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1
Sato, Yuichiro, Kiminori Matsubara, Takanori Kubo, Hirobumi Sunayama, Yuta Hatori, Kinjiro Morimoto, and Toshio Seyama. "High Mannose Binding Lectin (PFL) from Pseudomonas fluorescens Down-Regulates Cancer-Associated Integrins and Immune Checkpoint Ligand B7-H4." Cancers 11, no. 5 (April 30, 2019): 604. http://dx.doi.org/10.3390/cancers11050604.
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Pseudomonas fluorescens lectin (PFL), which belongs to the high mannose (HM)-binding OAAH (Oscillatoria agardhii agglutinin homologue) lectin family, induces cancer cell death. However, the detailed mechanisms underlying this process have not yet been elucidated. We found that PFL decreased various integrins as well as EGFR in cancer cells by promoting internalization and autophagic degradation of these molecules, subsequently inducing caspase-8 dependent cell apoptosis. As revealed by an ex vivo angiogenesis assay using the rat aortic model, PFL inhibited neovascularization in a dose-dependent manner, which was potentially mediated by down-regulation of endothelium integrins. Interestingly, PFL also down-regulated B7-H4 in cancer cells, which has been implicated as a negative regulator of T cell-mediated immunity. We found that B7-H4 co-localized with β3 integrin in MKN28 gastric cancer cells. siRNA silencing of B7-H4 in MKN28 cells decreased expression of β3 integrin, suggesting physical and functional association between these molecules. Direct interaction of PFL with integrin αvβ3 or B7-H4 was examined by surface plasmon resonance analysis, which detected high affinity glycan-dependent binding to PFL. These investigations suggest that PFL interaction with cell surface integrins is a key process for the anti-cancer activities of PFL.
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Damle, N. K., K. Klussman, G. Leytze, A. Aruffo, P. S. Linsley, and J. A. Ledbetter. "Costimulation with integrin ligands intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 augments activation-induced death of antigen-specific CD4+ T lymphocytes." Journal of Immunology 151, no. 5 (September 1, 1993): 2368–79. http://dx.doi.org/10.4049/jimmunol.151.5.2368.
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Abstract Integrin ligands intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) can efficiently costimulate proliferation of resting T cells but not that of Ag-specific T cells. In contrast, CD28 ligand B7 and CD2 ligand leukocyte function-associated Ag (LFA-3) can support IL-2 synthesis and proliferation of Ag-specific T cells more efficiently than that of resting T cells. The molecular basis for this differential costimulation of T cells is poorly understood. In this study, using mAb and soluble IgC gamma 1 chimeras of these adhesion molecules, we demonstrate that coligation of the TCR and CD11a/CD18 (LFA-1/beta 2 integrin) or CD29/CD49d (very late activation Ag-4/beta 1 integrin) using anti-TCR mAb and either ICAM-1 or VCAM-1 induces activation-dependent death of DRw6-specific CD4+ T cells. Similar coligation of the TCR with CD2 or CD28 using either mAb or ligands LFA-3 or B7 not only lacked the ability to induce death but also failed to reverse or inhibit integrin-facilitated death of DRw6-specific T cells. Each of these ligands augmented anti-TCR mAb-induced transcription of IL-2 and IL-4 genes. Exogenous addition of IL-2 and IL-4 did not reverse the integrin-supported T cell death. The death-promoting costimulatory effects of ICAM-1 and VCAM-1 were observed with Ag-specific chronically stimulated T cells but not with either resting T cells or those activated in short-term cultures. Treatment of T cells with cyclosporin A or a protein tyrosine kinase inhibitor herbimycin A inhibited ICAM-1 or VCAM-1-promoted activation-induced T cell death. The Ag-specific T cells that survived death-promoting effects of ICAM-1 or VCAM-1 proliferated efficiently upon restimulation with these ligands. Exposure of DRw6-specific T cells to DRw6+ B7+ ICAM-1+ LFA-3+ VCAM-1+ APC but not DR3+ B7+ ICAM-1+ LFA-3+ VCAM-1+ APC induced death of these T cells. This effect was blocked by pretreatment of T cells with mAb directed at CD18 or CD29 but not with those against CD2 or CD28. Taken together, these results suggest that TCR-directed engagement of integrins by their ligands ICAM-1 or VCAM-1 induces activation-dependent death of some perhaps more differentiated Ag-specific T cells and this may be an important homeostatic mechanism by which functional expression of Ag-specific T cells is regulated during an ongoing immune response.
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Graham, Zachary, Chad Touchberry, Paige Geiger, Anisha Gupte, Gregory Bomhoff, and Philip Gallagher. "Integrin Signaling in Heat-shocked Rat Skeletal Muscle Following Eccentric Exercise." Medicine & Science in Sports & Exercise 42 (October 2010): 58. http://dx.doi.org/10.1249/01.mss.0000389357.14247.b7.
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Damle, N. K., K. Klussman, G. Leytze, S. Myrdal, A. Aruffo, J. A. Ledbetter, and P. S. Linsley. "Costimulation of T lymphocytes with integrin ligands intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 induces functional expression of CTLA-4, a second receptor for B7." Journal of Immunology 152, no. 6 (March 15, 1994): 2686–97. http://dx.doi.org/10.4049/jimmunol.152.6.2686.
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Abstract Costimulation by the CD28 ligand B7/BB1 plays an important role during T cell proliferation primarily by augmenting synthesis of IL-2 and other cytokines. Resting CD4+ T cells express CD28 but not CTLA-4 on their surface. Costimulation of T cells with ICAM-1 or VCAM-1 induced CTLA-4 expression and up-regulated CD28 expression. CD28 and CTLA-4 were independently distributed on the surface of activated T lymphoblasts. When co-immobilized with anti-TCR mAb both anti-CD28 and anti-CTLA-4 mAb augmented T cell proliferation. Although anti-CD28-mediated augmentation of T cell proliferation was stronger than that seen with anti-CTLA-4 mAb, together these two mAb caused supraadditive augmentation of T cell proliferation. The augmentation of the effects of anti-CD28 mAb by anti-CTLA-4 mAb was greater at low occupancy of CD28 by anti-CD28 mAb. Costimulation of CD28+ CTLA-4+ T cells with anti-CTLA-4 caused three- to fivefold increase in IL-2 production, whereas similar treatment with anti-CD28 caused > 40-fold increase. The costimulatory effect of B7 on primed T cells was partially inhibited by Fab anti-CD28 mAb. Anti-CTLA-4 mAb alone did not inhibit B7-induced response but caused modest increase in the inhibitory effect of anti-CD28 Fab. On integrin-mediated costimulation, Ag-specific CD4+ T cell lines also up-regulated their CTLA-4 expression, and proliferation of these cells was augmented by anti-CTLA-4 mAb. Unlike that of CD28, ligation of CTLA-4 alone failed to mobilize intracellular [Ca2+]. However, coligation of CTLA-4 and TCR induced stronger [Ca2+] response in Ag-specific T cell lines than that seen with TCR alone. These results suggest that integrin-costimulated T cells express CTLA-4 and can be costimulated via CTLA-4. Optimal development of various immune functions may involve combined costimulation via both CD28 and CTLA-4.
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Hacsek, G., T. Örmälä, J. M. Kantele, and E. Savilahti. "B7 Integrin Expression of Lamina Propria Lymphocytes Increases in Rectum and Colon During Infancy 66." Pediatric Research 42, no. 3 (September 1997): 396. http://dx.doi.org/10.1203/00006450-199709000-00086.
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Rodger, B., I. Hoti, H. Gordon, J. Lindsay, and A. Stagg. "P007 Identification and characterisation of intestine-derived circulating resident memory T cells (ex-Trm) in health and Inflammatory Bowel Disease." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S128. http://dx.doi.org/10.1093/ecco-jcc/jjab076.136.
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Abstract Background Tissue resident memory T cells (Trm) persist in peripheral tissues where they protect against pathogens but can also contribute to inflammatory disease. Recent work shows that Trm can re-enter the circulation and give rise to new effector T cell and Trm populations in secondary tissue sites. Such ‘ex -Trm’ derived from the skin co-express the residency marker CD103 with cutaneous leukocyte antigen (CLA), a marker associated with skin tropism. Many T cells in the human intestine are Trm but it is unknown whether these cells re-enter the circulation; the existence of gut-derived ex-Trm would have important implications for IBD treatment targeting the recruitment of circulating gut-homing cells. Here, we identify a population of blood cells that co-express CD103 and the gut-homing integrin a4b7 and determine how they are changed in IBD. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers and patients with active IBD (Crohn’s disease or ulcerative colitis). Cell surface staining and multi-colour flow cytometry were used to identify CD4+ and CD8+ subsets of antigen experienced (CD45RA-) conventional T cells (abTCR+) and determine expression of markers associated with tissue tropism and residency. Results Staining with antibodies to CD103 and b7 integrin were used to define CD103b7+a4b7+ putative gut ex-Trm based on the excess per cell expression of b7 resulting from its contribution to both integrins. A separate CD103b7+a4b7- population defined by 1:1 expression of CD103 and b7 contained CLA+ skin ex-Trm. Gut ex-Trm comprised 0.3% total circulating CD8+ T cells (range 0.02–1.4%), and 1.2% CD4+ T cells (range 0.3–3%). Gut and skin ex-Trm were phenotypically similar; both expressed the residency associated markers CD101 and CD9 but lacked expression of CD69. Gut ex-Trm were phenotypically distinct from both traditional CD103-a4b7+ gut tropic CD45RA- antigen-experienced T cells and naïve T cells; significantly more gut ex-Trm expressed CD101 and CD9 and fewer expressed CD27. The proportion of gut ex-Trm did not differ between heath and IBD. However, the ratio of gut:skin ex Trm was significantly reduced in active Crohn’s disease but not ulcerative colitis indicating a selective reduction in the population derived from the intestine. Conclusion A putative population of gut-derived ex-Trm can be identified in the blood of healthy controls and IBD patients. This population has a distinctive phenotype similar to that of previously described skin-derived ex-Trm. Circulating ex-Trm could link discreet areas of intestinal inflammation in Crohn’s disease and there is a selective loss of the gut ex-Trm population from the blood of these patients. The role of ex-Trm in IBD merits further study.
