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1
Djebbi, A., W. K. Rebai, O. Bahri, N. Hogga, A. Sadraoui, and H. Triki. "Marqueurs sérologiques, ARN viral et génotype du virus de l’hépatite delta chez des patients tunisiens antigène HBs positifs." Pathologie Biologie 57, no. 7-8 (November 2009): 518–23. http://dx.doi.org/10.1016/j.patbio.2008.09.010.
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Cornillez-Ty, Cromwell T., and David W. Lazinski. "Determination of the Multimerization State of the Hepatitis Delta Virus Antigens In Vivo." Journal of Virology 77, no. 19 (October 1, 2003): 10314–26. http://dx.doi.org/10.1128/jvi.77.19.10314-10326.2003.
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ABSTRACT Hepatitis delta virus expresses two essential proteins, the small and large delta antigens, and both are required for viral propagation. Proper function of each protein depends on the presence of a common amino-terminal multimerization domain. A crystal structure, solved using a peptide fragment that contained residues 12 to 60, depicts the formation of an octameric ring composed of antiparallel coiled-coil dimers. Because this crystal structure was solved for only a fragment of the delta antigens, it is unknown whether octamers actually form in vivo at physiological protein concentrations and in the context of either intact delta antigen. To test the relevance of the octameric structure, we developed a new method to probe coiled-coil structures in vivo. We generated a panel of mutants containing cysteine substitutions at strategic locations within the predicted monomer-monomer interface and the dimer-dimer interface. Since the small delta antigen contains no cysteine residues, treatment of cell extracts with a mild oxidizing reagent was expected to induce disulfide bond formation only when the appropriate pairs of cysteine substitution mutants were coexpressed. We indeed found that, in vivo, both the small and large delta antigens assembled as antiparallel coiled-coil dimers. Likewise, we found that both proteins could assume an octameric quaternary structure in vivo. Finally, during the course of these experiments, we found that unprenylated large delta antigen molecules could be disulfide cross-linked via the sole cysteine residue located within the carboxy terminus. Therefore, in vivo, the C terminus likely provides an additional site of protein-protein interaction for the large delta antigen.
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Uyemura, K., R. J. Deans, H. Band, J. Ohmen, G. Panchamoorthy, C. T. Morita, T. H. Rea, and R. L. Modlin. "Evidence for clonal selection of gamma/delta T cells in response to a human pathogen." Journal of Experimental Medicine 174, no. 3 (September 1, 1991): 683–92. http://dx.doi.org/10.1084/jem.174.3.683.
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T cells bearing gamma/delta antigen receptors comprise a resident population of intraepithelial lymphocytes in organs such as skin, gut, and lungs, where they are strategically located to contribute to the initial defense against infection. An important unsolved question about antigen-driven gamma/delta T cell responses regards the breadth of their T cell receptor (TCR) repertoire, since many specific epithelial compartments in mice display limited diversity. We have examined the diversity of TCR delta gene expression among human gamma/delta T cells from skin lesions induced by intradermal challenge with Mycobacterium leprae. We show that the vast majority of gamma/delta cells from M. leprae lesions use either V delta 1-J delta 1 or V delta 2-J delta 1 gene rearrangements and, within a given region of the lesion, display limited junctional diversity. This contrasts markedly with the extensive diversity of gamma/delta T cells from peripheral blood of these same individuals, as well as skin from normal donors. These results indicate that the gamma/delta response to M. leprae involves the selection of a limited number of clones from among a diverse repertoire, probably in response to specific mycobacterial and/or host antigens.
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Wu, M., L. van Kaer, S. Itohara, and S. Tonegawa. "Highly restricted expression of the thymus leukemia antigens on intestinal epithelial cells." Journal of Experimental Medicine 174, no. 1 (July 1, 1991): 213–18. http://dx.doi.org/10.1084/jem.174.1.213.
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The TL region of the major histocompatibility complex of the mouse contains dozens of tandemly arranged class I genes, including those encoding the thymus leukemia (TL) antigens. TL antigens have been thought to be expressed only on the surface of some T lineage cells, namely immature thymocytes of some mouse strains (TL+ strains), some leukemia cells, and activated T cells. While the function of TL antigens is unknown, recent studies have implicated the products of at least some TL region class I genes as molecules that present antigens to gamma/delta T cells. Since some gamma/delta T cells are known to be specifically associated with certain epithelial tissues, we have investigated the expression of some TL region class I genes in a variety of epithelium-containing tissues. Our results show that the TL antigen gene of C57BL/6 mice, T3b, and the TL antigen genes of BALB/c mice, T3d (previously T3c) and T18d (previously T13c), are highly expressed in the epithelium of the small intestine. In the case of T3b, we further show, using a T3 product-specific antibody, that its product is expressed on the surface of the columnar epithelial cells. In addition, we demonstrated that two other TL region class I genes of C57BL/6 origin, T9b and T21b, are also expressed nearly exclusively in intestinal epithelial cells. These results are consistent with the hypothesis that the products of these TL region class I genes are recognized by gamma/delta T cell receptors of intestinal intraepithelial lymphocytes, a subset of gamma/delta T cells that is localized in the intestinal epithelium and has a restricted V gamma repertoire. Finally, our study indicates that the relative levels of expression of the two homologous TL antigen genes, T3d and T18d, differ widely between the thymus and the intestine.
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Bluestone, J. A., R. Q. Cron, M. Cotterman, B. A. Houlden, and L. A. Matis. "Structure and specificity of T cell receptor gamma/delta on major histocompatibility complex antigen-specific CD3+, CD4-, CD8- T lymphocytes." Journal of Experimental Medicine 168, no. 5 (November 1, 1988): 1899–916. http://dx.doi.org/10.1084/jem.168.5.1899.
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Analyses of TCR-bearing murine and human T cells have defined a unique subpopulation of T cells that express the TCR-gamma/delta proteins. The specificity of TCR-gamma/delta T cells and their role in the immune response have not yet been elucidated. Here we examine alloreactive TCR-gamma/delta T cell lines and clones that recognize MHC-encoded antigens. A BALB/c nu/nu (H-2d)-derived H-2k specific T cell line and derived clones were both cytolytic and released lymphokines after recognition of a non-classical H-2 antigen encoded in the TL region of the MHC. These cells expressed the V gamma 2/C gamma 1 protein in association with a TCR-delta gene product encoded by a Va gene segment rearranged to two D delta and one J delta variable elements. A second MHC-specific B10 nu/nu (H-2b) TCR-gamma/delta T cell line appeared to recognize a classical H-2D-encoded MHC molecule and expressed a distinct V gamma/C gamma 4-encoded protein. These data suggest that many TCR-gamma/delta-expressing T cells may recognize MHC-linked antigens encoded within distinct subregions of the MHC. The role of MHC-specific TCR-gamma/delta cells in immune responses and their immunological significance are discussed.
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Teitell, M., M. F. Mescher, C. A. Olson, D. R. Littman, and M. Kronenberg. "The thymus leukemia antigen binds human and mouse CD8." Journal of Experimental Medicine 174, no. 5 (November 1, 1991): 1131–38. http://dx.doi.org/10.1084/jem.174.5.1131.
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The thymus leukemia antigen (TLA) is a class Ib, or 'nonclassical' class I molecule, one of several encoded within the Tla locus of the mouse major histocompatibility complex (MHC). It structurally resembles the H-2K, D, and L class I transplantation antigens, which present processed peptides to cytotoxic T lymphocytes (CTLs). Although their function(s) are unknown, there has been recent speculation concerning the possibility that class Ib molecules may present antigens to T cells that express gamma delta T cell antigen receptors (TCRs). In this report, using both a cell-cell adhesion assay and adhesion of T lymphocyte clones to purified plate-bound TLA, we provide evidence that TLA can bind to both human and mouse CD8. We also show that a chimeric class I molecule containing the peptide antigen binding site of Ld and the alpha 3 domain, transmembrane, and cytoplasmic segments of TLA, can support a CD8-dependent immune response by CTLs. These results demonstrate for the first time binding of a class Ib molecule to CD8 with a functional outcome, as is observed for the class I transplantation antigens. The capacity to interact with CD8 has been conserved despite the extensive sequence divergence of TLA in the peptide antigen binding site, suggesting this interaction is highly significant. TLA is expressed by epithelial cells in the mouse small intestine. As these epithelial cells are in close contact with intestinal intraepithelial lymphocytes that are nearly all CD8+, and many of which express the gamma delta TCR, the data are consistent with the hypothesis that TLA is involved in antigen presentation, perhaps to gamma delta-positive lymphocytes in this site.
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Jensen, AW, M. Hokland, H. Jorgensen, J. Justesen, J. Ellegaard, and P. Hokland. "Solitary expression of CD7 among T-cell antigens in acute myeloid leukemia: identification of a group of patients with similar T-cell receptor beta and delta rearrangements and course of disease suggestive of poor prognosis." Blood 78, no. 5 (September 1, 1991): 1292–300. http://dx.doi.org/10.1182/blood.v78.5.1292.1292.
