expression correlates with an enrichment of Vδ1 T cells in tumor tissue. We report that human tumor cells spontaneously release a soluble form of Mica encompassing the three extracellular domains, which is present at high levels in sera of patients with gastrointestinal malignancies, but not in healthy donors. Release of Mica from tumor cells is blocked by inhibition of metalloproteinases, concomitantly causing accumulation of Mica on the cell surface. Shedding of Mica by tumor cells may modulate NKG2D-mediated tumor immune surveillance. In addition, determination of soluble Mica levels may be implemented as an immunological diagnostic marker in patients with epithelial malignancies.
-
interactions of human nkg2d with its ligands Mica micb and homologs of the mouse rae 1 protein family
Immunogenetics, 2001Co-Authors: Alexander Steinle, Veronika Groh, Pingwei Li, Daniel L Morris, Lewis L Lanier, Roland K Strong, Thomas SpiesAbstract:NKG2D is an activating receptor that is expressed on most natural killer (NK) cells, CD8 αβ T cells, and γδ T cells. Among its ligands is the distant major histocompatibility complex class I homolog Mica, which has no function in antigen presentation but is induced by cellular stress. To extend previous functional evidence, the NKG2D-Mica interaction was studied in isolation. NKG2D homodimers formed stable complexes with monomeric Mica in solution, demonstrating that no other components were required to facilitate this interaction. Mica glycosylation was not essential but enhanced complex formation. Soluble NKG2D also bound to cell surface MICB, which has structural and functional properties similar to those of Mica. Moreover, NKG2D stably interacted with surface molecules encoded by three newly identified cDNA sequences (N2DL-1, -2, and -3), which are identical to the human ULBP proteins and may represent homologs of the mouse retinoic acid-early inducible family of NKG2D ligands. Because of the substantial sequence divergence among these molecules, these results indicated promiscuous modes of receptor binding. Comparison of allelic variants of Mica revealed large differences in NKG2D binding that were associated with a single amino acid substitution at position 129 in the α2 domain. Varying affinities of Mica alleles for NKG2D may affect thresholds of NK-cell triggering and T-cell modulation.
Jeffry W Stevenson - One of the best experts on this subject based on the ideXlab platform.
-
Phlogopite Mica-based compressive seals for solid oxide fuel cells: effect of Mica thickness
Journal of Power Sources, 2003Co-Authors: Yeongshyung Chou, Jeffry W StevensonAbstract:Abstract Commercially available Phlogopite Mica papers of varying thickness, ∼0.1, ∼0.2, and ∼0.5 mm, were evaluated as potential solid oxide fuel cell (SPFC) seal materials. The Micas were tested in two forms: plain and hybrid. The hybrid form involved the addition of glass interlayers between the Mica and the adjacent components. For each sample, about 30 thermal cycles were conducted and the 800 °C leak rates were determined. The results showed an excellent thermal cycle stability of the Phlogopite Micas in the hybrid design in that the leak rates remained almost constant after ∼10 cycles. In addition, the leak rate appeared to increase with increasing Mica thickness in the hybrid design, but showed no thickness dependence for Mica in the plain design. The Phlogopite Micas also showed good mid-term (∼500 h) stability in both air and reducing environments. Microstructure characterization showed no distinct degradation such as fragmentation and particle formation after thermal cycle and the mid-term stability tests.
-
thermal cycling and degradation mechanisms of compressive Mica based seals for solid oxide fuel cells
Journal of Power Sources, 2002Co-Authors: Yeongshyung Chou, Jeffry W StevensonAbstract:Abstract Thermal cycling was conducted on compressive Mica seals at 800 °C in air. Thin (∼0.1 mm) Muscovite Mica was pressed between a metal pipe and an alumina substrate and tested for leak rates at a stress of 100 psi in the plain (Mica only) and the hybrid design. The hybrid design involves adding two glass interlayers and was found to greatly reduce the leak rates in an earlier paper. Two metals (Inconel #600 and SS430) with high and low coefficients of thermal expansion (CTE) were used to evaluate the effect of CTE mismatch on thermal cycling. The results showed that the leak rates were lower for the hybrid design than the plain Micas. In addition, using the lower CTE (SS430) metal pipe resulted in lower leak rates as compared to Inconel #600 metal (high CTE). In general, the leak rates increased with the number of thermal cycles; however, it tended to level off after several tens of thermal cycles. Microstructure examination using scanning electron microscopy revealed steps, indents, fragmentation and particle formation on the Mica after thermal cycling. CTE measurement of the heat-treated Muscovite Mica showed a relatively low value of ∼7 ppm/°C. The cause for the degradation of the Mica is discussed.