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Tsai, FC. "143B: CORRELATION BETWEEN THE EXPRESSION PATTERN OF INTEGRIN ALPHA V AND CANCER INVASION IN CANCERS." Plastic and Reconstructive Surgery 125, Supplement (June 2010): 96. http://dx.doi.org/10.1097/01.prs.0000371877.11202.b7.
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Sumen, Cenk, Michael L. Dustin, and Mark M. Davis. "T cell receptor antagonism interferes with MHC clustering and integrin patterning during immunological synapse formation." Journal of Cell Biology 166, no. 4 (August 16, 2004): 579–90. http://dx.doi.org/10.1083/jcb.200404059.
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T cell activation by nonself peptide–major histocompatibility complex (MHC) antigenic complexes can be blocked by particular sequence variants in a process termed T cell receptor antagonism. The inhibition mechanism is not understood, although such variants are encountered in viral infections and may aid immune evasion. Here, we study the effect of antagonist peptides on immunological synapse formation by T cells. This cellular communication process features early integrin engagement and T cell motility arrest, referred to as the “stop signal.” We find that synapses formed on membranes presenting antagonist–agonist complexes display reduced MHC density, which leads to reduced T cell proliferation that is not overcome by the costimulatory ligands CD48 and B7-1. Most T cells fail to arrest and crawl slowly with a dense ICAM-1 crescent at the leading edge. Similar aberrant patterns of LFA-1/ICAM-1 engagement in live T–B couples correlate with reduced calcium flux and IL-2 secretion. Hence, antagonist peptides selectively disable MHC clustering and the stop signal, whereas LFA-1 valency up-regulation occurs normally.
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Maile, Laura A., and David R. Clemmons. "Integrin-Associated Protein Binding Domain of Thrombospondin-1 Enhances Insulin-Like Growth Factor-I Receptor Signaling in Vascular Smooth Muscle Cells." Circulation Research 93, no. 10 (November 14, 2003): 925–31. http://dx.doi.org/10.1161/01.res.0000101754.33652.b7.
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Hermangild Kottoor, S., H. Ibraheim, P. Polychronis, B. Senthuran, E. Jameson, M. Samaan, P. Irving, and N. Powell. "P009 Integrin-b7+ cytotoxic MAIT cells are expanded in the colon of Ulcerative Colitis patients, correlate with disease severity and are targeted by vedolizumab therapy." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i140. http://dx.doi.org/10.1093/ecco-jcc/jjab232.138.
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Abstract Background Mucosal-associated invariant T (MAIT) cells are major histocompatibility complex (MHC) class Ib-restricted innate-like lymphocytes with anti-bacterial functions that are enriched at mucosal sites. Their role in ulcerative colitis (UC) is unknown. Methods Colonic biopsies and peripheral blood were collected from patients with active UC (n=34) and healthy control subjects (n=14). Peripheral blood mononuclear cells (PBMC) and Lamina propria mononuclear cells (LPMC) were isolated and activated in vitro with PMA/ionomycin followed by surface and intracellular staining and multiparametric flow cytometry analysis. T cell populations, including gamma delta T cells (TCR gamma delta+), iNKT cells (TCR Vα24-Jα18+), MAIT cells (TCR Vα7.2+ CD161+), CD4, CD8 T cells and their intracellular expression of IL17A, TNF, IFN-g, IL22, IL13 and granzyme B (GZMB) were determined. MAIT cells were further characterised as CD8+, CD4+, CD8 CD4 double positive (DP), CD8 CD4 double negative (DN) cells and expression of the gut homing integrin-b7. Results DN cells were the most common MAIT subset in the colon and were significantly increased in both UC patients and HC subjects compared to peripheral blood. In UC, DN MAIT cells exhibited a cytotoxic phenotype, with significantly higher production of Granzyme B (median 45.0% of cells) compared to DN MAIT cells in HC (median 17%, P<0.005). DN MAIT cells in UC gut also co-produced significantly higher proportion of IL17A (median 22% in UC vs 7% in HC, P<0.006) and TNF (median 61% in UC vs 10% in HC, P<0.02) compared to DN MAIT cells from HC. In UC patients, the proportional abundance of cytotoxic DN MAIT cells accumulating in the colon significantly correlated with disease activity (UCEIS) score (r2=0.34, P<0.0007). The number of DN MAIT cells expressing integrin-b7 was also significantly higher in UC patients compared to HC (median 66% in UC vs 32% in HC, p<0.001). In UC patients initiated on vedolizumab therapy, the proportional abundance of cytotoxic, DN MAIT cells accumulating in the colon significantly fell at week 14 in comparison with their pre-treatment abundance (median 25% vs 51%, P<0.001). Following vedolizumab induction, the reduction in the abundance of colonic cytotoxic DN MAIT cells correlated with endoscopic improvement (r2=0.45, p=0.0085). Conclusion DN MAIT cells with cytolytic activity and augmented expression of multiple cytokines are enriched in the colon of UC patients in numbers that correlate with the magnitude of mucosal injury. Vedolizumab treatment reduces DN MAIT cell accumulation in the colon and the magnitude of reduction correlates with treatment response.
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Sedwick, Caitlin E., Margaret M. Morgan, Lismaida Jusino, Judy L. Cannon, Jim Miller, and Janis K. Burkhardt. "TCR, LFA-1, and CD28 Play Unique and Complementary Roles in Signaling T Cell Cytoskeletal Reorganization." Journal of Immunology 162, no. 3 (February 1, 1999): 1367–75. http://dx.doi.org/10.4049/jimmunol.162.3.1367.
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Abstract T cells interacting with APCs undergo rearrangement of surface receptors and cytoskeletal elements to face the zone of contact with the APC. This polarization process is thought to affect T cell signaling by organizing a specialized domain on the T cell surface and to direct T cell effector function toward the appropriate APC. We have investigated the contribution of TCR, CD28, and LFA-1 signaling to T cell cytoskeletal polarization by assaying the response of an Ag-specific Th1 clone toward a panel of transfected APCs expressing MHC class II alone or in combination with ICAM-1 or B7-1. We show that polarization of talin, an actin-binding protein, occurs in response to integrin engagement. In contrast, reorientation of the T cell microtubule-organizing center (MTOC) is dependent on and directed toward the site of TCR signaling, regardless of whether integrins or costimulatory molecules are engaged. MTOC reorientation in response to peptide-MHC complexes is sensitive to the phosphatidylinositol 3-kinase inhibitor wortmannin. CD28 coengagement overcomes this sensitivity, as does activation via Ab cross-linking of the TCR or via covalent peptide-MHC complexes, suggesting that phosphatidylinositol 3-kinase is not required per se but rather plays a role in signal amplification. Engagement of TCR in trans with LFA-1 results in separation of MTOC reorientation and cortical cytoskeletal polarization events, indicating that the two processes are not directly mechanistically linked. These studies show that T cells mobilize individual cytoskeletal components in response to distinct and specific cell surface interactions.
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Lamb, C. A., G. O'Boyle, D. E. Jones, J. C. Mansfield, and J. A. Kirby. "PMO-238 Blockade of the B7 integrin prevents adherence of t lymphocytes to MAdCAM-1 in an in vitro model of vascular microcirculation post-capillary shear flow." Gut 61, Suppl 2 (May 28, 2012): A171.2—A171. http://dx.doi.org/10.1136/gutjnl-2012-302514b.238.
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Cerwenka, A., D. Bevec, O. Majdic, W. Knapp, and W. Holter. "TGF-beta 1 is a potent inducer of human effector T cells." Journal of Immunology 153, no. 10 (November 15, 1994): 4367–77. http://dx.doi.org/10.4049/jimmunol.153.10.4367.
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Abstract TGF-beta 1 is known to modulate lymphocyte activation affecting cell proliferation and the production of cytokines and Igs. Little is known about the characteristics of T cells grown in the presence of TGF-beta 1. We have stimulated human T cells with PHA in the presence of TGF-beta 1 under serum-free conditions for 7 days and characterized the resulting cell population. TGF-beta 1 (0.0032 to 10 ng/ml) affected neither [3H]thymidine incorporation (day 4) nor cell yield (day 7) in these cultures. However, cells activated in the presence of TGF-beta 1 proliferated vigorously in secondary cultures and produced highly elevated amounts of IL-2 (12 +/- 3-fold enhancement of IL-2 production in response to CD2 plus CD28 stimulation compared with control cells, mean +/- SEM; n = 10). The enhancing effects of TGF-beta 1 were demonstrable over a wide range of concentrations (0.4 to 10 ng/ml). The increased IL-2 protein production was paralleled by a dramatic up-regulation of IL-2 mRNA. In addition, cells precultured with TGF-beta 1 responded with enhanced cluster formation in the secondary cultures. With regard to their phenotype, we observed an increased expression of the alpha E beta 7-integrin human mucosal lymphocyte-1 and of the CD2-restricted epitope CD2R, whereas the expression of CD11a was slightly decreased. In contrast, TGF-beta 1 did not influence the constitutive or activation-induced expression of CD4, CD8, CD45RA, CD45RO, CD25, CD71, CD54, CD58, CD59, and B7. We conclude that TGF-beta 1 supports the generation of human effector cells with a strongly enhanced capacity to respond to subsequent restimulation.
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Lehnert, Klaus, Cristin G. Print, Yi Yang, and Geoffrey W. Krissansen. "MAdCAM-1 costimulates T cell proliferation exclusively through integrin α4β7, whereas VCAM-1 and CS-1 peptide use α4β1: evidence for “remote” costimulation and induction of hyperresponsiveness to B7 molecules." European Journal of Immunology 28, no. 11 (November 1998): 3605–15. http://dx.doi.org/10.1002/(sici)1521-4141(199811)28:11<3605::aid-immu3605>3.0.co;2-j.
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Ogata, T., M. Yamakawa, Y. Imai, and T. Takahashi. "Follicular dendritic cells adhere to fibronectin and laminin fibers via their respective receptors." Blood 88, no. 8 (October 15, 1996): 2995–3003. http://dx.doi.org/10.1182/blood.v88.8.2995.bloodjournal8882995.