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Abstract In a series of 100 acute myeloid leukemia (AML) patients defined by cytochemistry and immunophenotyping, 20 expressed T-lymphocyte associated antigens on the surface of their blasts. While 15 expressed two or more T-cell antigens, five were found to express only CD7. All patients belonged to the French-American-British type M4, and four were under the age of 40. Despite intensive chemotherapy, four never obtained a complete remission and the fifth died of relapse after an allogenic bone marrow transplantation. While 12 randomly selected T- cell antigen negative AML patients showed only few rearrangements in Ig- or T-cell receptor (TCR) genes, such genetic alterations were demonstrated in four of five patients for the TCR delta gene and in all patients for the TCR beta gene. Interestingly, DNA fragments of similar size were demonstrated in three of five patients for both the beta and delta genes. These data suggest that the solitary presence of CD7 among T-cell antigens in otherwise clearcut AML cases identifies a group of patients with similarities in antigen receptor gene configuration as well as outcome.
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Jensen, AW, M. Hokland, H. Jorgensen, J. Justesen, J. Ellegaard, and P. Hokland. "Solitary expression of CD7 among T-cell antigens in acute myeloid leukemia: identification of a group of patients with similar T-cell receptor beta and delta rearrangements and course of disease suggestive of poor prognosis." Blood 78, no. 5 (September 1, 1991): 1292–300. http://dx.doi.org/10.1182/blood.v78.5.1292.bloodjournal7851292.
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In a series of 100 acute myeloid leukemia (AML) patients defined by cytochemistry and immunophenotyping, 20 expressed T-lymphocyte associated antigens on the surface of their blasts. While 15 expressed two or more T-cell antigens, five were found to express only CD7. All patients belonged to the French-American-British type M4, and four were under the age of 40. Despite intensive chemotherapy, four never obtained a complete remission and the fifth died of relapse after an allogenic bone marrow transplantation. While 12 randomly selected T- cell antigen negative AML patients showed only few rearrangements in Ig- or T-cell receptor (TCR) genes, such genetic alterations were demonstrated in four of five patients for the TCR delta gene and in all patients for the TCR beta gene. Interestingly, DNA fragments of similar size were demonstrated in three of five patients for both the beta and delta genes. These data suggest that the solitary presence of CD7 among T-cell antigens in otherwise clearcut AML cases identifies a group of patients with similarities in antigen receptor gene configuration as well as outcome.
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van der Harst, D., A. Brand, SA van Luxemburg-Heijs, YM Kooij-Winkelaar, FE Zwaan, and F. Koning. "Selective outgrowth of CD45RO+ V gamma 9+/V delta 2+ T-cell receptor gamma/delta T cells early after bone marrow transplantation." Blood 78, no. 7 (October 1, 1991): 1875–81. http://dx.doi.org/10.1182/blood.v78.7.1875.1875.
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Abstract Before and after bone marrow transplantation (BMT) for hematologic malignancies, peripheral blood mononuclear cells from 10 patients were obtained. The relative and absolute numbers of CD3+ T-cell receptor gamma delta+ (TCR gamma delta+) cells, as defined by the reaction of monoclonal antibodies (MoAbs) directed against CD3 and the TCR gamma delta (anti-TCR gamma delta-1), were determined. Before transplantation, eight of nine patients tested had less than 10% CD3+TCR gamma delta+ cells. Consistent increased numbers of gamma delta cells up to eightfold the pretransplant level can be seen in four of nine patients tested within the first 4 months after BMT. The large majority of early posttransplant gamma delta and alpha beta T cells express the CD45RO antigen, which is usually expressed on “memory” cells only. The V-region usage of the TCR gamma delta+ T cells was analyzed using fresh mononuclear cells and MoAbs against known V gamma and V delta regions. For more detailed analysis, CD3+TCR gamma delta+ cells were sorted and cultured in bulk and cloned. Using fresh cells and bulk cultures, mainly V gamma 9+V delta 1-V delta 2+ cells were found during engraftment. Only after 6 weeks post-BMT, V gamma 9-V delta 1+V delta 2- cells appear. Analysis of the V gamma and V delta usage at the clonal level confirmed the observation that early after BMT only V gamma 9+V delta 2+ cells are present, whereas gamma delta T- cell clones expressing other gamma delta TCR phenotypes can only be detected 4 to 6 weeks post-BMT. The predominance of V gamma 9+ cells during early engraftment could be explained by several mechanisms: (A) sequential rearrangements during T-cell development, leading to an early wave of V gamma 9+ cells, or (B) selective outgrowth of preexisting V gamma 9+V delta 2+CD45RO+ TCR gamma delta cells in the bone marrow graft, possibly as a result of antigen driven expansion due to exposure to environmental antigens.
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van der Harst, D., A. Brand, SA van Luxemburg-Heijs, YM Kooij-Winkelaar, FE Zwaan, and F. Koning. "Selective outgrowth of CD45RO+ V gamma 9+/V delta 2+ T-cell receptor gamma/delta T cells early after bone marrow transplantation." Blood 78, no. 7 (October 1, 1991): 1875–81. http://dx.doi.org/10.1182/blood.v78.7.1875.bloodjournal7871875.
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Before and after bone marrow transplantation (BMT) for hematologic malignancies, peripheral blood mononuclear cells from 10 patients were obtained. The relative and absolute numbers of CD3+ T-cell receptor gamma delta+ (TCR gamma delta+) cells, as defined by the reaction of monoclonal antibodies (MoAbs) directed against CD3 and the TCR gamma delta (anti-TCR gamma delta-1), were determined. Before transplantation, eight of nine patients tested had less than 10% CD3+TCR gamma delta+ cells. Consistent increased numbers of gamma delta cells up to eightfold the pretransplant level can be seen in four of nine patients tested within the first 4 months after BMT. The large majority of early posttransplant gamma delta and alpha beta T cells express the CD45RO antigen, which is usually expressed on “memory” cells only. The V-region usage of the TCR gamma delta+ T cells was analyzed using fresh mononuclear cells and MoAbs against known V gamma and V delta regions. For more detailed analysis, CD3+TCR gamma delta+ cells were sorted and cultured in bulk and cloned. Using fresh cells and bulk cultures, mainly V gamma 9+V delta 1-V delta 2+ cells were found during engraftment. Only after 6 weeks post-BMT, V gamma 9-V delta 1+V delta 2- cells appear. Analysis of the V gamma and V delta usage at the clonal level confirmed the observation that early after BMT only V gamma 9+V delta 2+ cells are present, whereas gamma delta T- cell clones expressing other gamma delta TCR phenotypes can only be detected 4 to 6 weeks post-BMT. The predominance of V gamma 9+ cells during early engraftment could be explained by several mechanisms: (A) sequential rearrangements during T-cell development, leading to an early wave of V gamma 9+ cells, or (B) selective outgrowth of preexisting V gamma 9+V delta 2+CD45RO+ TCR gamma delta cells in the bone marrow graft, possibly as a result of antigen driven expansion due to exposure to environmental antigens.
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Snapper, C. M., T. M. McIntyre, R. Mandler, L. M. Pecanha, F. D. Finkelman, A. Lees, and J. J. Mond. "Induction of IgG3 secretion by interferon gamma: a model for T cell-independent class switching in response to T cell-independent type 2 antigens." Journal of Experimental Medicine 175, no. 5 (May 1, 1992): 1367–71. http://dx.doi.org/10.1084/jem.175.5.1367.
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T cell-independent type 2 (TI-2), in contrast to T-dependent, antigens stimulate the production of murine IgG3. To investigate a possible role for cytokines in mediating the induction of this IgG subclass, we established an in vitro polyclonal model system for studying TI-2 antigen-mediated B cell activation by using dextran-conjugated anti-IgD antibody (alpha delta-dex). We demonstrate that interferon gamma (IFN-gamma) stimulates, and interleukin 4 inhibits, the expression of IgG3 by alpha delta-dexactivated cells. The production of IFN-gamma by non-T cells in response to bacterial products, possibly capsular polysaccharides, may provide an explanation underlying the ability of TI antigens, which are unable to directly stimulate T cell-derived cytokines to induce Ig isotype switching.
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Fujihashi, K., J. R. McGhee, M. N. Kweon, M. D. Cooper, S. Tonegawa, I. Takahashi, T. Hiroi, J. Mestecky, and H. Kiyono. "gamma/delta T cell-deficient mice have impaired mucosal immunoglobulin A responses." Journal of Experimental Medicine 183, no. 4 (April 1, 1996): 1929–35. http://dx.doi.org/10.1084/jem.183.4.1929.
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Mucosal tissues of mice are enriched in T cells that express the gamma/delta T cell receptor. Since the function of these cells remains unclear, we have compared mucosal immune responses in gamma/delta T cell receptor-deficient (TCRdelta-/-) mice versus control mice of the same genetic background. The frequency of intestinal immunoglobulin (Ig) A plasma cells as well as IgA levels in serum, bile, saliva, and fecal samples were markedly reduced in TCRdelta-/- mice. The TCRdelta-/- mice produced much lower levels of IgA antibodies when immunized orally with a vaccine of tetanus toxoid plus cholera toxin as adjuvant. Conversely, the antigen-specific IgM and IgG antibody responses were comparable to orally immunized control mice. Direct assessment of the cells forming antibodies against the tetanus toxoid and cholera toxin antigens indicated that significantly lower numbers of IgA antibody-producing cells were present in the intestinal lamina propria and Peyer's patches of TCRdelta-/- mice compared with the orally immunized control mice. The selective reduction of IgA responses to ingested antigens in the absence of gamma/delta T cells suggests a specialized role for gamma/delta cells in mucosal immunity.