-
ultra low leak rate of hybrid compressive Mica seals for solid oxide fuel cells
Journal of Power Sources, 2002Co-Authors: Yeongshyung Chou, Jeffry W Stevenson, L A ChickAbstract:Abstract A novel hybrid compressive Mica seal was developed that showed a reduction of leak rate by about 4300 times (compared to simple Mica seals) at 800 °C. The hybrid compressive Mica seal is composed of 2 compliant glass layers and a Mica layer. Three commercially available Micas were tested in hybrid compressive seals for solid oxide fuel cell applications. The best results were obtained using Muscovite single crystal Mica. The normalized leak rate for this seal at 800 °C was only 1.55×10 −4 sccm/cm at a stress of 100 psi and a pressure gradient of 2 psi. Seals based on the other commercial Micas (Muscovite and Phlogopite Mica papers), also exhibited superior leak rates (∼0.011 sccm/cm) compared to simple Mica seals without the compliant glass layer (about 6–9 sccm/cm). The microstructure of the Mica was examined before and after the 800 °C leak tests using scanning electron microscopy. The cause for the substantial reduction of the leak rate was discussed. In addition, the effect of the compressive stresses was also investigated.
-
compressive Mica seals for sofc applications
Journal of Power Sources, 2001Co-Authors: Steven P Simner, Jeffry W StevensonAbstract:Abstract Muscovite and phlogopite Micas have been assessed as SOFC seals at 800°C. Paper gaskets, composed of pressed Mica platelets in an organic binder, proved ineffective seal materials predominantly because of their uneven surface. However, cleaved natural Mica sheets (with no binder) indicated far superior sealing characteristics with leak rates lower than 0.1 sccm cm −1 at 800°C, and approximately 0.7 MPa (100 psi) compressive stress.
Veronika Groh - One of the best experts on this subject based on the ideXlab platform.
-
expression and role of Mica and micb in human hepatocellular carcinomas and their regulation by retinoic acid
International Journal of Cancer, 2003Co-Authors: Masahisa Jinushi, Tetsuo Takehara, Tomohide Tatsumi, Tatsuya Kanto, Veronika Groh, Thomas Spies, Ritsuko Kimura, Takuya Miyagi, Kiyoshi Mochizuki, Yutaka SasakiAbstract:Natural killer (NK) cells are important effector cells for the first line of defense against tumor, but the mechanisms by which they recognize and kill human hepatocellular carcinoma (HCC) remains to be elucidated. Distant MHC class I homologs Mica and MICB are recently identified human ligands for NK cell activating receptor NKG2D. In our present study, Mica or MICB transcript was detected in 6 of 10 human hepatocellular carcinoma tissues, but not in the surrounding non-cancerous tissues. ImmunohistocheMical analysis showed that Mica/B were expressed in the tumor cells of the cancerous tissues. Huh7 and HepG2 hepatoma cells, but not Hep3B cells, substantially expressed Mica/B on their cell surface. Mica/B expressed on hepatoma cells contributed to their NK sensitivity, because Huh7 and HepG2 were less susceptible to NK cytolysis when MAb against Mica/B was added during the cytolysis assay. Of interest is the finding that retinoic acid upregulated expression of Mica/B in Huh7 and HepG2 cells. Retinoic acid-treated hepatoma cells induced IFNγ production from cocultured NK cells and rendered themselves more susceptible to NK cells. This was clearly dependent on upregulation of Mica/B, because both the enhanced IFNγ production and NK cytolysis were completely abolished by MAb-mediated masking of Mica/B. These results suggest that Mica/B, expressed on a subset of human HCCs, may play an important role in their susceptibility to NK cells. Furthermore, retinoic acid can function as a modulator of Mica/B expression and thereby further activate NK cells. © 2003 Wiley-Liss, Inc.