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The expression of adhesion molecules on human tonsillar follicular dendritic cells (FDCs) in the secondary lymphoid follicle (LF) in vivo and in vitro was investigated using cryostat sections and cytospin preparations of FDCs isolated with a magnetic cell sorter, respectively. FDCs were immunochemically positive for Mac-1 (CD11b), sialyl-Lex (CD15s), CD22, integrin beta 1 (CD29), CD40, very late activation antigen (VLA)-alpha 3 (CD49c), VLA-alpha 5 (CD49e), VLA-alpha 6 (CD49f), intercellular adhesion molecule (ICAM)-3 (CD50), ICAM-1 (CD54), B7 (CD80), and vascular cell adhesion molecule (VCAM)-1 (CD106). With respect to ligands on B cells for these adhesion molecules, the CD11b-CD54, CD50-leukocyte function-associated molecule (LFA)-1 (CD11a/18), and CD106-VLA-4 (CD49d/29) interactions in the apical light (ALZ) and basal light (BLZ) zones; the CD15s-L-selectin (CD62L) and CD106-CD49d/29 interactions in the mantle zone; and the CD54-CD11a/18 interaction in the entire LF may participate in FDC-B cell adhesion. Namely, the adhesion molecules participating in FDC-B cell interactions may differ in each of the five zones. Furthermore, the immunochemical evidence that FDCs were fibronectin (VLA-5, CD49e/29) and laminin (VLA-6, CD49l/29) receptor-positive discussed above was confirmed by immunoelectron microscopy and binding assays. Immunoelectron microscopy revealed fibers surrounded by cytoplasmic FDC extensions that were CD29-, CD49e-, and CD49f-positive. In the binding assays, the numbers of FDCs bound to fibronectin- and laminin-coated dishes and LFs of cryostat sections of human tonsils were reduced markedly by pretreatment with monoclonal antibodies against CD29, CD49e, and CD49f. These data indicate clearly that FDCs bind to reticulin and laminin fibers in LFs via their respective receptors.
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Tai, Yu-Tzu, Xian-Feng Li, Iris Breitkreutz, Weihua Song, Peter Burger, Matthew Rumizen, Teru Hideshima, et al. "Inhibition of ERK1/2 Activity by the MEK1/2 Inhibitor AZD6244 (ARRY-142886) Induces Human Multiple Myeloma Cell Apoptosis in the Bone Marrow Microenvironment: A New Therapeutic Strategy for MM." Blood 108, no. 11 (November 16, 2006): 3460. http://dx.doi.org/10.1182/blood.v108.11.3460.3460.
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Abstract Activation of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK1/2 MAPK) signaling pathway mediates tumor cell growth in many cancers, including human multiple myeloma (MM). Specifically, this pathway mediates MM cell growth and survival induced by cytokines/growth factors (i.e. IL-6, IGF-1, CD40, BAFF) and adhesion to bone marrow stromal cells (BMSCs), thereby conferring resistance to apoptosis in the bone marrow (BM) milieu. In this study, we therefore examined the effect of the MEK1/2 inhibitor AZD6244 (ARRY-142886), on human MM cell lines, freshly isolated patient MM cells and MM cells adhered to BMSCs. AZD6244, inhibits constitutive and cytokine (IL-6, IGF-1, CD40)-stimulated ERK1/2, but not AKT phosphorylation. Importantly, AZD6244 inhibits the proliferation and survival of human MM cell lines, regardless of sensitivity to conventional chemotherapy, as well as freshly isolated patient MM cells. AZD6244 induces apoptosis in patient MM cells even in the presence of BMSCs, as evidenced by caspase 3 activity and PARP cleavage at concentrations as low as 20 nM. AZD6244 overcomes resistance to apoptosis in MM cells conferred by IL-6 and BMSCs, and inhibits IL-6 secretion induced by MM adhesion to BMSCs. AZD6244 suppresses MM cell survival/growth signaling pathways (i.e., STAT3, Bcl-2, cyclin E1, CDK1, CDK3, CDK7, p21/Cdc42/Rac1-activated kinase 1, casein kinase 1e, IRS1, c-maf) and up-regulates proapoptotic cascades (i.e., BAX, BINP3, BIM, BAG1, caspase 3, 8, 6). AZD6244 also upregulates proteins triggering cell cycle arrest (i.e. p16INK4A, p18INK4C, p21/WAF1 [Cdkn1a], p27 [kip1], p57). In addition, AZD6244 inhibits adhesion molecule expression in MM cells (i.e. integrin a4 [VLA-4], integrin b7, ICAM-1, ICAM-2, ICAM-3, catenin a1, c-maf) associated with decreased MM adhesion to BMSCs. These pleiotropic proapoptotic, anti-survival, anti-adhesion and -cytokine secretion effects of AZD6244 abrogate BMSC-derived protection of MM cells, thereby sensitizing them to both conventional (dexamethasone) and novel (perifosine, lenalidomide, and bortezomib) therapies. In contrast, AZD6244 has minimal cytotoxicity in BMSCs and does not inhibit DNA synthesis in CD40 ligand-stimulated CD19 expressing B-cells derived from normal donors at concentrations toxic to MM cells (between 0.02–2 mM). Furthermore, AZD6244 inhibits the expression/secretion of osteoclast (OC)-activating factors (i.e., macrophage inflammatory protein (MIP)-1a, MIP-1b, IL-1b, VEGF) from MM cells. It also downregulates MM growth and survival factors (IL-6, BAFF, APRIL) in OC cultures derived from MM patient peripheral blood mononuclear cells (PBMCs). Significantly, AZD6244 inhibits OC differentiation from MM PBMCs (n=10) in a dose-dependent manner. Together these results provide the preclinical basis for clinical trials with AZD6244 (ARRY-142886) in MM.
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Rossi, Edmund A., Rosana Michel, Chien-Hsing Chang, and David M. Goldenberg. "Bispecific Hexavalant Antibodies With Enhanced Trogocytosis For Treatment Of Lupus." Blood 122, no. 21 (November 15, 2013): 2282. http://dx.doi.org/10.1182/blood.v122.21.2282.2282.
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Abstract Background The humanized anti-CD22 antibody, epratuzumab, has demonstrated therapeutic activity in clinical trials of lymphoma and autoimmune diseases (AIDs), treating currently over 1500 cases of non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemias, Waldenström's macroglobulinemia, Sjögren's syndrome, and systemic lupus erythematosus (SLE). Because epratuzumab, which is currently in worldwide Phase III registration trials for SLE, reduces on average only 35% of circulating B cells in patients, and has minimal antibody-dependent cellular cytotoxicity (ADCC) and negligible complement-dependent cytotoxicity (CDC) when evaluated in vitro, its therapeutic activity may not result completely from B-cell depletion. Instead, ligation of epratuzumab to CD22 could modulate other surface molecules involved in regulating B-cell antigen receptor (BCR) signaling, activation, homing, and re-circulation, leading to altered B-cell functions that ultimately mitigate symptoms of the underlying diseases. We reported recently that epratuzumab mediates Fc/FcR-dependent membrane transfer from B cells to effector cells via trogocytosis, resulting in a substantial reduction of multiple BCR modulators, including CD22, CD19, CD21, and CD79b, as well as key cell adhesion molecules, including CD44, CD62L, and b7 integrin, on the surface of B cells in peripheral blood mononuclear cells (PBMCs) obtained from normal donors or SLE patients, and of NHL cells spiked into normal PBMCs (Rossi et al., Blood 2013 PMID: 23821660). Rituxmab has clinical efficacy in SLE, but failed to achieve primary endpoints in a Phase III trial. Here we show for the first time that a bispecific hexavalent antibody (bsHexAb), comprising epratuzumab and veltuzumab (humanized anti-CD20), exhibits enhanced trogocytosis compared to epratuzumab, with considerably less B-cell depletion than observed with anti CD20 mAbs. Methods and Results A pair of bsHexAbs were generated using DOCK-AND-LOCKTM (DNLTM) to comprise epratuzumab fused with four additional Fab fragments of either veltuzumab [designated 22*-(20)-(20)] or of a humanized anti-CD19 mAb [22*-(19)-(19)]. PBMCs were incubated with the bsHexAbs or the parental mAbs (10 µg/mL) overnight, and the relative surface levels of the key antigens were analyzed by flow cytometry. The 22*-(20)-(20) exhibited the broadest and most extensive trogocytosis, reducing each of CD22, CD20, CD19, CD21, CD79b, CD44, CD62L, and Beta-7 integrin more than epratuzumab, and to a similar extent as veltuzumab, except for CD22, which was much lower with the 22*-(20)-(20) (Table 1). In general, 22*-(19)-(19) showed intermediate trogocytosis, with less antigen reduction than 22*-(20)-(20), but more than epratuzumab. Veltuzumab and rituximab caused considerable (40-50%) B-cell depletion in the ex-vivo assay. Alternatively, epratuzumab, hA19, and both bsAbs did not significantly deplete B cells. ADCC, which is presumably, the primary mechanism of B-cell depletion in the ex-vivo assay, is less potent for 22*-(20)-(20), compared to veltuzumab. CDC, which along with ADCC is an important mechanism for B-cell depletion in vivo, is ∼25-fold less potent for 22*-(20)-(20) compared to veltuzumab. Epratuzumab has minimal CDC and ADCC. Conclusion The bsHexAb 22*-(20)-(20) is an excellent candidate for treatment of SLE and other AIDs due to its ability to mediate potent trogocytosis without wholesale depletion of B cells, which leads to increased risk of serious infections associated with anti-CD20 therapy. Disclosures: Rossi: Immunomedics, Inc.: Employment. Michel:Immunomedics, Inc.: Employment. Chang:Immunomedics, Inc: Employment, Stock option Other; IBC Pharmaceuticals, Inc.: Employment, Stock option, Stock option Other. Goldenberg:Immunomedics: Employment, stock options, stock options Patents & Royalties.