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Rivera-Molina, Yisel, Juan Fueyo, Hong Jiang, Teresa Nguyen, Dong Ho Shin, Gilbert Youssef, Xuejun Fan, et al. "EXTH-27. ACTIVATING THE IMMUNITY WITHIN THE TUMOR USING VIROIMMUNOTHERAPY: DELTA-24-RGD ONCOLYTIC ADENOVIRUS ARMED WITH THE IMMUNOPOSITIVE REGULATOR GITRL." Neuro-Oncology 21, Supplement_6 (November 2019): vi87. http://dx.doi.org/10.1093/neuonc/noz175.359.
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Abstract Based on promising results of recent clinical trials using oncolytic viruses, virotherapy is evolving as an alternative to treat patients with malignant glioma. Our group developed the oncolytic adenovirus Delta-24-RGD (DNX-2401) that is being tested, alone or in combination with anti-PD1, in clinical trials for recurrent glioblastoma (NCT00805376; NCT01956734; NCT02798406). The results suggest that, besides the expected oncolytic effect, the injection of the pathogen initiated, in a subset of patients, an anti-tumoral immunity that led to 20% of long-term survivors (3.5–5 years). To further enhance this effect, we have armed Delta-24-RGD to express the co-stimulatory ligand GITRL, and generated Delta-24-GREAT. The intracranial injection of Delta-24-GREAT prolonged the survival of GL261 glioma-bearing immunocompetent mice when compared to Delta-24-RGD treatment (P=0.002, log-rank test). Delta-24-GREAT treatment resulted in enhanced frequency of tumor-infiltrating lymphocytes: T lymphocytes (CD45+/CD3+) and cytotoxic T lymphocytes (CD45+CD3+CD8+). Functional studies performed by culturing splenocytes from Delta-24-GREAT-treated mice with glioma cells and analyzing secretion of Th1 cytokines, such as IL2 and IFN-γ, showed that lymphocytes recognized not only viral antigens but also tumoral antigens, suggesting the triggering of anti-tumoral immunity. Of interest, Delta-24-GREAT treatment resulted in an antigen-restricted anti-tumor memory effect and in the generation of central immune memory. Thus, rechallenging the survivor mice from the first experiment with a second implantation of glioma cells did not lead to tumor growth, and we detected an increased frequency of central memory CD8+ T cells (CD45+CD62L+). However, survivor mice developed lethal tumors when implanted intracranially with B16/F10 melanoma cells, strongly indicating that the developed immune response was specific for GL261 glioma antigens. This is a novel approach using an oncolytic adenovirus expressing GITRL to target cancer and to stimulate the immunity within the tumor. Our data strongly indicate that this type of strategy may be further developed to treat patients with malignant glioblastoma.
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Eynon, E. E., and D. C. Parker. "Small B cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens." Journal of Experimental Medicine 175, no. 1 (January 1, 1992): 131–38. http://dx.doi.org/10.1084/jem.175.1.131.
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We have investigated the ability of resting B cells, acting as antigen-presenting cells, to induce tolerance to soluble protein antigens in mice, using an antigen targeted specifically to B cells. We inject mice intravenously with ultracentrifuged Fab fragments of rabbit anti-mouse immunoglobulin D (IgD) (Fab anti-delta). Treatment with Fab anti-delta results in profound tolerance to challenge with 100 micrograms Fab nonimmune rabbit Ig (Fab NRG), precipitated in alum, as measured by antibody production. Tolerance to rabbit Fab is antigen specific, since the treated mice make normal antibody responses to a control antigen, chicken Ig. Tolerance is dependent on antigen presentation by B cells, since intravenous injection of soluble Fab NRG, which is not targeted to B cells, results in a much lower frequency and degree of tolerance, especially at lower doses. T cell help in this system is affected, since T cells from Fab anti-delta-treated mice fail to provide help for an adoptive primary antibody response to Fab NRG when transferred together with normal B cells into severe combined immunodeficient (SCID) mice. The antigen-specific B cell compartment is also affected during tolerance induction, since B cells from treated animals make less antibody than normal B cells when transferred into SCID mice with normal T cells. Although the mechanism of nonresponsiveness in the helper T cell compartment remains to be determined, we think it is likely that the precursors of helper T cells are inactivated or deleted by encountering antigen presented by small, resting B cells, which lack accessory signals necessary to induce helper T cell proliferation and differentiation to effector function.(ABSTRACT TRUNCATED AT 250 WORDS)
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Xia, Yu-Ping, Ming-Fu Chang, David Wei, Sugantha Govindarajan, and Michael M. C. Lai. "Heterogeneity of hepatitis delta antigen." Virology 178, no. 1 (September 1990): 331–36. http://dx.doi.org/10.1016/0042-6822(90)90415-n.
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Kanavaros, P., MC Lescs, J. Briere, M. Divine, F. Galateau, I. Joab, J. Bosq, JP Farcet, F. Reyes, and P. Gaulard. "Nasal T-cell lymphoma: a clinicopathologic entity associated with peculiar phenotype and with Epstein-Barr virus." Blood 81, no. 10 (May 15, 1993): 2688–95. http://dx.doi.org/10.1182/blood.v81.10.2688.2688.
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Abstract Recent evidence has shown that most nasal lymphomas (NL) are associated with a T-cell phenotype and are thus called nasal T-cell lymphomas (NTCL), but little information is available about the T-cell receptor (TCR) expression. The presence of Epstein-Barr virus (EBV) genome has been recently reported in NTCL in Oriental populations in which NL and EBV-associated tumors are more common and in occasional Occidental cases. This prompted us to investigate lymphoma biopsies from 7 non- Oriental patients with NTCL for the expression of natural killer (NK) and T-cell antigens, including TCR proteins, for the presence of EBV- encoded latent membrane protein (LMP) using immunohistochemistry and for the presence of EBV DNA and Epstein-Barr early region (EBER) RNA using in situ hybridization (ISH). Six cases displayed a CD3-, TCR alpha beta-, TCR gamma delta-, CD2+, CD7+, CD5-, CD4-, CD8-, CD56+ phenotype, suggesting that these tumors may be peripheral T-cell lymphomas (PTCL) with extensive loss of T-cell antigens and expression of the NK-cell (CD56) antigen or, alternatively, NK-cell neoplasias. The remaining case was a gamma delta PTCL, as shown by the CD3+, TCR gamma delta+ phenotype and the biallelic gamma and delta TCR gene rearrangements. Using ISH, EBER RNA transcripts were detected in tumor cells in all cases and EBV DNA was shown in the 6 tested cases. In all cases, tumor cells expressed LMP. These findings support the concept that NTCL constitute a distinct group of lymphomas that, in addition to their peculiar clinical features, exhibit an unusual TCR “silent” CD56+ or TCR gamma delta+ phenotype and harbor the EBV. In view of the LMP transforming potential, these data suggest that EBV may play a role in the pathogenesis of NTCL.
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Kanavaros, P., MC Lescs, J. Briere, M. Divine, F. Galateau, I. Joab, J. Bosq, JP Farcet, F. Reyes, and P. Gaulard. "Nasal T-cell lymphoma: a clinicopathologic entity associated with peculiar phenotype and with Epstein-Barr virus." Blood 81, no. 10 (May 15, 1993): 2688–95. http://dx.doi.org/10.1182/blood.v81.10.2688.bloodjournal81102688.
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Recent evidence has shown that most nasal lymphomas (NL) are associated with a T-cell phenotype and are thus called nasal T-cell lymphomas (NTCL), but little information is available about the T-cell receptor (TCR) expression. The presence of Epstein-Barr virus (EBV) genome has been recently reported in NTCL in Oriental populations in which NL and EBV-associated tumors are more common and in occasional Occidental cases. This prompted us to investigate lymphoma biopsies from 7 non- Oriental patients with NTCL for the expression of natural killer (NK) and T-cell antigens, including TCR proteins, for the presence of EBV- encoded latent membrane protein (LMP) using immunohistochemistry and for the presence of EBV DNA and Epstein-Barr early region (EBER) RNA using in situ hybridization (ISH). Six cases displayed a CD3-, TCR alpha beta-, TCR gamma delta-, CD2+, CD7+, CD5-, CD4-, CD8-, CD56+ phenotype, suggesting that these tumors may be peripheral T-cell lymphomas (PTCL) with extensive loss of T-cell antigens and expression of the NK-cell (CD56) antigen or, alternatively, NK-cell neoplasias. The remaining case was a gamma delta PTCL, as shown by the CD3+, TCR gamma delta+ phenotype and the biallelic gamma and delta TCR gene rearrangements. Using ISH, EBER RNA transcripts were detected in tumor cells in all cases and EBV DNA was shown in the 6 tested cases. In all cases, tumor cells expressed LMP. These findings support the concept that NTCL constitute a distinct group of lymphomas that, in addition to their peculiar clinical features, exhibit an unusual TCR “silent” CD56+ or TCR gamma delta+ phenotype and harbor the EBV. In view of the LMP transforming potential, these data suggest that EBV may play a role in the pathogenesis of NTCL.