-
interactions of human nkg2d with its ligands Mica micb and homologs of the mouse rae 1 protein family
Immunogenetics, 2001Co-Authors: Alexander Steinle, Veronika Groh, Pingwei Li, Daniel L Morris, Lewis L Lanier, Roland K Strong, Thomas SpiesAbstract:NKG2D is an activating receptor that is expressed on most natural killer (NK) cells, CD8 αβ T cells, and γδ T cells. Among its ligands is the distant major histocompatibility complex class I homolog Mica, which has no function in antigen presentation but is induced by cellular stress. To extend previous functional evidence, the NKG2D-Mica interaction was studied in isolation. NKG2D homodimers formed stable complexes with monomeric Mica in solution, demonstrating that no other components were required to facilitate this interaction. Mica glycosylation was not essential but enhanced complex formation. Soluble NKG2D also bound to cell surface MICB, which has structural and functional properties similar to those of Mica. Moreover, NKG2D stably interacted with surface molecules encoded by three newly identified cDNA sequences (N2DL-1, -2, and -3), which are identical to the human ULBP proteins and may represent homologs of the mouse retinoic acid-early inducible family of NKG2D ligands. Because of the substantial sequence divergence among these molecules, these results indicated promiscuous modes of receptor binding. Comparison of allelic variants of Mica revealed large differences in NKG2D binding that were associated with a single amino acid substitution at position 129 in the α2 domain. Varying affinities of Mica alleles for NKG2D may affect thresholds of NK-cell triggering and T-cell modulation.
-
broad tumor associated expression and recognition by tumor derived γδ t cells of Mica and micb
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Veronika Groh, Rebecca Rhinehart, Heather Secrist, Stefan Bauer, Kenneth H Grabstein, Thomas A SpiesAbstract:Human MHC class I-related molecules, Mica and MICB, are stress-induced antigens that are recognized by a subset of γδ T cells expressing the variable region Vδ1. This functional association has been found to be limited to intestinal epithelium, where these T cells are prevalent and where Mica and, presumably, MICB are mainly expressed. However, increased frequencies of Vδ1 γδ T cells have been observed in various epithelial tumors; moreover, Mica/B are expressed on diverse cultured epithelial tumor cells. With freshly isolated tumor specimens, expression of Mica/B was documented in many, but not all, carcinomas of the lung, breast, kidney, ovary, prostate, and colon. In tumors that were positive for Mica/B, the frequencies of Vδ1 γδ T cells were significantly higher than in those that were negative. Vδ1 γδ T cell lines and clones derived from different tumors recognized Mica/B on autologous and heterologous tumor cells. In accord with previous evidence, no constraints were observed in these interactions, such as those imposed by specific peptide ligands. Thus, Mica/B are tumor-associated antigens that can be recognized, in an apparently unconditional manner, by a subset of tumor-infiltrating γδ T cells. These results raise the possibility that an induced expression of Mica/B, by conditions that may be related to tumor homeostasis and growth, could play a role in immune responses against tumors.
Angelique Pichot - One of the best experts on this subject based on the ideXlab platform.
-
matching for the nonconventional mhc i Mica gene significantly reduces the incidence of acute and chronic gvhd
Blood, 2016Co-Authors: Raphael Carapito, Nicolas Jung, Marius Kwemou, Meiggie Untrau, Sandra Michel, Angelique PichotAbstract:Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain–related gene A, Mica , encodes a stress-induced glycoprotein expressed primarily on epithelia. Mica interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B . Hence, Mica has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of Mica , we retrospectively analyzed the clinical effect of Mica mismatches in a multicenter cohort of 922 unrelated donor HLA-A , HLA-B , HLA-C , HLA-DRB1 , and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in Mica . Mica mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P P P P Mica -matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between Mica and HLA-B renders identifying a Mica -matched donor readily feasible in clinical practice.