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Na, Il-Kang, Sydney X. Lu, Gabrielle L. Goldberg, Daniel Daniel Hirschhorn-Cymerman, Christopher G. King, Odette M. Smith, David Suh, et al. "The T Cell Cytolytic Molecules Fas Ligand and TRAIL, the Trafficking Molecules CCR9, β7 Integrin and PSGL-1, and the Immune Modulating Molecules OX40, CEACAM1, and CTLA4 Are Required for Thymic Graft-Versus-Host Disease." Blood 112, no. 11 (November 16, 2008): 65. http://dx.doi.org/10.1182/blood.v112.11.65.65.
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Abstract Although thymic graft-versus-host-disease (tGVHD) has been recognized as an important contributor to impaired T cell reconstitution, limited T cell repertoire and increased infection risk in patients with GVHD, the molecular basis of interactions between donor alloreactive T cells, donor bone marrow (BM)-derived thymocytes, and host hematopoietic and non-hematopoietic thymic stromal cells in GVHD has not been well-defined. Here we analyzed the role of molecules relevant for T cell trafficking, cytolytic function, and co-stimulation and co-inhibition of alloreactive T cells in tGVHD. We first demonstrated that thymic output (as measured by RAG2+ splenic recent thymic emigrants) as well as the thymic cellularity (especially of CD4+CD8+ thymocytes) were inversely proportional to numbers of mature donor T cells infused with the allograft, suggesting that tGVHD severity was inversely associated with thymic function. We then studied the migration of alloreactive donor T cells in vivo with bioluminescence imaging (BLI) and found that luciferase-expressing donor T cells infiltrated the thymus within one week after allogeneic bone marrow transplantation (BMT) (Fig. 1). Upon adoptive transfer of CFSE-labeled donor T cells we noted that thymus-infiltrating alloreactive donor T cells were largely fast-proliferating (CFSElo) and highly activated (CD25+ CD44+). We analyzed the importance of T cell trafficking molecules for tGVHD using mice deficient for certain trafficking molecules, and assessed tGVHD by loss of BM-derived CD4+CD8+ thymocytes. We found that CCR9, b7 integrin subunit, and PSGL-1 were all partially required for tGVHD, while L-selectin and aE integrin subunit may be dispensable (Fig. 2A). Similarly, we examined the role of T cell cytolytic pathways for tGVHD, and found that FasL and TRAIL were required for tGVHD, but that perforin and TNF were dispensable (Fig. 2B). Finally, we assessed the role of various T cell co-stimulatory and co-inhibitory molecules for tGVHD, and found that CEACAM1, OX40 and CTLA4 were required, while GITR was partially required and ICOS was dispensable (Fig. 2C). Upon further analysis of donor BM-derived thymocytes, we observed that Bcl-2 expression in donor BM-derived thymocytes was decreased in recipients with GVHD vs. those without GVHD, which suggests that survival of thymocytes is decreased during tGVHD. Hollander and others have previously demonstrated in non-irradiated GVH reaction models that host non-hematopoietic thymic stroma may be an important target for donor alloreactive T cells. We assessed the expression of the death receptors Fas and DR5 in thymic stroma from normal and irradiated (850 cGy) BALB/c mice. We observed that in particular, MHC class II-negative stroma (endothelial cells and fibroblasts), as well as a population of MHC class II-intermediate stroma (epithelial cells) upregulated the expression of both Fas and DR5 after irradiation. Our study defines the specific pathways for cytolysis, trafficking and immune modulation involved in tGVHD and suggests selective therapeutic targets to attenuate tGVHD and improve post-transplant T-cell reconstitution in patients with GVHD. Fig 1. BLI demonstrate a distinct distribution pattern for alloreactive donor T cells in allogeneic BMT recipients, Allogeneic Balb/c recipients show a strong signal on day 4 post-transparent after transfer of 10×108 luc+ splenocytes as measured by total body photon emission. Ex vivo imaging confirms the infiltration of luc+ splenocytes to the thymus. Fig 1. BLI demonstrate a distinct distribution pattern for alloreactive donor T cells in allogeneic BMT recipients, Allogeneic Balb/c recipients show a strong signal on day 4 post-transparent after transfer of 10×108 luc+ splenocytes as measured by total body photon emission. Ex vivo imaging confirms the infiltration of luc+ splenocytes to the thymus. Fig 2. We assessed the role of molecules relevant for T cell trafficking (A), cytolytic function (B), and co-stimulation, co-inhibition (C). Irradiated BALB/c mice received 5×106 T cell depleted C57BL/6 bone marrow + 0.25×106 purified splenic T cells. Absolute numbers of donor-BM-derived CD4+CD8+ thymocytes are shown. Black bars indicate means. p-values were calculated vs. recipients of WT T cells(*p<0.05, **p<0.01) Fig 2. We assessed the role of molecules relevant for T cell trafficking (A), cytolytic function (B), and co-stimulation, co-inhibition (C). Irradiated BALB/c mice received 5×106 T cell depleted C57BL/6 bone marrow + 0.25×106 purified splenic T cells. Absolute numbers of donor-BM-derived CD4+CD8+ thymocytes are shown. Black bars indicate means. . / p-values were calculated vs. recipients of WT T cells(*p<0.05, **p<0.01)
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Storkus, W. J., J. Alexander, J. A. Payne, P. Cresswell, and J. R. Dawson. "The alpha 1/alpha 2 domains of class I HLA molecules confer resistance to natural killing." Journal of Immunology 143, no. 11 (December 1, 1989): 3853–57. http://dx.doi.org/10.4049/jimmunol.143.11.3853.
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Abstract The expression of transfected HLA class I Ag has previously been shown to protect human target cells from NK-mediated conjugation and cytolysis. In this same system, transfected H-2 class I Ag fail to impart resistance to NK. In this study, we have mapped the portion of the HLA class I molecule involved in this protective effect by exploiting this HLA/H-2 dichotomy. Hybrid class I genes were produced by exon-shuffling between the HLA-B7 and H-2Dp genes, and transfected into the class I Ag-deficient B-lymphoblastoid cell line (B-LCL) C1R. Only those transfectants expressing class I Ag containing the alpha 1 and alpha 2 domains of the HLA molecule are protected from NK, suggesting the "protective epitope" is located within these domains. Since a glycosylation difference exists between HLA and H-2 class I Ag within these domains (i.e., at amino acid residue 176), the role of carbohydrate in the class I protective effect was examined. HLA-B7 mutant genes encoding proteins which either lack the normal carbohydrate addition site at amino acid residue 86 (B7M86-) or possess an additional site at residue 176 (B7M176+) were transfected into C1R. Transfectants expressing either mutant HLA-B7 Ag were protected from NK. Thus, carbohydrate is probably not integral to a class I "protective epitope." The potential for allelic variation in the ability of HLA class I Ag to protect C1R target cells from NK was examined in HLA-A2, A3, B7, and Bw58 transfectants. Although no significant variation exists among the HLA-A3, B7, and Bw58 alleles, HLA-A2 appears unable to protect. Comparison of amino acid sequences suggests a restricted number of residues which may be relevant to the protective effect.
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Vacca, Vincent M., and Stephen Violett. "Teamwork integral to treating cerebral arteriovenous malformation." Nursing Critical Care 3, no. 3 (May 2008): 20–27. http://dx.doi.org/10.1097/01.ccn.0000318734.75050.b7.
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Bennett, Lynda, Sunati Sahoo, Cheryl Lewis, Indu Raman, Candace Frerich, Guanchun Chen, Min Xu, and Suzanne Conzen. "Abstract PO4-28-09: Upregulation of the immune checkpoint protein B7-H3 is associated with an immune suppressive microenvironment in progression from in situ to invasive lobular breast cancer." Cancer Research 84, no. 9_Supplement (May 2, 2024): PO4–28–09—PO4–28–09. http://dx.doi.org/10.1158/1538-7445.sabcs23-po4-28-09.
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Abstract Invasive lobular breast cancer (ILC) is an understudied subtype of breast cancer characterized by late recurrence, metastasis to serosal surfaces including the peritoneum, and poor long-term outcomes. Lobular carcinoma in situ (LCIS) is a non-obligate precursor to ILC but is associated with a 30% increased risk of developing ILC. Therefore, understanding the underlying changes that occur in the invasive lobular cells as well as their tumor microenvironment (TME) during the transition from LCIS to ILC is critical for the development of novel therapeutic targets that could be used in early disease. To address this, we used combined spatial whole genome transcriptomics and a 97-protein proteomics assay to examine the spatial molecular profiles of coexistent LCIS and ILC. PanCK-positive tumor cells and panCK-negative stromal cells were segmented and analyzed separately for both RNA and protein. Despite the close spatial proximity of LCIS and ILC, there were notable differences in gene and protein expression in the tumor cells as well as the tumor microenvironment (TME). RNA profiling revealed significant upregulation of genes encoding essential components of the extracellular matrix, including type I, 3 and 5 collagens, small leucine-rich proteoglycans byglycan (BGN) and lumican (LUM), periostin (POSTN) and secreted protein acidic and cysteine rich (SPARC). Metalloprotease genes MMP2 and MMP11 were also upregulated. Genes highly expressed in the LCIS tumor compartment were KRT5, KRT14 KRT17 and MYLK which are highly expressed in myoepithelial cells at the periphery of the LCIS. One of the most upregulated proteins in ILC cells was B7 homology 3 protein (B7-H3) or Cluster of Differentiation 276 (CD276). B7-H3 is a transmembrane immunoregulatory protein belonging to the B7 family (that also includes PD-L1 and PD-L2). This immune checkpoint protein is overexpressed in many tumors but is barely expressed in normal cells. B7-H3 has been associated with several aspects of cancer progression, such as evasion of tumor immune surveillance and metastasis, and is strongly linked to poor prognosis in cancer. Compared to the LCIS TME, B7-H3 was also the most upregulated protein in the ILC TME along with the tumor-promoting M1 macrophage marker CD68 and the regulatory T-cell marker FOXP3. The lymphocyte marker CD45 was downregulated as well as T-cell proteins CD3, CD40 and granzyme B. Moreover, CD27, a memory B-cell marker was most highly expressed in the TME surrounding LCIS compared to ILC. Overall, these molecular profiles support a transition to a toward a much more immunosuppressive environment for invasive tumor cells compared to LCIS. Based on these data, our working hypothesis is that upregulation of B7-H3 on lobular tumor cells promotes invasion allowing interaction with laminins, integrins and other ECM proteins in the basement membrane and the interstitial membrane as LCIS acquire invasive properties of ILC. Furthermore, upregulation of B7-H3 on CD3+ HLA-DR+ expressing antigen presenting cells also promotes a suppressive immune microenvironment by inhibiting T-cell proliferation and downregulating cytokine production. In sum, these strongly concurrent spatial transcriptome and protein data suggest that B7-H3 and the immune suppressive network of ILC may be a promising target for early stage lobular breast cancer. B7-H3 Inhibitors could be explored in the neoadjuvant setting to evaluate the efficacy of immunotherapy in primary ILC. Citation Format: Lynda Bennett, Sunati Sahoo, Cheryl Lewis, Indu Raman, Candace Frerich, Guanchun Chen, Min Xu, Suzanne Conzen. Upregulation of the immune checkpoint protein B7-H3 is associated with an immune suppressive microenvironment in progression from in situ to invasive lobular breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-28-09.