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Silva, Suresh De, George Fromm, Louis Gonzalez, Arpita Patel, Kyung Yoon, Zachery Opheim, Robert Farmer, Dean Chamberlain, and Taylor Schreiber. "688 In vivo expansion of gamma delta T cells by a CD19-targeted butyrophilin heterodimer leads to elimination of peripheral B cells." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A727. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0688.
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BackgroundA primary mechanism of cancer immunotherapy resistance involves downregulation of specific antigens or major histocompatibility complex based antigen presentation, which renders tumor cells invisible to alpha-beta T cells, but not gamma-delta T cells. Recently, a two-step model of gamma-delta T cell activation has emerged, wherein one butyrophilin (BTN, ie. BTN2A1) directly binds the gamma-delta TCR but is only activated if certain molecular patterns (eg. phosphoantigens) facilitate recruitment of a second BTN (ie. BTN3A1) into a complex to form a BTN2A1/3A1 heterodimer. The BTN2A1/3A1 complex specifically activates the predominant gamma-delta T cell population in the peripheral blood, comprising the Vg9d2 T cell receptor (TCR), but does not activate the primary gamma-delta T cell population in mucosal tissues, comprising the Vg4 TCR. The unique mechanism of action and specificity of gamma-delta TCR/BTN interactions suggests that therapeutic proteins comprising specific BTN heterodimers could be used to target specific gamma-delta T cell populations, with a lower risk of off-target activation common with CD3-directed T cell engagers.MethodsHuman BTN2A1/3A1-Fc-CD19scFv and mouse BTNL1/6-Fc-CD19scFv heterodimeric fusion proteins were purified and binding to CD19 or the respective gamma-delta TCRs was assessed by ELISA, Octet and flow cytometry using gd T-cells isolated from human peripheral blood and mouse intestinal tissue. The functionality of the constructs to activate gamma-delta T cells and mediate killing of tumor cells was assessed using live cell imaging in vitro as well as a murine B-cell lymphoma model in vivo.ResultsThe CD19-targeting scFv domains of the BTN heterodimer fusion proteins bound to human and mouse CD19 with low nanomolar affinity. The BTN2A1/3A1-Fc-CD19scFv compound specifically bound to the Vg9d2 TCR on human gd T cells while the mouse BTNL1/6-Fc-CD19scFv bound to Vg7d4 TCR on mouse gd T cells. Both compounds were able to activate gd T cells in a co-culture assay resulting in degranulation and increased surface expression of CD107a and also increased apoptosis of CD19+ tumor cells. Intraperitoneal administration of the mouse BTNL1/6-Fc-CD19scFv led to anti-tumor effects in A20 tumor bearing BALB/c mice. Phenotyping from BTNL1/6-Fc-CD19scFv treated mice revealed profound and rapid expansion of the endogenous gamma-delta T cells in the circulation and tumor, with concomitant depletion of peripheral CD19+ B-cells, confirming the mechanism of action of the heterodimer as a gamma-delta T cell specific engager.ConclusionsThese results provide proof of mechanism for in vivo manipulation of gamma-delta T cells using antigen-targeted butyrophilin heterodimeric fusion proteins for the treatment of cancer.
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Kozbor, D., G. Trinchieri, D. S. Monos, M. Isobe, G. Russo, J. A. Haney, C. Zmijewski, and C. M. Croce. "Human TCR-gamma+/delta+, CD8+ T lymphocytes recognize tetanus toxoid in an MHC-restricted fashion." Journal of Experimental Medicine 169, no. 5 (May 1, 1989): 1847–51. http://dx.doi.org/10.1084/jem.169.5.1847.
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We have analyzed the ability of human gamma+/delta+ T cells to recognize a nominal antigen in association with MHC molecules. A TT-specific T cell line with approximately 40% gamma+/delta+ T cells was established from a hyperimmunized donor, D.F., by stimulation with antigen and autologous APC. Three DF-derived gamma+/delta+ clones were CD8+ as determined by immunofluorescence staining, and by Southern and Northern blotting with probes detecting delta chain rearrangement and delta and gamma chain transcripts, respectively. The gamma+/delta+ clones responded to stimulation with TT, but not TNP-BSA, and autologous APC by proliferation and IFN-gamma production. No proliferation or IFN-gamma production was detected when TT-specific T cell clones were stimulated with either TT or autologous APC only. The response to TT was enhanced by addition of exogenous IL-2. The use of allogeneic APC from 19 donors sharing one HLA-determinant with the autologous donor D.F., showed that the gamma+/delta+ T cells responded to TT with HLA-DR4-related restriction as measured by proliferation and IFN-gamma production. These results demonstrate that gamma/delta receptors can recognize non-MHC-encoded foreign antigen in a self-MHC-restricted fashion.
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Rellahan, B. L., J. A. Bluestone, B. A. Houlden, M. M. Cotterman, and L. A. Matis. "Junctional sequences influence the specificity of gamma/delta T cell receptors." Journal of Experimental Medicine 173, no. 2 (February 1, 1991): 503–6. http://dx.doi.org/10.1084/jem.173.2.503.
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T lymphocytes bearing the gamma/delta T cell receptor (TCR-gamma/delta) express a limited number of germline variable gene segments, generating receptor sequence diversity primarily through junctional mechanisms. To examine the role of V(D)J junctional sequences in antigen recognition by TCR-gamma/delta, we derived an alloreactive murine TCR-gamma/delta+ T cell line, LKD1, specific for the I-Ad class II major histocompatibility complex (MHC) molecule, and compared its receptor with that expressed by a previously characterized class II MHC alloreactive T cell line, LBK5, specific for I-Ek,b,s Ia molecules. Both LKD1 and LBK5 express receptors encoded by rearranged V gamma 1.2J gamma 2 and V delta 5D delta 2J delta 1 gene elements, differing in sequence only in the V(D)J junctional regions of the gamma and delta genes. These results demonstrate that junctionally encoded sequences corresponding to the putative third complementarity determining region can influence the antigen specificity of TCR-gamma/delta.
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Havran, W., Y. Chien, and J. Allison. "Recognition of self antigens by skin-derived T cells with invariant gamma delta antigen receptors." Science 252, no. 5011 (June 7, 1991): 1430–32. http://dx.doi.org/10.1126/science.1828619.
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Macintyre, E., L. d'Auriol, F. Amesland, P. Loiseau, Z. Chen, L. Boumsell, F. Galibert, and F. Sigaux. "Analysis of junctional diversity in the preferential V delta 1-J delta 1 rearrangement of fresh T-acute lymphoblastic leukemia cells by in vitro gene amplification and direct sequencing." Blood 74, no. 6 (November 1, 1989): 2053–61. http://dx.doi.org/10.1182/blood.v74.6.2053.2053.
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Abstract To define the junctional diversity of T-cell antigen receptor delta gene rearrangements in fresh T-acute lymphoblastic cells and to correlate cell phenotype with the coding potential of rearrangements, we determined the junctional nucleotide sequences of 13 T-cell antigen receptor delta gene rearrangements involving the preferentially rearranged V (V delta 1) and J (J delta 1) segments using in vitro gene amplification and direct sequencing. We showed that, as in gamma delta+ cell lines, extensive junctional diversity exists in these clones and that this diversity is due both to random nucleotide deletions/additions and to the use of at least two D delta segments. We also showed that a high percentage of these rearrangements are potentially translatable (7:13) and that such functional rearrangements occur in both surface CD3+ and CD3- cells. Comparison of alpha beta versus gamma delta surface expression demonstrates that all CD3+ T acute lymphoblastic leukemias with a functional V delta 1-J delta 1 rearrangement express a surface gamma delta receptor and are recognized by the anti-delta monoclonal antibody delta TCS1, whereas a control CD3+ gamma delta+ leukemic case that had not undergone V delta 1 rearrangement was delta TCS1-. In addition, expression of this monoclonal antibody is not restricted by V gamma or C gamma usage or by the covalent or noncovalent link between gamma and delta chains.
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Macintyre, E., L. d'Auriol, F. Amesland, P. Loiseau, Z. Chen, L. Boumsell, F. Galibert, and F. Sigaux. "Analysis of junctional diversity in the preferential V delta 1-J delta 1 rearrangement of fresh T-acute lymphoblastic leukemia cells by in vitro gene amplification and direct sequencing." Blood 74, no. 6 (November 1, 1989): 2053–61. http://dx.doi.org/10.1182/blood.v74.6.2053.bloodjournal7462053.