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Xu, Y. G., K. Behdinan, and Z. Fawaz. "Molecular dynamics calculation of the J-integral fracture criterion for nano-sized crystals." International Journal of Fracture 130, no. 2 (November 2004): 571–83. http://dx.doi.org/10.1023/b:frac.0000049499.53799.b7.
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Shaw, Tanya J., Xiang Y. Zhang, Zhiming Huo, David Robertson, Patricia A. Lovell, Angus G. Dalgleish, and Desmond P. J. Barton. "Human Peritoneal Mesothelial Cells Display Phagocytic and Antigen-Presenting Functions to Contribute to Intraperitoneal Immunity." International Journal of Gynecologic Cancer 26, no. 5 (June 2016): 833–38. http://dx.doi.org/10.1097/igc.0000000000000697.
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AbstractMesothelial cells lining the peritoneal cavity are strategically positioned to respond to and counter intraperitoneal infections, cancer cells, and other challenges. We have investigated human peritoneal mesothelial cells (HPMCs) for phagocytic activity, expression of surface Major Histocompatibility Complex (MHC) class II and accessory molecules involved in antigen presentation, and the ability to present recall antigens to T cells. Phagocytosis of dextran, latex beads, andEscherichia coliwas observed by flow cytometry, and internalization was visualized using confocal and electron microscopy. Flow cytometry and/or cellular enzyme-linked immunosorbent assay showed constitutive expression of ICAM-1, LFA-3, and B7-1, but not B7-2 or MHC class II. Interferon-gamma induced MHC II and ICAM-1 expression in a dose- and time-dependent manner. Importantly, HPMCs induced autologous CD3+T-lymphocyte proliferation (3H incorporation) after pulse with recall antigen. Human peritoneal mesothelial cells equipped with phagocytic and antigen-presenting machinery are anticipated to have an integral role in intraperitoneal immune surveillance.
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Grzywacz, Bartosz J., Nandini Kataria, Jeffrey S. Miller, and Michael R. Verneris. "Stromal Cells Support a Myeloid Pathway of Human NK Cell Differentiation." Blood 110, no. 11 (November 16, 2007): 1336. http://dx.doi.org/10.1182/blood.v110.11.1336.1336.
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Abstract Natural killer (NK) cells belong to the lymphocyte lineage; however a myeloid origin has been debated in the past based on nascent experimental evidence. We studied the in vitro development of human NK cells from UCB-derived CD34+ cells following culture with cytokines (IL15, IL7, SCF, FLT3L, IL3) on a murine fetal stromal cell line EL08.1D2 (Blood, 2006; 108: 3824–3833). We investigated the differential requirement of CD34+ subsets for stromal cell support. Limiting dilution experiments showed that CD34+ cells negative for phenotypic markers of NK commitment (CD7, CD161, integrin B7, CD122, CD45RA) absolutely require stromal cells and/or addition of hydrocortisone (HC) to differentiate into functional NK cells. Without stromal cells or HC those progenitors give rise to myeloid lineage cells, but not NK cells. Thus, we hypothesized that stromal cells could instruct myeloid precursors to convert to the NK lineage. Indeed, CD56+ cells generated in stroma supported cultures frequently co-express CD33 and CD13. To determine whether myeloid cells developing from CD34+ cells after 2–3 wk cultures could give rise to NK cells, we FACS sorted the CD56−CD33+CD13high and CD56−CD14+ populations. Such CD33+CD13high and CD14+ cells express macrosialin (CD68) and acquire lyzozyme (by FACS), confirming their myeloid characteristics. Sorted cells cultured further in cytokines alone (IL15, IL7, SCF, FLT3L) did not give rise to NK cells. However, in the presence of cytokines, stromal cells and HC, NK cells were generated. To exclude the possibility of NK cell contamination, CD33+CD13high and CD14+ cells were isolated from cultures of CD34+ cells in conditions not supportive of NK cell development (GM-CSF, IL3, FLT3L, SCF, without stroma, IL15 or IL7). Such cells gave the same results as above (i.e., NK cells developed only with stroma and HC). In additional studies, a fraction (∼16%) of CFU-GM colonies isolated from methylocellulose cultures could generate NK cells only in the presence of stromal cells, HC and cytokines, but not cytokines alone. As more of a definitive marker of the monocytic lineage, we used the surface expression of M-CSF receptor (CD115) on hematopoietic precursors. CD56−CD117+CD115+ and CD56−CD117+CD115− fractions were FACS sorted from 2–3 wk cultures of CD34+ cells. While both populations could differentiate into NK cells, only the CD115+ monocytic precursors required stromal cells. Quantitatively the CD117+CD115− cells were the main source of NK cells in this culture system. Notably the NK cells derived from CD115+ precursors were remarkably different, showing significantly higher expression of Killer Immunoglobulin-like Receptors (KIR: CD158a, CD158b and CD158e) than their CD115− derived counterparts (52% vs 15% KIR+, n=3, p=0.002). With respect to the repertoire of HLA-specific inhibitory receptors, NK cells derived from monocytic precursors resemble the dominant fraction of peripheral blood NK cells, including potentially alloreactive NK cells (KIR+CD94/NKG2A−). Collectively we present evidence that NK cells can be derived from developmental intermediates of the monocytic lineage and this differentiation pathway is dependent upon interaction with stroma. Our data indicate that the developmental trajectory shapes the pattern of inhibitory receptor expression on mature NK cells. Such findings have bearing on our understanding of NK cell biology, post transplant NK cell reconstitution and could explain the paucity of recognized immature NK cell leukemias coinciding with the occurrence of AML variants with NK specific antigen expression.
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Frumento, Guido, Andrea White, Stephen Kissane, Zsuzsanna Nagy, Steven Lee, Graham Anderson, Paul Moss, and Frederick Chen. "Differentiated Human CD8+ Memory T Cells Can Revert to a Naive-like Phenotype with Memory Stem Cell Functions." Blood 126, no. 23 (December 3, 2015): 5429. http://dx.doi.org/10.1182/blood.v126.23.5429.5429.
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Abstract The mechanisms leading to the establishment of the memory T-cell pool in humans remain to be fully elucidated. Murine models of memory T-cell generation propose an irreversible differentiation process from naïve to memory and effector cells. T-memory stem cells (TSCM) have been recently described in humans as constituting a key precursor subset of memory cells along this pathway. To study the generation of memory T-cells, primary naive T-cells (TN) derived from human cord blood (CB) were exposed to different activating stimuli, and then incubated with various cytokine combinations, and monitored throughout for phenotypic and functional changes. Between 3 to 9 days after antigen activation, the proportion of CD45RA+/CCR7+ CD8+ TN cells dropped from 86.64±5.84 (mean±1SD, n=50) to less than 20% (10.36±6.23). Specific cytokines mixtures were then added to the cultures and within 13 to 28 days after initial activation CD8+ cells re-expressed CD45RA, reverting back to a TN-like phenotype, characterized by the co-expression of CCR7, CD62L, CD27 and CD45RA, and loss of CD45RO. These constituted 71%±11.68 (1SD n=50) of the CD8+ T-cell population. The kinetics of 3 representative cultures are shown in Figure 1. Recently differentiated central memory (TCM) and effector memory (TEM) CD8+ T-cells could be both induced to revert to a naïve-like phenotype (TNrev). Functional analysis showed that compared to TN, CD8+ TNrev displayed higher proliferative capacity upon antigenic stimulation, differentiated more quickly into progeny memory cells and acquired cytolytic effector function. CD8+ TNrev also had the ability to undergo several cycles of activation and differentiation whilst retaining the ability to revert back to TNrev. CD8+ TNrev had an extended phenotype almost identical to TSCM, including the expression of CD95, and differed from TN in the expression of CXCR3 and Integrin b7. However, the expression of the latter markers and of CD95, became virtually undetectable following prolonged steady state culture and/or after modifying the cytokine milieu. Here we describe for the first time the capacity of CD8+ TCM and TEM cells that have recently differentiated from primary TN to revert back to a naïve-like phenotype. CD8+ TNrev are functionally and phenotypically indistinguishable from TSCM, but with further changes to the cytokine milieu, they reacquire, with time, a phenotype resembling TN. TN Reversion may represent a way for the immune system to maintain a pool of antigen-experienced CD8+ T-cells with naïve characteristics, with implications for current models of memory T-cell generation. We demonstrate how understanding the T-cell differentiation process made possible the large scale in vitro generation of TSCM-like cells that can be used for adoptive immunotherapy strategies. Figure 1. Kinetics of phenotype reversion following anti-CD3/IL2-activation of CB T-cells. When the percentage of TN cells dropped below 20%, cytokines were added and cells were monitored for phenotypic changes. Results of 3 representative experiments out of 50. Figure 1. Kinetics of phenotype reversion following anti-CD3/IL2-activation of CB T-cells. When the percentage of TN cells dropped below 20%, cytokines were added and cells were monitored for phenotypic changes. Results of 3 representative experiments out of 50. Disclosures No relevant conflicts of interest to declare.