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To define the junctional diversity of T-cell antigen receptor delta gene rearrangements in fresh T-acute lymphoblastic cells and to correlate cell phenotype with the coding potential of rearrangements, we determined the junctional nucleotide sequences of 13 T-cell antigen receptor delta gene rearrangements involving the preferentially rearranged V (V delta 1) and J (J delta 1) segments using in vitro gene amplification and direct sequencing. We showed that, as in gamma delta+ cell lines, extensive junctional diversity exists in these clones and that this diversity is due both to random nucleotide deletions/additions and to the use of at least two D delta segments. We also showed that a high percentage of these rearrangements are potentially translatable (7:13) and that such functional rearrangements occur in both surface CD3+ and CD3- cells. Comparison of alpha beta versus gamma delta surface expression demonstrates that all CD3+ T acute lymphoblastic leukemias with a functional V delta 1-J delta 1 rearrangement express a surface gamma delta receptor and are recognized by the anti-delta monoclonal antibody delta TCS1, whereas a control CD3+ gamma delta+ leukemic case that had not undergone V delta 1 rearrangement was delta TCS1-. In addition, expression of this monoclonal antibody is not restricted by V gamma or C gamma usage or by the covalent or noncovalent link between gamma and delta chains.
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Hsieh, S. Y., M. Chao, L. Coates, and J. Taylor. "Hepatitis delta virus genome replication: a polyadenylated mRNA for delta antigen." Journal of Virology 64, no. 7 (1990): 3192–98. http://dx.doi.org/10.1128/jvi.64.7.3192-3198.1990.
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Long, M. "Delta-Interacting Protein A and the Origin of Hepatitis Delta Antigen." Science 276, no. 5313 (May 2, 1997): 824–25. http://dx.doi.org/10.1126/science.276.5313.824.
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Hsu, Sheng-Chieh, Jaw-Ching Wu, I.-Jane Sheen, and Wan-Jr Syu. "Interaction and Replication Activation of Genotype I and II Hepatitis Delta Antigens." Journal of Virology 78, no. 6 (March 15, 2004): 2693–700. http://dx.doi.org/10.1128/jvi.78.6.2693-2700.2004.
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ABSTRACT The nucleotide sequences of hepatitis D viruses (HDV) vary 5 to 14% among isolates of the same genotype and 23 to 34% among different genotypes. The only viral-genome-encoded antigen, hepatitis delta antigen (HDAg), has two forms that differ in size. The small HDAg (HDAg-S) trans-activates viral replication, while the large form (HDAg-L) is essential for viral assembly. Previously, it has been shown that the packaging efficiency of HDAg-L is higher for genotype I than for genotype II. In this study, the question of whether other functional properties of the HDAgs are affected by genotype differences is addressed. By coexpression of the two antigens in HuH-7 cells followed by specific antibody precipitation, it was found that HDAgs of different origins interacted without genotypic discrimination. Moreover, in the presence of hepatitis B virus surface antigen, HDAg-S was incorporated into virion-like particles through interaction with HDAg-L without genotype restriction. As to the differences in replication activation of genotype I HDV RNA, all HDAg-S clones tested had some trans-activation activity, and this activity varied greatly among isolates. As to the support of HDV genotype II replication, only clones of HDAg-S from genotype II showed trans-activation activity, and this activity also varied among isolates. In conclusion, genotype has no effect on HDAg interaction and genotype per se only partly predicts how much the HDAg-S of an HDV isolate affects the replication of a second HDV isolate.
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Russell, D. A., and G. A. Castro. "Immunological regulation of colonic ion transport." American Journal of Physiology-Gastrointestinal and Liver Physiology 256, no. 2 (February 1, 1989): G396—G403. http://dx.doi.org/10.1152/ajpgi.1989.256.2.g396.
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Challenge of distal colonic epithelium from Trichinella spiralis-infected guinea pigs with parasite-derived antigen elevated short-circuit current (Isc) for approximately 60 min. The maximum elevation (delta Isc) was approximately 250 microA/cm2 at 5 min after the addition of trichinella antigen. The antigen-induced alterations in Isc were of greater magnitude and duration than those evoked in jejunum. Colonic electrical resistance was transiently reduced after exposure to antigen. There was no significant effect of antigen on electrical parameters of colon from nonimmunized (uninfected) guinea pigs. The antihistamine pyrilamine (10(-5) M) and the prostaglandin synthesis inhibitor indomethacin (10(-6) M) reduced the colonic Isc response to antigen by 40% when used in combination but had insignificant effects when used singly. In contrast, the jejunal Isc response to antigen was totally eliminated by the combined use of those inhibitors. Antigenic stimulation of sensitized colon released histamine and prostaglandin E2 (PGE2). However, the histamine released was only about one-tenth that stimulated by antigen in the jejunum, and PGE2 released was only one-tenth of that stimulated by bradykinin in the colon. PGE2 was not released after antigenic stimulation of jejunum. The antigen-induced colonic delta Isc was reduced approximately 50% by either furosemide or tetrodotoxin. Although histamine- and indomethacin-sensitive factors contribute greatly to the mediation of the antigen-induced delta Isc in jejunum, these autacoids contribute to a lesser extent to the antigen-induced delta Isc in guinea pig colon.
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Fujihashi, K., T. Taguchi, W. K. Aicher, J. R. McGhee, J. A. Bluestone, J. H. Eldridge, and H. Kiyono. "Immunoregulatory functions for murine intraepithelial lymphocytes: gamma/delta T cell receptor-positive (TCR+) T cells abrogate oral tolerance, while alpha/beta TCR+ T cells provide B cell help." Journal of Experimental Medicine 175, no. 3 (March 1, 1992): 695–707. http://dx.doi.org/10.1084/jem.175.3.695.
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Past work has shown that a subset of effector T cells with unique characteristics could abrogate hapten- or antigen-induced tolerance, and the reconstitution of this immune response has been termed contrasuppression. We have studied contrasuppression in a model of oral tolerance (OT) in which adoptively transferred antigen-specific T contrasuppressor (Tcs) cells reverse OT and result in antibody responses to the eliciting antigen. In the present study, we show that murine intraepithelial lymphocytes (IELs) from mice orally immunized with sheep red blood cells (SRBC) contain T cells that exhibit Tcs cell activity. This effect was mediated by CD3+ gamma/delta T cell receptor-positive (TCR+), but not alpha/beta TCR+ T cells, and gamma/delta TCR+ Tcs cells were associated with both the CD4-,CD8+ and CD4-,CD8- (double-negative) IEL fractions. The CD4-,CD8+ gamma/delta TCR+ IELs were further separated into Vicia villosa-adherent and -nonadherent fractions. Adoptive transfer of V. villosa-adherent gamma/delta TCR+ T cells to mice with OT to SRBC resulted in splenic IgA, IgM, and IgG subclass anti-SRBC responses, while V. villosa-nonadherent gamma/delta TCR+ T cells were without activity. The gamma/delta TCR+ IELs did not support in vitro antibody responses in B cell cultures, while alpha/beta TCR+ IELs were effective T helper cells. Further, cytokine production by the gamma/delta TCR+ IELs was examined, and the gamma/delta TCR+ V. villosa-adherent fraction, which possessed contrasuppressor function, contained low levels of IL-5 mRNA and small numbers of IL-5-producing cells when compared with alpha/beta TCR+ IELs and V. villosa-nonadherent gamma/delta TCR+ IELs. Our results now show that mouse IELs contain two distinct types of T cells that function in the immune response, e.g., alpha/beta TCR+ T cells that produce IL-5 and function as helper cells, and gamma/delta TCR+ T cells that restore antibody responses in mice that had been orally tolerized with antigen.
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Asou, N., T. Hattori, M. Matsuoka, F. Kawano, and K. Takatsuki. "Rearrangements of T-cell antigen receptor delta chain gene in hematologic neoplasms." Blood 74, no. 8 (December 1, 1989): 2707–12. http://dx.doi.org/10.1182/blood.v74.8.2707.2707.
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Abstract Rearrangements of the T-cell antigen receptor (TCR) delta chain gene were studied in primary neoplastic cells from 137 patients with leukemia or lymphoma. TCR delta gene rearrangements or deletions were observed in all 50 T-cell neoplasms: 5 of 8 CD3- T-cell neoplasms showed rearrangements, whereas biallelic deletion of TCR delta gene was the most common pattern in CD3+ T-cell neoplasm (39 of 42 patients). Rearrangements of TCR delta gene were also detected in 23 of 40 immature B-cell leukemias, including 22 of 25 patients with rearrangements of TCR gamma gene, 2 of 17 mature B-cell neoplasms, and 3 of 30 myeloid leukemias. Thus, TCR delta gene rearrangement or deletion is always found in T-cell neoplasms and is frequently found in immature B-cell leukemias associated with TCR gamma gene rearrangement. Furthermore, TCR delta gene rearrangements associated with the germline configuration of the TCR beta, gamma, and immunoglobulin heavy chain genes were observed in two immature T-cell leukemias, suggesting that TCR delta gene rearrangements precede TCR gamma and beta gene rearrangements. These results indicate that an analysis of TCR delta gene rearrangement provides potential tools to establish the clonality of immature T-cell neoplasms and to identify the normal stages of lymphocyte differentiation.
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Asou, N., T. Hattori, M. Matsuoka, F. Kawano, and K. Takatsuki. "Rearrangements of T-cell antigen receptor delta chain gene in hematologic neoplasms." Blood 74, no. 8 (December 1, 1989): 2707–12. http://dx.doi.org/10.1182/blood.v74.8.2707.bloodjournal7482707.