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Krmencikova, Monika, Martina Petrackova, and Vladimir Vonka. "Protein Profiling of Two Mouse BCR-ABL-Transformed Cell Lines." Blood 118, no. 21 (November 18, 2011): 4720. http://dx.doi.org/10.1182/blood.v118.21.4720.4720.
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Abstract Abstract 4720 Introduction: Our efforts aim at the development of effective experimental vaccines against bcr-abl-transformed cells. For our study two mouse (Balb/c) bcr-abl-transformed cell lines were chosen, viz. Ba-p210 (B210) and 12B1. They express comparable amounts of p210bcr-abl protein and both are of early B cell lineage, but they differ in a number of properties, namely morphology, expression of MHC I molecules and some other surface markers (such as AA4.1, CD 19, CD10 and B7.H4) and oncogenic potential. Both induce leukemia after intravenous administration, but 12B1 cells are approximately 100x more oncogenic and, in addition, induce lymphoma-like solid tumours after subcutaneous administration (Sobotkova et al., 2005). Studies carried out in our laboratory with both B210 and 12B1 cells gene-engineered to secrete various immunostimulatory cytokines indicated that they were capable of inducing protection in immunization/challlenge experiments and, to a certain degree, had the potential to serve as therapeutic vaccines. Our results indicated that the fusion zone of the p210bcr-abl protein does not carry an epitope immunogenic for Balb/c mice, and that the two cell lines differ in their antigenic make-up. In general, it was much easier to induce immunity against the B210 cells than against the 12B1 cells. It has been the aim of the present undertaking to broaden the knowledge on the antigenic make-up of the two cell lines and, hopefully, to identify cell proteins carrying the immunodominant epitopes. Furthermore we hope that this investigation, which is still under way, may help us to understand the different in vivo behavior of B210 and 12B1 cells. Methods: Kinex™ antibody microarray monitoring the presence of 800 cell signaling proteins in cell lysates was used. Attempts were made to verify a portion of the microarray results by Western blotting (WB). Furthermore, using WB we have started a systematic search for the presence of proteins in the cell lysates, which were recognized to be overexpressed in human CML cells and found to be immunogenic in the patients. Results: Significant differences in the expression of the Kinex™-monitored proteins between the 12B1 and B210 were detected in the total of 31 instances. Most marked differences were the overexpression of integrin β1 in 12B1 cells and overexpression of pro-capase proteins in B210 cells. Eighteen of these proteins were selected for WB. These tests demonstrated overexpression of intergrin β 1 and calcium/calmodulin-dependent protein-serine kinase 2 (CaMK2b) in 12B1 cells and pro-caspase proteins 5 and 7, Hsp90a, mitogen-activated protein-serine kinase p38γ (MAKP12) and mitogen-activated protein-serine kinase p38α (MAPK14) in B210 cells. In the other cases there was no difference or the differences were quite small or the respective proteins were not detected at all. Till now no marked differences between the two lines were detected in the production of proteins, the analogues of which are overexpressed in human CML cells. Neither WT-1 nor Pr-3 proteins were detected in lysates of either 12B1 or B210 cells. Conclusion: Although the characterization of the two cell lines has not yet been completed, the present data reveal a number of differences in the protein composition of the two cell lines. Some of the differences revealed may be associated with the different oncogenic potential of the two cell lines. However, thus far no clear data are available which might explain the higher immunogenicity of B210 cells. This work was supported by MZCR IGA NS 10634–3/2009 and by MZ0UHKT 2005. Disclosures: No relevant conflicts of interest to declare.
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Zhao, J., G. J. Freeman, G. S. Gray, L. M. Nadler, and L. H. Glimcher. "A cell type-specific enhancer in the human B7.1 gene regulated by NF-kappaB." Journal of Experimental Medicine 183, no. 3 (March 1, 1996): 777–89. http://dx.doi.org/10.1084/jem.183.3.777.
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The costimulatory molecule B7.1 provides a second signal critical for T cell activation. The distribution of this integral membrane protein is restricted to certain tissues where its level of expression is modulated by multiple exogenous stimuli. To identify the molecular basis for specificity and inducibility, the chromatin configuration of the human B7.1 gene was examined in intact nuclei from various cell types. The identification of a tissue-specific deoxyribonuclease I hypersensitive site approximately 3kb upstream of the transcription start site led to the characterization of a cell type-specific enhancer region. This 183-bp region was both cell type specific and responsive to two distinct stimuli, lipopolysaccharide and dibutyryl cAMP, known to regulate B7.1 expression. Deletional and site-directed mutagenesis revealed the presence of multiple functionally critical cis elements within this region, one of which was a nuclear factor (NF)-kappaB consensus sequence. In B7.1-positive B cells, this element bound several members of the NF-kappaB family, transcription factors already implicated in signal transduction pathways relevant to B7.1 expression. This is the first description, to our knowledge, of regulatory elements that control expression of a gene encoding a B7 costimulatory molecule.
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Collins, Julie Marie, Renee Nicole Donahue, Yo-Ting Tsai, Claudia Palena, Jennifer L. Marte, Ravi Amrit Madan, Fatima Karzai, et al. "Phase I trial of a modified vaccinia ankara (MVA) priming vaccine followed by a fowlpox virus (FPV) boosting vaccine modified to express brachyury and costimulatory molecules in advanced solid tumors." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 2640. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2640.
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2640 Background: Brachyury, a transcription factor, plays an integral role in epithelial-to-mesenchymal transition, metastasis, poor prognosis, and resistance to chemotherapy. It is expressed in many tumor types, and rare in normal tissue, making it an ideal immunologic target. BN-Brachyury comprises heterologous vaccination with recombinant MVA priming followed by FPV boosting, each encoding transgenes for brachyury and three costimulatory molecules (B7-1, ICAM1, and LFA-3). Heterologous prime boost approach is intended to optimize immunogenicity, as previously observed. Methods: Pts with metastatic solid tumors were treated with 2 monthly doses of MVA-brachyury SC at the previously tested dose, 2.2 x 109 infectious units (IU), followed by FPV-brachyury SC, 1 x 109 IU, for 6 monthly doses and then every 3 months for up to 2 years. The primary objective was to determine safety and tolerability and establish the RP2D. Immune assays were conducted to evaluate immunogenicity. Results: In 10 pts (3 chordoma, 6 GI, 1 papillary thyroid), no dose-limiting toxicities or serious treatment-related adverse events (TRAEs) were observed. The only Grade 3 TRAE was sedation associated with fever, which resolved spontaneously and did not recur with subsequent cycles. All other TRAEs were Grade 1 or 2; the most common was injection-site reaction in all patients. Five pts have had stable disease for > 24 wks (per RECIST v1.1) and remain on treatment. One pt with chordoma, for which BN-Brachyury was granted orphan drug designation, has had a 13.2% reduction in tumor size. As previously demonstrated, brachyury-specific T cell responses were observed, as were responses against cascade antigens (non-encoded antigens) CEA and MUC-1. Conclusions: Heterologous MVA- and FPV-brachyury is well tolerated and induced immune responses to brachyury and cascade antigens, suggesting induction of immunologically relevant tumor cell destruction. These data have informed combining BN-Brachyury with checkpoint inhibition (NCT03493945) and radiation (NCT03595228) to evaluate potential for synergetic activity in selected populations. Clinical trial information: NCT03349983.
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Miura, Yuji, Christopher J. Thoburn, Emilie C. Bright, Elizabeth C. Matsui, William H. Matsui, Richard J. Jones, and Allan D. Hess. "T Cell Activation and Regulation in Graft-Versus-Host Disease: Integral Role of CD28, CTLA4 and GITR Splice Variants." Blood 104, no. 11 (November 16, 2004): 3054. http://dx.doi.org/10.1182/blood.v104.11.3054.3054.
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Abstract Graft-versus-host disease (GVHD) is a serious, life-threatening complication that occurs following allogeneic (allo) bone marrow transplantation (BMT). The use of non-specific immunosuppression or T cell depletion has reduced the incidence of GVHD but at the expense of increased rates of infection and leukemic relapse. Modulation of the major costimulatory pathway (CD28/CTLA4:B7) involved in T cell activation and regulation may lead to specific immune tolerance in the absence of global non-specific immunosuppression. The identification of mRNA splice variants encoding for soluble forms of CD28, CTLA4 and GITR suggests that costimulation of T cells is complex and is not limited to cell-cell contact. The present studies examined the hypothesis that the onset of GVHD and the re-establishment of immune tolerance correlate with the expression levels of these costimulatory molecules. mRNA transcript levels for the soluble (s) and full-length (fl; cell surface associated) variants assessed by quantitative PCR, were temporally examined in peripheral blood lymphocytes (PBLs) from patients undergoing alloBMT (n=38) or autologous (auto) BMT (n=39) with the induction of autoGVHD by cyclosporin A treatment post-transplant. Levels of s and fl CD28 mRNA transcripts in PBLs were significantly increased (>1.5 fold, P<0.05) in patients developing either allo or autoGVHD compared to patients who do not develop GVHD. s and flCTLA4 levels in patients at the onset of allo and autoGVHD were significantly decreased compared to healthy controls (n=22) (>2.3-fold, P<0.01). s and flCTLA4 expression in patients with autoGVHD was significantly decreased compared to patients without autoGVHD (>2.1-fold). sCTLA4 expression in patients with alloGVHD was significantly decreased than patients without alloGVHD. Interestingly, temporal analysis revealed that the levels for sCTLA4 paralleled the recovery from GVHD implicating an active process in the establishment of non-responsiveness. CD28, CTLA4 and GITR s and fl mRNA levels in CD4+CD25+ T regulatory (Treg) cells from allo and autoBMT patients were significantly increased (7-, 41- or 22-fold, P<0.01) compared to the CD4+CD25− subset. Additional studies attempted to identify the potential role of the sCTLA4 protein (encoded by the mRNA splice variant) on the regulation of the lymphocyte response mediated by Treg cells. Addition of the Treg cells to a mixed lymphocyte reaction suppressed the proliferative response of CD8+ T cells to alloantigens (75% suppression; >4 fold reduction of 3H-thymidine incorporation). However, pretreatment of the Treg subset with short interfering RNA (siRNA) to knockdown sCTLA4 gene (confirmed by quantitative PCR) significantly reduced the ability of these cells to suppress the response (minimal suppression was detected, 6%). In vitro siRNA studies also indicated that Treg cells with inhibited sCTLA4 expression were unable to suppress the response of IL-2-stimulated autoreactive CD8+ T cells. Taken together, the results indicate that increased expression of CTLA4 (soluble and cell-surface associated) and the “negative” signal delivered by this molecule to the T cell may regulate the development of GVHD and help to re-establish self tolerance after BMT. Defining the role of costimulation and the modulation of this pathway on immune recognition and regulation not only provides opportunities to enhance the re-establishment of tolerance but also may help to intensify anti-tumor immunotherapeutic strategies.