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Rearrangements of the T-cell antigen receptor (TCR) delta chain gene were studied in primary neoplastic cells from 137 patients with leukemia or lymphoma. TCR delta gene rearrangements or deletions were observed in all 50 T-cell neoplasms: 5 of 8 CD3- T-cell neoplasms showed rearrangements, whereas biallelic deletion of TCR delta gene was the most common pattern in CD3+ T-cell neoplasm (39 of 42 patients). Rearrangements of TCR delta gene were also detected in 23 of 40 immature B-cell leukemias, including 22 of 25 patients with rearrangements of TCR gamma gene, 2 of 17 mature B-cell neoplasms, and 3 of 30 myeloid leukemias. Thus, TCR delta gene rearrangement or deletion is always found in T-cell neoplasms and is frequently found in immature B-cell leukemias associated with TCR gamma gene rearrangement. Furthermore, TCR delta gene rearrangements associated with the germline configuration of the TCR beta, gamma, and immunoglobulin heavy chain genes were observed in two immature T-cell leukemias, suggesting that TCR delta gene rearrangements precede TCR gamma and beta gene rearrangements. These results indicate that an analysis of TCR delta gene rearrangement provides potential tools to establish the clonality of immature T-cell neoplasms and to identify the normal stages of lymphocyte differentiation.
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Dubois, F., and A. Goudeau. "Kinetics of delta antigen and delta antibody in acute delta hepatitis: evaluation with different enzyme immunoassays." Journal of Clinical Microbiology 26, no. 7 (1988): 1339–42. http://dx.doi.org/10.1128/jcm.26.7.1339-1342.1988.
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Asbury, Sarah, Seung Mi Yoo, and Jonathan Bramson. "101 Engineering gamma/delta T cells with the T-Cell antigen coupler receptor effectively induces antigen-specific tumor cytotoxicity in vitro and in vivo." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A112. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0101.
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BackgroundEngineered T cell therapies have revolutionized treatment of relapsed refractory haematological malignancies, however the cost of treatment for autologous products remains a significant challenge to their widespread use. The high cost is driven largely by the need for personalized manufacturing of autologous cell products. A non-conventional class of T cells, the gamma/delta T cell, can be safely transplanted into an unrelated recipient without inducing graft-versus host disease,1 making them an ideal candidate for mass-manufactured off-the-shelf T cell therapies. We have previously described a novel method of directing conventional alpha/beta T cells towards tumour targets by co-opting the T cell receptor using the T cell Antigen Coupler (TAC) receptor.2 Here, we describe the use of TAC receptors to engineer antigen-specific reactivity into gamma/delta T cells, resulting in highly potent anti-tumor cytotoxicity.MethodsEngineered gamma/delta T cells were manufactured by activating PBMCs with Zoledronate and IL-2. The TAC transgene was introduced into T cells using either VSV-G pseudotype lentivirus or GALV-psuedotyped gamma-retrovirus vectors.Through optimization studies, we determined transduction was highest 24 hours post-activation for lentivirus and 72 hours post-activation for gamma-retrovirus. Cultures were fed with IL-2 supplemented media every 2 – 3 days and enriched on Day 14 to >99% gamma/delta T cell purity using CD4/CD8 magnetic-activated cell sorting depletion (Miltenyi Biotec).ResultsBoth methods of gene transfer tested for our pilot study yielded excellent gene transduction (40% - 70%). Using lentivirus-engineered gamma/delta T cells, we demonstrated that the TAC receptor re-directs gamma/delta T cells to attack tumors in an antigen-specific manner. The presence of the TAC receptor did not interfere with lysis of tumor cells via the natural tumor-reactive gamma/delta T cell receptors. Importantly, TAC-engineered gamma/delta T cells displayed robust cytotoxicity at very low effector:target ratios (<1) and caused regression of human tumor xenografts that were otherwise resistant to non-engineered gamma/delta T cells. Curiously, gamma/delta T cell manufacturing was sensitive to the quality of the lentivirus product, where products with low titers were associated with outgrowth of conventional alpha/beta T cells. Outgrowth of alpha/beta T cells was not observed with gamma-retroviruses. We are presently evaluating the anti-tumor activity of gamma-retrovirus-engineered gamma/delta T cells.ConclusionsOff-the-shelf engineered gamma/delta T cells represent a strategy to reduce manufacturing cost and may represent the next generation of engineered T cell therapies.TAC receptors provide a robust tool for directing gamma/delta T cells to attack tumors that are otherwise resistant to gamma/delta T cells and should be evaluated further.AcknowledgementsThis work was supported by the Samuel Family Foundation, the Ontario Centres of Excellence and Triumvira Immunologics.Ethics ApprovalThe study was approved by McMaster’s Animal Research Ethics Board, AUP#19-02-10.ReferencesArruda LCM, Gaballa A, Uhlin M. Impact of γδ T cells on clinical outcome of hematopoietic stem cell transplantation: systematic review and meta-analysis. Blood Adv 2019;3(21):3436–3448.Helsen CW, Hammill JA, Lau VWC, et al. The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity. Nat Commun 2018;9(1):3049.
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O'Malley, Brendan, and David Lazinski. "A Hepatitis B Surface Antigen Mutant That Lacks the Antigenic Loop Region Can Self-Assemble and Interact with the Large Hepatitis Delta Antigen." Journal of Virology 76, no. 19 (October 1, 2002): 10060–63. http://dx.doi.org/10.1128/jvi.76.19.10060-10063.2002.
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ABSTRACT A novel hepatitis B virus surface antigen mutant harboring a deletion of most of the major antigenic loop region was competent for self-assembly and secretion. Although the mutant protein was competent for interaction with and incorporation of free large hepatitis delta antigen, it was partially defective in hepatitis delta virus RNP incorporation.
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Dong, Henry Y., Patti Cohen, and Po-Shing Lee. "Biphenotypic Gamma-Delta T-Cell Leukemia/Lymphoma with Coexpression of Pax-5 and Other B-Cell Specific Antigens." Blood 104, no. 11 (November 16, 2004): 4549. http://dx.doi.org/10.1182/blood.v104.11.4549.4549.
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Abstract Lineage commitment of B- and T-lymphocytes occurs in early stages of normal differentiation. Pax-5 promotes commitment of B-cell and blocks early development of T-cell. Under neoplastic conditions, aberrant expression of less specific T-cell antigens (CD2, CD5 and CD8) has been detected in certain B-cell lymphomas, and B-cell antigens CD20 and CD79a have been seen in rare cases of T-cell lymphomas. However, coexpression of true lineage specific B-cell antigens Pax-5 and CD19 in T-cells with surface CD3 and T-cell receptors has not been reported in either normal or neoplastic T-cells. We report 4 cases of aggressive T-cell lymphoma/leukemia with a consistent but unusual immunophenotype, which was determined by immunohistochemistry (IHC) in all four cases with paraffin embedded tissue and by flow cytometry (FCM) in 2/4 cases. Molecular and cytogenetic analyses were also attempted in two patients and clinical information will be provided. All patients were male aged 21-79 years. Three patients, including 2 cases of T-ALL, presented with generalized lymphadenopathy and bone marrow involvement (clinical stage IV); 1/3 also had splenic involvement. A distinct mediastinal mass was not identified in any of the patients. Two patients undergoing therapy received the hyper-CVAD regimen and had a poor response to early treatment. One of the two was subsequently treated with Campath without success. The 4th patient presented with an isolated chest wall mass. Detailed clinical information is currently unavailable for 2 patients. In all cases, the neoplastic cells were characterized by blastic morphology and coexpression of bilineage lymphoid antigens. The neoplastic cells in 3 cases with systemic disease were immunoreactive with T-cell antigens CD3, CD5, CD7, CD43, and B-cell antigens CD79a and Pax-5; 2/3 cases that had FCM data both showed expression of CD19 and surface γ/δ-TCR, as well as myeloid antigens CD11c and CD33. The case without FCM data lacked βF1 (α/β-TCR) expression by IHC. In addition, 2/3 cases also had immunophenotypic features of typical T-lymphoblastic leukemia or lymphoma (T-ALL) (CD34+ and TdT+). All three cases lacked NK cell antigen CD56 and T-cell antigen CD2, and were double negative for CD4 and CD8. The tumor cells from the 4th case were positive for all pan-T cell antigens (CD2, CD3, CD7, CD43) except CD5 by IHC, and were double negative for CD4 and CD8. These features were phenotypically consistent with a γ/δ-T cell lymphoma, which was also supported by lack of detectable βF1 expression. Similar to other cases, however, these cells were also positive for B cell antigens Pax-5 and CD79a, as well as CD20. The only patient who had successful molecular and cytogenetic analyses had isochromosome 9 and clonal TCR gamma gene rearrangement. In summary, T-cell lymphoma or leukemia with bi-lineage lymphoid antigens is associated with Pax-5 expression, which may account for the upregulation of CD19. It appears to be a rare disease of γ/δ-T-cell origin with a unique phenotypic profile. Further study is needed to determine if the observed i(9) involves disruption of the Pax-5 locus at 9q13.