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Cantwell, MJ, S. Sharma, T. Friedmann, and TJ Kipps. "Adenovirus vector infection of chronic lymphocytic leukemia B cells." Blood 88, no. 12 (December 15, 1996): 4676–83. http://dx.doi.org/10.1182/blood.v88.12.4676.bloodjournal88124676.
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Adenovirus vectors have several features that make them attractive for potential use in gene therapy, including a broad tissue tropism and an ability to infect quiescent or postmitotic cells. In light of this, we examined whether recombinant adenovirus vectors could transfer genes into neoplastic cells of patients with chronic lymphocytic leukemia (CLL), a leukemia of “resting” B cells. Using high-titer recombinant adenovirus vectors, we found we could transfer genes encoding beta-galactosidase or murine CD80 (B7–1) into the CLL B cells of all patients tested (n = 10). The efficiency of gene transduction into CLL B cells was approximately 100 to 1,000-fold lower than into HeLa cells at any given multiplicity of infection (MOI). At a MOI of 500, 10% to 70% of the CLL B cells from different patients were made to express the transgene, as assessed by multiparameter flow cytometric analysis. Sustained levels of expression with little loss in the percentage of infected cells were maintained for up to 9 days, at which point the analysis was stopped. We found that CLL B cells have markedly lower expression levels of integrins that facilitate internalization of adenovirus particles into target cells, perhaps accounting, in part, for the reduced efficiency of adenovirus-mediated gene transfer compared with that in HeLa cells. Although HeLa cells express high levels of alpha(v)beta5, and detectable amounts of alpha(v)beta3, we find CLL cells from all patients tested express only low amounts of alpha(v)beta3, and no detectable alpha(v)beta5. Activation of CLL cells via CD40 cross-linking enhances expression of alpha(v)beta3, and induces expression of alpha(v)beta5. This phenotypic change is associated with a fivefold increase in the efficiency of adenovirus-mediated gene transfer into such activated CLL B cells. This study demonstrates that adenovirus vectors can transduce genes into CLL B cells and that the efficiency of gene transduction is enhanced by activation via CD40 cross-linking. This is the first demonstration that high proportions of CLL B cells can be made to express a selected transgene, suggesting that such gene transfer methods may become useful for the study of the pathogenesis and/or treatment of this disease.
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Stirling, Elizabeth, Adam Wilson, Katherine Cook, Alexandra Thomas, Pierre Triozzi, and David Soto-Pantoja. "616 CD47 blockade modulates immunosuppressive checkpoint molecules and cellular metabolism to sensitize triple-negative breast cancer tumors to immune checkpoint blockade therapy." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A646. http://dx.doi.org/10.1136/jitc-2021-sitc2021.616.
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BackgroundTriple-negative breast cancer(TNBC) lacks druggable targets and has high metastatic incidence. Immune checkpoint blockades (ICB) are FDA approved for TNBC treatment, but therapeutic response and biomarkers are limited. CD47 is an integral membrane protein overexpressed on cancer cells that alters anti-tumor immunosurveillance, resulting in tumor progression. CD47 is involved in metabolic reprogramming but whether CD47 is a marker of progression and its role in ICB response for TNBC remains unknown.MethodsHuman TNBC biopsies were subjected to immunohistochemical analysis to determine CD47 role in TNBC progression. To determine CD47 impact on tumor burden, a carcinogen-induced TNBC model was performed in female wild type(WT) and cd47 null(cd47-/-) C57Bl/6 mice. To evaluate immune infiltrate signaling, tumors underwent spatial tissue proteomics by multiplexing photo-cleavable antibodies in Formalin-Fixed Paraffin-Embedded samples. An orthotopic EMT-6 murine TNBC model was performed to investigate tumor burden for CD47 monotherapy or in combination with anti-PD-L1 therapy.ResultsHuman matched primary, and metastatic TNBC biopsies increased immunoreactivity to CD47, signifying a potential therapeutic target(n=24). CD47 deficiency in the carcinogen-induced DMBA model decreased tumor incidence, weight, and area compared to WT(n=8/group,*p<0.003). Since CD47 can regulate metabolism, tumors underwent metabolomic analysis. Principal component analysis displayed differentially regulated metabolites between WT and cd47-/- tumors. Decreased carnitine conjugated fatty acids and ketone bodies were observed in cd47-/- tumors compared to WT, suggesting decreased fatty acid availability and/or metabolism(n=9/group,*p<0.05). TNBC cell respiratory measurements validated that targeting CD47 shifted metabolic dependency from fatty acid oxidation to glycolysis(n=3,*p<0.05). Kynurenine/tryptophan pathway metabolites, which catabolize Indoleamine-2,3-dioxygenase(IDO1) and involved in anti-PD-1/PD-L1 resistance, were decreased in cd47-/- tumors compared to WT(n=9/group,*p<0.05). Spatial proteomic analysis determined that cd47-/- tumors had elevated immune cell infiltration(CD45+, CD3+), suggesting CD47 absence enhances tumor immunogenicity and immune-mediated tumor ablation. Multiplexing of photo-cleavable antibodies increased protein expression of immune checkpoint molecules(PD-L1,VISTA,B7-H3,BatF3) and immunosuppressive cell types(CD11b+,Ly6c+) in WT tumors compared to cd47-/-, suggesting CD47 absence limits immunosuppressive signaling(n=16/group,*p<0.05). Since anti-PD-L1 therapies are approved to treat TNBC and WT tumors have PD-L1 upregulation, we examined how targeting CD47 would impact tumor burden of mice receiving anti-PD-L1 therapy. Targeting CD47 or PD-L1 as monotherapy decreased tumor burden; however, in combination it further reduced tumor burden compared to anti-PD-L1 treatment due to increased intratumoral granzyme B secreting cytotoxic T cells(n=4–8/group,*p<0.05).ConclusionsOur data indicates that CD47 may serve as a marker of anti-PD-L1 response, and targeting CD47 enhances immunogenicity and decreases immunosuppressive molecules, sensitizing TNBC tumors to anti-PD-L1 therapy to reduce tumor burden.AcknowledgementsDSP is supported by the NCI R21 (CA249349) and the American Cancer Society Research Scholar Grant (133727-RSG-19-150-01-LIB). ERS is supported by the NIAID Immunology and Pathogenesis T32 Training Grant (T32AI007401).Ethics ApprovalAnimal studies were approved by the Institutional Care and Use Committee, Wake Forest Health Sciences.
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Zhou, Xinyan, Mengchao Yu, Luzhen Ma, Jinyu Fu, Jingwei Guo, Jieqiong Lei, Zheng Fu, et al. "In vivo self-assembled siRNA as a modality for combination therapy of ulcerative colitis." Nature Communications 13, no. 1 (September 28, 2022). http://dx.doi.org/10.1038/s41467-022-33436-0.
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AbstractGiven the complex nature of ulcerative colitis, combination therapy targeting multiple pathogenic genes and pathways of ulcerative colitis may be required. Unfortunately, current therapeutic strategies are usually based on independent chemical compounds or monoclonal antibodies, and the full potential of combination therapy has not yet been realized for the treatment of ulcerative colitis. Here, we develop a synthetic biology strategy that integrates the naturally existing circulating system of small extracellular vesicles with artificial genetic circuits to reprogram the liver of male mice to self-assemble multiple siRNAs into secretory small extracellular vesicles and facilitate in vivo delivery siRNAs through circulating small extracellular vesicles for the combination therapy of mouse models of ulcerative colitis. Particularly, repeated injection of the multi-targeted genetic circuit designed for simultaneous inhibition of TNF-α, B7-1 and integrin α4 rapidly relieves intestinal inflammation and exerts a synergistic therapeutic effect against ulcerative colitis through suppressing the pro-inflammatory cascade in colonic macrophages, inhibiting the costimulatory signal to T cells and blocking T cell homing to sites of inflammation. More importantly, we design an AAV-driven genetic circuit to induce substantial and lasting inhibition of TNF-α, B7-1 and integrin α4 through only a single injection. Overall, this study establishes a feasible combination therapeutic strategy for ulcerative colitis, which may offer an alternative to conventional biological therapies requiring two or more independent compounds or antibodies.
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Hosen, Naoki. "Identification of cancer-specific cell surface targets for CAR-T cell therapy." Inflammation and Regeneration 44, no. 1 (March 29, 2024). http://dx.doi.org/10.1186/s41232-024-00329-2.
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AbstractOne should identify appropriate cell surface targets to develop new CAR-T cells. Currently, lineage-specific antigens such as CD19 or B cell maturation antigen (BCMA) are being used as targets for CAR-T cells. However, in most cancers, lineage-specific antigens cannot be used as targets because targeting normal counterparts expressing them causes fatal toxicity. Cancer-specific transcripts have been extensively searched for using transcriptome analysis, but only a few candidates were reported. We have been working on identifying tumor-specific antigen structures, for example constitutively activated conformer of integrin b7 in multiple myeloma. Recently, several researchers have been working on a logic gate system that can react only when two antigens are expressed on the cell surface.
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Yang, Yue, Xinwei Guo, Chenyan Huang, Chen Chen, Yingying Zhou, Zhengrong Gao, Chuanliang Feng, Shengjie Jiang, Xuliang Deng, and Yan Wei. "Chirality Regulates Macrophage Polarization for Tissue Regeneration Through Bidirectionally Modulating WTAP‐Mediated m6A Modification." Small Structures, February 2, 2024. http://dx.doi.org/10.1002/sstr.202300412.
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Chirality, a fundamental design feature at all levels of life organization, has shown great capability in guiding cell‐fate determination and tissue regeneration. Chirality‐directed differentiation programs involve remarkable changes in transcriptional networks, yet whether epigenetic regulatory events are also required is less well understood. Herein, by combining high‐throughput m6A MeRIP sequencing, RIP‐qPCR, and gene modulation techniques, it is demonstrated that biomimetic chiral nanofibrils can bidirectionally regulate wilms tumor 1 associated protein (WTAP)‐mediated m6A RNA methylation to guide macrophages polarization for tissue regeneration. The biomimic chiral nanofibril hydrogels are fabricated using a self‐assembly approach based on C2‐symmetric phenylalanine derivatives. In vitro and in vivo studies indicated that the L‐nanofibrils exhibit a greater propensity to promote M2‐macrophage polarization than D‐nanofibrils, thereby favoring osteogenesis. Then, m6A‐MeRIP sequencing revealed a unique chirality‐dependent m6A methylation level in macrophages, which was gated by a competitive pair of CCM3‐FAK through enantioselectively integrin recognition. L‐nanofibrils considerably suppressed WTAP‐mediated m6A methylation by promoting Itgα3‐FAK expression and paxillin‐driven mechanotransduction, whereas D‐nanofibrils induced WTAP‐mediated m6A methylation by favoring ItgαV‐CCM3 expression and suppressing mechanotransduction. Furthermore, the gain‐of‐function and loss‐of‐function experiments and RIP‐qPCR demonstrate that the WTAP expression could direct macrophage polarization via manipulating the functional molecule B7‐H3 (CD276). Thus, a mechano‐epigenetic mechanism of chirality‐mediated cell‐fate determination is unveiled, which holds remarkable promise in the realm of assisted regenerative material design.
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Ball, Jennifer A., Andrew James Clear, James Aries, Sarah Charrot, Caroline Besley, Matt Mee, Andrew Stagg, et al. "Retinoic acid-responsive CD8 effector T-cells are selectively increased in IL-23-rich tissue in gastrointestinal GvHD." Blood, September 9, 2020. http://dx.doi.org/10.1182/blood.2020005170.
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Gastrointestinal (GI) graft-versus-host disease (GvHD) is a major barrier in allogeneic hematopoietic stem-cell transplantation (AHST). The metabolite retinoic acid (RA) potentiates GI-GvHD in mice via alloreactive T-cells expressing the RA-receptor-alpha (RARα), but the role of RA-responsive cells in human GI-GvHD remains undefined. We therefore used conventional and novel sequential immunostaining and flow cytometry to scrutinize RA-responsive T-cells in tissues and blood of AHST patients and characterize the impact of RA on human T-cell alloresponses. Expression of RARα by human mononuclear cells was increased after RA exposure. RARαhi mononuclear cells were increased in GI-GvHD tissue, contained more cellular RA-binding proteins, localized with tissue damage and correlated with GvHD severity and mortality. Using a targeted candidate protein approach we predicted the phenotype of RA-responsive T-cells in the context of increased microenvironmental IL-23. Sequential immunostaining confirmed the presence of a population of RARahi CD8 T-cells with the predicted phenotype, co-expressing the effector T-cell transcription factor T-bet and the IL-23-specific receptor. These cells were increased in GI- but not skin-GvHD tissues and were also selectively expanded in GI-GvHD patient blood. Finally, functional approaches demonstrated RA predominantly increased alloreactive GI-tropic RARahi CD8 effector T-cells, including cells with the phenotype identified in vivo. IL-23-rich conditions potentiated this effect by selectively increasing b7 integrin expression on CD8 effector T-cells and reducing CD4 T-cells with a regulatory cell phenotype. In conclusion we have identified a population of RA-responsive effector T-cells with a distinctive phenotype which are selectively expanded in human GI-GvHD and represent a potential new therapeutic target.
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Boulaaras, Salah, Abdelbaki Choucha, Djamel Ouchenane, Mohamed Abdalla, and Aldo Jonathan Muñoz Vazquez. "Solvability of the Moore-Gibson-Thompson equation with viscoelastic memory type II and integral condition." Discrete and Continuous Dynamical Systems - S, 2022, 0. http://dx.doi.org/10.3934/dcdss.2022151.
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<p style='text-indent:20px;'>This paper deals with the existence and uniqueness of solutions of a new class of Moore-Gibson-Thompson equation with respect to the nonlocal mixed boundary value problem and memory kernel of type II. This work is a generalization and improved of recent result in ([<xref ref-type="bibr" rid="b7">7</xref>], Math. Meth. App. Sci. <b>42</b>, 2664-2679) and ([<xref ref-type="bibr" rid="b15">15</xref>], J. Evol. Equ. <b>20</b>, 1251–1268 (2020)).</p>
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Cherneha, A. O., V. V. Liubych, T. A. Nebykova, and T. M. Marchenko. "Biochemical composition of fresh and dried currant fruits of different varieties." Advanced Agritechnologies, no. 9 (December 26, 2021). http://dx.doi.org/10.47414/na.9.2021.256394.
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Purpose. To study the peculiarities of quality formation (biochemical component, content of vitamins, macro- and microelements, integral score) of fresh and dried currant fruits as affected by the variety. Methods. Laboratory, mathematical and statistical, physicochemical. Results. In fresh fruits. the content of mono- and disaccharides varied from 6.2 to 7.4%, fiber from 4.3 to 4.8, the fat from 3.4 to 4.1. The content of ash was the lowest and varied between 0.77 and 0.87% over the studied varieties. In the dried fruits, the content of the analyzed components was 4.4–4.5 times higher in comparison with fresh ones due to the reduction of the water content. The content of vitamins varied as affected by variety and the condition of currant berries. Of the vitamins in fresh fruits, the leader was vitamin C with the content ranged between196 and 203 mg/100 g, while the lowest was the content of vitamin K ranging between 0.1 mcg and 100 g. The content of vitamin B7 varied from 2.1 to 2.4 mcg/100 g, and the content of other vitamins varied between 0.1 and 12.6 mg/100 g. It should be noted that in terms of dry weight, the content of all vitamins in dried fruits decreased compared to fresh ones. Vitamin B5 content decreased by 44 times, while vitamin C 18.5 times, and other vitamins from 1.1 to 7.7 times. Fresh currant fruits contained the most potassium (347–352 mg/100 g) and the least selenium (1.1 mcg/100 g). The copper content ranged between 131 and132 mcg/100 g. The content of other mineral elements varied from 0,26 to 59 mg/100 g. In dried currant fruits this indicator increased by 4.4–4.5 times. Conclusions. The biochemical composition of fruits varies as affected by variety and condition of currant fruits. ‘Volodymyrska’ currant berries have a lower biological value, as the integrated rate is lower than that of the ‘Chereshneva’ variety. In addition to high water content, fresh fruits contained sugars, fat and dietary fiber. Fresh currant fruits contain the most vitamins B9 and C. In dried fruits, the content of all vitamins is reduced and has almost no effect on the composition of mineral elements. Dried currant fruits contain vitamins B9 and C, as well as B1, B6, B3 and E (integral score 16–24%).
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Cherneha, A. O., V. V. Liubych, L. L. Novak, and N. V. Pavliuk. "Quality formation of frozen berries and jam from sea buckthorn (Hippophae rhanoides L.) of different varieties." Scientific Papers of the Institute of Bioenergy Crops and Sugar Beet, no. 29 (December 29, 2021). http://dx.doi.org/10.47414/np.29.2021.247434.
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Purpose. Examine the formation of quality (biochemical component, vitamin content) of frozen berries and jam from sea buckthorn as affected by varietal characteristics.
Methods. Laboratory, mathematical and statistical, physicochemical.
Results. The main component of frozen sea buckthorn berries is water, 75.5–77.4%. In jam, water content mades up 57.5%. Studies have shown that frozen berries of different varieties contain ash (0.3%), protein (from 0.85 to 0.89), carbohydrates (mono- and disaccharides, 4.5–5.0), fat (5.0– 5.3%). The content of carbohydrates in the jam at the actual humidity was 32.0%, the content of ash and protein was also the lowest, 0.5–0.6%, and the fat content was 3.8%. The carbohydrate content increased due to the addition of sugar during the preparation of the jam. The content of vitamins in frozen sea buckthorn berries varied significantly depending on the variety. Thus, the content of vitamin C in the berries of variety ‘Uliublena’ was 178 mg/100 g, while in the variety ‘Yelyzaveta’ 167 mg/100 g. In sea buckthorn jam, the content of vitamins B9, B3 and E was 46–72% higher compared to berries, apparently due to the reduction of its humidity during cooking. The content of vitamin C decreased to 55.5 mg/100 g, and the remaining vitamins did not change compared to frozen berries. The content of vitamins B9 and B3 decreased by 16%, vitamin C by 82%, and the content of vitamins B7, B1, B2, B6 and B5 by 45–50% compared to frozen berries. The integrated score of 100 g of frozen sea buckthorn berries satisfies this need with vitamin C – 185–197%, depending on the variety. The need for vitamin E is satisfied only by 15.3–16.7%, and the rest of the vitamins – by 0.5–3.8%, depending on the variety of sea buckthorn. The integral rate of 100 g of sea buckthorn jam satisfies the daily requirement of an adult with vitamin C by 61.7%, vitamin E by 28.7%, and the rest of the vitamins by 0.8–4.0%.
Conclusions. The quality of frozen berries significantly depends on the variety of sea buckthorn. Frozen sea buckthorn berries contain the most vitamin C, 167–178 mg/100 g, and jam 55.5 mg/100 g of product. The content of vitamin E is 2.30–2.50 and 4.31 mg/100 g of product, respectively. The content of other vitamins is low, which is confirmed by the analysis of the calculation of the integrated score. The greatest daily requirement of 100 g of frozen berries and jam is provided by vitamin C and E. Therefore it is necessary to use freezing and preparation of jam as sources of vitamin C and E.