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Schittek, B., and K. Rajewsky. "Natural occurrence and origin of somatically mutated memory B cells in mice." Journal of Experimental Medicine 176, no. 2 (August 1, 1992): 427–38. http://dx.doi.org/10.1084/jem.176.2.427.
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While most murine peripheral B cells express germline-encoded antibodies of classes M and D (mu+ delta+ cells), small numbers of memory B cells expressing somatically mutated immunoglobulin G antibodies are generated upon T cell-dependent immunization. Analyzing the antibody repertoire of the mu-delta- B cell pool in unimmunized mice, we show that these cells express somatically mutated VH genes and that most of these genes derive from a set of germline VH genes dominantly expressed by mu+delta+ B cells. Thus, class-switched memory B cells are generated in the absence of intentional immunization, presumably in response to environmental antigens. These cells are either recruited from mu+delta+ B cells or selected from newly arising B cells in parallel to the latter, by the same antigens.
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Bichko, V., S. Barik, and J. Taylor. "Phosphorylation of the hepatitis delta virus antigens." Journal of virology 71, no. 1 (1997): 512–18. http://dx.doi.org/10.1128/jvi.71.1.512-518.1997.
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Born, Willi K., Li Zhang, Maki Nakayama, Niyun Jin, Jennifer L. Chain, Yafei Huang, M. Kemal Aydintug, and Rebecca L. O’Brien. "Peptide antigens for gamma/delta T cells." Cellular and Molecular Life Sciences 68, no. 14 (May 8, 2011): 2335–43. http://dx.doi.org/10.1007/s00018-011-0697-3.
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Lin, J. H., M. F. Chang, S. C. Baker, S. Govindarajan, and M. M. Lai. "Characterization of hepatitis delta antigen: specific binding to hepatitis delta virus RNA." Journal of Virology 64, no. 9 (1990): 4051–58. http://dx.doi.org/10.1128/jvi.64.9.4051-4058.1990.
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Chou, Huei-Chi, Tsai-Yuan Hsieh, Gwo-Tarng Sheu, and Michael M. C. Lai. "Hepatitis Delta Antigen Mediates the Nuclear Import of Hepatitis Delta Virus RNA." Journal of Virology 72, no. 5 (May 1, 1998): 3684–90. http://dx.doi.org/10.1128/jvi.72.5.3684-3690.1998.
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ABSTRACT Hepatitis delta virus (HDV) RNA replicates in the nuclei of virus-infected cells. The mechanism of nuclear import of HDV RNA is so far unknown. Using a fluorescein-labeled HDV RNA introduced into partially permeabilized HeLa cells, we found that HDV RNA accumulated only in the cytoplasm. However, in the presence of hepatitis delta antigen (HDAg), which is the only protein encoded by HDV RNA, the HDV RNA was translocated into the nucleus, suggesting that nuclear import of HDV RNA is mediated by HDAg. Deletion of the nuclear localization signal (NLS) or RNA-binding motifs of HDAg resulted in the failure of nuclear import of HDV RNA, indicating that both the NLS and an RNA-binding motif of HDAg are required for the RNA-transporting activity of HDAg. Surprisingly, any one of the three previously identified RNA-binding motifs was sufficient to confer the RNA-transporting activity. We have further shown that HDAg, via its NLS, interacts with karyopherin α2 in vitro, suggesting that nuclear import of the HDAg-HDV RNA complex is mediated by the karyopherin α2β heterodimer. The nuclear import of HDV RNA may be the first biological function of HDAg in the HDV life cycle.
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Wang, H. W., P. J. Chen, C. Z. Lee, H. L. Wu, and D. S. Chen. "Packaging of hepatitis delta virus RNA via the RNA-binding domain of hepatitis delta antigens: different roles for the small and large delta antigens." Journal of Virology 68, no. 10 (1994): 6363–71. http://dx.doi.org/10.1128/jvi.68.10.6363-6371.1994.
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Wells, F. B., Y. Tatsumi, J. A. Bluestone, S. M. Hedrick, J. P. Allison, and L. A. Matis. "Phenotypic and functional analysis of positive selection in the gamma/delta T cell lineage." Journal of Experimental Medicine 177, no. 4 (April 1, 1993): 1061–70. http://dx.doi.org/10.1084/jem.177.4.1061.
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Recent evidence suggests that T cells expressing gamma/delta antigen receptors (T cell receptor [TCR]) are subject to positive selection during development. We have shown that T cells expressing a class I major histocompatibility complex (MHC)-specific gamma/delta TCR transgene (tg) are not positively selected in class I MHC-deficient, beta 2-microglobulin (beta 2m) gene knockout mice (tg+ beta 2m-). In this report, we examine phenotypic and functional parameters of gamma/delta positive selection in this transgenic model system. TCR-gamma/delta tg+ thymocytes of mature surface phenotype (heat stable antigen-, CD5hi) were found in beta 2m+ but not in beta 2m- mice. Moreover, subsets of tg+ thymocytes with the phenotype of activated T cells (interleukin [IL]2R+, CD44hi, or Mel-14lo) were also present only in the beta 2m+ mice. Cyclosporine A, which blocks positive selection of TCR-alpha/beta T cells, also inhibited gamma/delta tg+ T cell development. These results support the idea that positive selection of TCR-gamma/delta requires active TCR-mediated signal transduction. Whereas tg+ beta 2m+ thymocytes produced IL-2 and proliferated when stimulated by alloantigen, TCR engagement of tg+ beta 2m- thymocytes by antigen induced IL-2R expression but was uncoupled from the signal transduction pathway leading to IL-2 production and autocrine proliferation. Overall, these results demonstrate significant parallels between gamma/delta and alpha/beta lineage development, and suggest a general role for TCR signaling in thymic maturation.
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Rock, E. P., P. R. Sibbald, M. M. Davis, and Y. H. Chien. "CDR3 length in antigen-specific immune receptors." Journal of Experimental Medicine 179, no. 1 (January 1, 1994): 323–28. http://dx.doi.org/10.1084/jem.179.1.323.
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In both immunoglobulins (Ig) and T cell receptors (TCR), the rearrangement of V, D, and J region sequence elements during lymphocyte maturation creates an enormous degree of diversity in an area referred to as the complementarity determining region 3 (CDR3) loop. Variations in the particular V, D, and J elements used, precise points of recombination, and random nucleotide addition all lead to extensive length and sequence heterogeneity. CDR3 loops are often critical for antigen binding in Igs and appear to provide the principal peptide binding residues in TCRs. To better understand the physical and selective constraints on these sequences, we have compiled information on CDR3 size variation for Ig H, L (kappa and lambda) and TCR alpha, beta, gamma, and delta. Ig H and TCR delta CDR3s are the most variable in size and are significantly longer than L and gamma chains, respectively. In contrast, TCR alpha and beta chain distributions are highly constrained, with nearly identical average CDR3 lengths, and their length distributions are not altered by thymic selection. Perhaps most significantly, these CDR3 length profiles suggest that gamma/delta TCRs are more similar to Igs than to alpha/beta TCRs in their putative ligand binding region, and thus gamma/delta and alpha/beta T cells may have fundamentally different recognition properties.
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Glenn, Jeffrey S., James C. Marsters, and Harry B. Greenberg. "Use of a Prenylation Inhibitor as a Novel Antiviral Agent." Journal of Virology 72, no. 11 (November 1, 1998): 9303–6. http://dx.doi.org/10.1128/jvi.72.11.9303-9306.1998.
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ABSTRACT No specific therapy exists for hepatitis delta virus (HDV), which can cause severe liver disease. Molecular genetic studies have implicated the prenylation site of large delta antigen as a critical determinant of HDV particle assembly. We have established a cell culture model which produces HDV-like particles, and we show that delta antigen prenylation can be pharmacologically inhibited by the prenylation inhibitor BZA-5B. Furthermore, BZA-5B specifically abolishes particle production in a dose-dependent manner. These results demonstrate that the use of such a prenylation inhibitor-based antiviral therapy may be feasible and identify a novel class of potential antiviral agents.
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Tsalouchos, Aris, and Maurizio Salvadori. "Principi di immunobiologia del trapianto ed attivazione della risposta immune." Giornale di Clinica Nefrologica e Dialisi 31, no. 1 (February 13, 2019): 65–70. http://dx.doi.org/10.33393/gcnd.2019.506.
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To achieve an effective immune response it is important that T cells can recognize a wide variety of non-self antigens; this allows for restrained immune activation and subsequent antigen-specific killing. This task is accomplished through the generation of a repertoire of T cells in a single individual with specificity for an enormous number of potential foreign antigens presented as peptides on the surface of major histocompatibility complex (MHC) molecules. Variations in MHC structure among individuals increase the variety of peptides that can be presented to T cells; this mechanism protects the species as a whole by ensuring adequate T-cell responses to a given foreign organism. Although slightly different, these MHC polymorphisms expressed in the donor kidney are recognized after kidney transplantation between non genetically-identical humans, and induce alloresponses that in the absence of immunosuppression result in rejection of the allograft. In this chapter, we review basic immunological principles important to the field of kidney transplantation.
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Diacovo, T. G., S. J. Roth, C. T. Morita, J. P. Rosat, M. B. Brenner, and T. A. Springer. "Interactions of human alpha/beta and gamma/delta T lymphocyte subsets in shear flow with E-selectin and P-selectin." Journal of Experimental Medicine 183, no. 3 (March 1, 1996): 1193–203. http://dx.doi.org/10.1084/jem.183.3.1193.
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We have compared the ability of human alpha/beta and gamma/delta T lymphocytes to adhere to selectin-bearing substrates, an interaction thought to be essential for homing and localization at sites of inflammation. Both T cell populations form rolling adhesions on E- and P-selectin substrates under physiologic flow conditions. Although equivalent to alpha/beta T cells in binding to E-selectin, gamma/delta T cells demonstrated greater ability to adhere to P-selectin that was purified or expressed on the surface of activated, adherent platelets. Under static conditions, 80% of gamma/delta T cells and 53% of alpha/beta T cells formed shear-resistant adhesions to P-selectin, whereas only 30% of gamma/delta and alpha/beta T cells adhered to E-selectin. The enhance ability of gamma/delta T cells to adhere to P-selectin cannot be attributed to differences in expression of the P-selectin glycoprotein ligand (PSGL-1), as all alpha/beta T cells versus approximately 75% of gamma/delta T cells expressed PSGL-1. Both cell populations expressed a similar percentage of the carbohydrate antigens sialyl LewisX and cutaneous lymphocyte-associated antigen. Depletion of lymphocyte populations or T cell clones bearing these oligosaccharides with the monoclonal antibody CSLEX-1 and HECA-452, respectively, resulted in a substantial reduction in adhesion to E-selectin and slight reduction in adhesion to P-selectin under flow conditions. Treatment of cells with an endopeptidase that selectively degrades O-sialomucins such as PSGL-1, abolished P-selectin but not E-selectin adhesion. Removal of terminal sialic acids with neuraminidase or protease treatment of cells abrogated cell adhesion to both selectin substrates. These results provide direct evidence for the presence of distinct E- and P-selectin ligands on T lymphocytes and suggest that gamma/delta T cells may be preferentially recruited to inflammatory sites during the early stages of an immune response when P-selectin is upregulated.
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Shaikh, Hafeezullah, Ahsan Mobin, Imtiaz Manzoor, and Muhammad Ashraf Ebrahim. "HEPATITIS DELTA." Professional Medical Journal 25, no. 01 (January 10, 2018): 73–77. http://dx.doi.org/10.29309/tpmj/2018.25.01.541.
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Objectives: The objective of this study is to prevalence of hepatitis delta inpatients with chronic hepatitis B infection. Study Design: Cross-sectional study. Period: Oneyear starting from February 2016 to January 2017. Setting: Patients OPD and admitted to Dowuniversity hospital and Zubaida Medical Center Karachi. Methods: Hepatitis B surface antigen(HbsAg) were analyzed for the presence or absence of Hepatitis D antibody (Anti HDV). 368patients with chronic hepatitis B were included to be part of this study. Patient’s age, duration ofillness and previous treatments were recorded. HBV and HDV virus presence was confirmed byusing Polymerase chain reaction (PCR). Results: Out of 368 patients with chronic HBV infection,291 (79.07%) were males and 77 (20.92%) were females. The male to female ratio was 3.7:1.Patients were aged between 35-60 years. 251 (68.2%) were positive for anti HDV. 211 of themwere males (84%) and 40 were females (15.9%). Conclusion: We have concluded that HDVinfection is associated with higher incidence of hepatocellular carcinoma in patients. Effectiveand early treatment of HDV can reduce the frequency of patients advancing to decompensatedchronic liver disease and hepatocellular carcinoma.
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Bichko, V. V., Y. E. Khudyakov, and J. M. Taylor. "A novel form of hepatitis delta antigen." Journal of virology 70, no. 5 (1996): 3248–51. http://dx.doi.org/10.1128/jvi.70.5.3248-3251.1996.
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Parker, C. M., V. Groh, H. Band, S. A. Porcelli, C. Morita, M. Fabbi, D. Glass, J. L. Strominger, and M. B. Brenner. "Evidence for extrathymic changes in the T cell receptor gamma/delta repertoire." Journal of Experimental Medicine 171, no. 5 (May 1, 1990): 1597–612. http://dx.doi.org/10.1084/jem.171.5.1597.
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The germline repertoire of variable genes for the TCR-gamma/delta is limited. This, together with the availability of several V delta-specific and a C delta-specific mAbs, has made it possible to assess differences in the TCR-gamma/delta repertoire in man. TCR-gamma/delta cells expressing particular V gene segments have been previously shown to be localized in different anatomical sites. In this study, analysis of TCR-gamma/delta V gene segment usage performed on subjects from the time of birth through adulthood revealed striking age-related changes in the TCR-gamma/delta repertoire in peripheral blood. V delta 1+ gamma/delta T cells predominated in thymus as well as in peripheral blood at birth and then persisted as a relatively constant proportion of CD3+ PBL. However, V delta 2+ gamma/delta T cells that constitute a small proportion of the CD3+ cells in thymus and in peripheral blood at birth, then expand and account for the major population of gamma/delta T cells in PBL in adults. No parallel postnatal expansion of V delta 2+ cells in the thymus was observed, even when paired thymus-peripheral blood specimens were obtained on subjects between the ages of 3 d and 8 yr. The subset of V delta 2+ lymphocytes that was expanded in peripheral blood expressed high levels of CD45RO suggesting prior activation of these cells, consistent with the possibility that their expansion might have resulted from exposure to foreign antigens or superantigens. In contrast, V delta 1+ T cells in PBL showed no comparable increase in relative numbers and were either negative or expressed only low levels of CD45RO. Consistent with evidence for extrathymic peripheral expansion of selective TCR-gamma/delta subsets, no link between MHC haplotype and differences in the TCR-gamma/delta V gene usage between individuals was apparent, and identical twins displayed TCR-gamma/delta variable gene segment phenotypes that were strikingly different from one another. The elements that determine the TCR-gamma/delta repertoire in individuals are not known. It is possible that both thymic selection and extrathymic factors may influence the peripheral repertoire. Recently, TCR-gamma/delta+ lymphocytes have been shown to expand markedly in peripheral lymphoid tissues and infectious lesions in response to mycobacterial antigens, and a correlation between mycobacterial responses and TCR-gamma/delta V gene usage has been shown in mice. The data presented here demonstrated peripheral age-related changes in the gamma/delta repertoire and point to the importance of extrathymic expansion of specific gamma/delta subsets in generating the human TCR-gamma/delta repertoire.
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Casey, John L., and John L. Gerin. "Genotype-Specific Complementation of Hepatitis Delta Virus RNA Replication by Hepatitis Delta Antigen." Journal of Virology 72, no. 4 (April 1, 1998): 2806–14. http://dx.doi.org/10.1128/jvi.72.4.2806-2814.1998.
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ABSTRACT Characterizations of genetic variations among hepatitis delta virus (HDV) isolates have focused principally on phylogenetic analysis of sequences, which vary by 30 to 40% among three genotypes and about 10 to 15% among isolates of the same genotype. The significance of the sequence differences has been unclear but could be responsible for pathogenic variations associated with the different genotypes. Studies of the mechanisms of HDV replication have been limited to cDNA clones from HDV genotype I, which is the most common. To perform a comparative analysis of HDV RNA replication in genotypes I and III, we have obtained a full-length cDNA clone from an HDV genotype III isolate. In transfected Huh-7 cells, the functional roles of the two forms of the viral protein, hepatitis delta antigen (HDAg), in HDV RNA replication are similar for both genotypes I and III; the short form is required for RNA replication, while the long form inhibits replication. For both genotypes, HDAg was able to support replication of RNAs of the same genotype that were mutated so as to be defective for HDAg production. Surprisingly, however, neither genotype I nor genotype III HDAg was able to support replication of such mutated RNAs of the other genotype. The inability of genotype III HDAg to support replication of genotype I RNA could have been due to a weak interaction between the RNA and HDAg. The clear genotype-specific activity of HDAg in supporting HDV RNA replication confirms the original categorization of HDV sequences in three genotypes and further suggests that these should be referred to as types (i.e., HDV-I and HDV-III) rather than genotypes.
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Kuo, Yung-Bin, Mei Chao, Yi-Hsuan Lee, Chau-Ting Yeh, and Err-Cheng Chan. "New Enzyme-Linked Immunosorbent Assay for Detection of Antibodies against Hepatitis Delta Virus Using a Hepatitis Delta Antigen Derived from a Taiwanese Clone and Comparison to the Abbott Radioimmunoassay." Clinical and Vaccine Immunology 19, no. 5 (March 7, 2012): 817–19. http://dx.doi.org/10.1128/cvi.05687-11.
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ABSTRACTAn anti-hepatitis delta (HD) enzyme-linked immunosorbent assay (ELISA) using a specific recombinant hepatitis delta antigen derived from a local dominant hepatitis delta virus (hepatitis D virus; HDV) strain in Taiwan has been established. The detection efficiency of this assay was comparable to that of the commercially available Abbott anti-HD radioimmunoassay (RIA) and could be useful in routine laboratory diagnoses of HDV infection.