Journal articles on the topic 'CD30L T cell'
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1
Younes, A., U. Consoli, V. Snell, K. Clodi, K. O. Kliche, J. L. Palmer, H. J. Gruss, et al. "CD30 ligand in lymphoma patients with CD30+ tumors." Journal of Clinical Oncology 15, no. 11 (November 1997): 3355–62. http://dx.doi.org/10.1200/jco.1997.15.11.3355.
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PURPOSE CD30 ligand (CD30L), which is expressed on resting B and activated T lymphocytes, can induce cell death in several CD30+ cell lines. Patients with CD30+ tumors (Hodgkin's disease and Ki-1+ non-Hodgkin's lymphoma) frequently have elevated soluble CD30 (sCD30) levels in their serum, which correlates with a poor prognosis. The role of sCD30 in protecting tumor cells from CD30L-mediated cell death and the pattern of CD30L expression on human peripheral-blood lymphocytes (PBLs) of normal donors and patients with CD30+ tumors are investigated. MATERIALS AND METHODS CD30L surface protein expression was determined by two-color flow cytometry on PBLs of patients with CD30+ tumors and normal individuals. CD30L levels were determined on subsets of PBLs before and after stimulation with phytohemagglutinin (PHA), anti-CD3 antibody, or CD40L. sCD30 was measured by enzyme-linked immunosorbent assay (ELISA). The apoptotic activity of membrane-bound CD30L was tested in a CD30+ cell line by the annexin V-binding method. RESULTS Unstimulated T lymphocytes of normal donors and patients with lymphoma rarely expressed CD30L surface protein, but were able to express it after stimulation with PHA or anti-CD3 antibody. Resting B cells of patients with CD30+ tumors had lower levels of detectable surface CD30L compared with normal donors (mean, 55% and 80.6%, respectively; P = .0008). Patients with high levels of serum sCD30 had lower detectable levels of CD30L on their PBLs (R2 = .72, P = .0008) and exogenous sCD30 blocked membrane-bound CD30L-mediated apoptosis in a CD30+ cell line. CONCLUSION In patients with CD30+ tumors, sCD30 can decrease the availability of CD30L on PBLs. Blocking the apoptosis-inducing activity of CD30L by its soluble receptor may explain how CD30+ tumors escape immunosurveillance and may be related to the reported poor prognosis of patients who have elevated sCD30 levels.
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Willis, Cynthia R., Yi-Ling Hu, Anh Leith, and James B. Rottman. "CD30 / CD30L interactions promote class-switched antibody responses to T-dependent antigens (34.3)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 34.3. http://dx.doi.org/10.4049/jimmunol.182.supp.34.3.
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Abstract The cell-surface glycoproteins CD30 and CD30L are members of the TNFR and TNF superfamilies, respectively. CD30 is expressed on subpopulations of activated T and B cells. CD30L is expressed on activated T cells, macrophages, and dendritic cells, as well as germinal center B cells. CD30 / CD30L interactions provide activation-induced costimulatory signals that sustain T-cell responses, mediate B-cell activity, and generate long-lived memory T cells for chronic B-cell help. Although other activation-induced costimulatory molecules induce antibody isotype class switching, it is less clear what the function is of CD30 signaling on class switching and antibody production. Therefore, we tested the effect of in vivo blockade of the CD30 / CD30L pathway on antibody class switching in response to T-dependent antigens using two systems that require activated-T cells to stimulate B-cell responses. First, BALB/c mice immunized with a T-dependent antigen and treated with anti-CD30L antibodies produced less antigen-specific antibodies of IgG1 and IgE isotypes as compared to control-treated mice, whereas antigen-specific antibodies of the IgM isotype were similar in all groups. Likewise, NZB/W F1 lupus-prone mice treated with anti-CD30L antibodies produced less anti-dsDNA antibodies of the IgG1 and IgG2a isotypes as compared to control-treated mice, whereas anti-dsDNA antibodies of the IgM isotype were similar in all groups. In both systems, specific subpopulations of lymphocytes necessary for responses to T-dependent antigens were reduced by blockade of the CD30 / CD30L pathway. Our results demonstrate that CD30 / CD30L interactions positively regulate T-cell dependent B-cell responses necessary for class-switched antibody responses.
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Mori, M., C. Manuelli, N. Pimpinelli, C. Mavilia, E. Maggi, M. Santucci, B. Bianchi, P. Cappugi, B. Giannotti, and M. E. Kadin. "CD30-CD30 Ligand Interaction in Primary Cutaneous CD30+T-Cell Lymphomas: A Clue to the Pathophysiology of Clinical Regression." Blood 94, no. 9 (November 1, 1999): 3077–83. http://dx.doi.org/10.1182/blood.v94.9.3077.
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Abstract Primary CD30+ cutaneous T-cell lymphomas (CTCLs) represent a spectrum of non-Hodgkin’s lymphomas (NHLs) that have been well defined at the clinical, histologic, and immunologic level. This group, which includes 2 main entities (large cell lymphoma and lymphomatoid papulosis [LyP]) and borderline cases, is characterized by the expression of CD30 antigen by neoplastic large cells at presentation, possible spontaneous regression of the skin lesions, and generally favorable clinical course. Although the functional relevance of CD30 and its natural ligand (CD30L) expression in most cases of NHL is presently undefined, previous studies indicate that CD30L is likely to mediate reduction of proliferation in CD30+ anaplastic large-cell NHL. No information is currently available concerning the expression of CD30L in primary CD30+ CTCLs. In this study, we investigated the immunophenotypic and genotypic expression of CD30 and CD30L in different developmental phases of skin lesions (growing v spontaneously regressing). By immunohistochemistry, CD30L expression was detected in regressing lesions only; by molecular analysis, the expression of CD30L was clearly higher in regressing lesions than in growing ones. CD30L, while expressed by some small lymphocytes, was most often coexpressed by CD30+neoplastic large cells, as demonstrated by 2-color immunofluorescence and by immunohistochemistry on paraffin sections. Taken together, these data suggest that CD30-CD30L interaction may play a role in the pathobiology of primary cutaneous CD30+lymphoproliferative disorders. In particular, CD30L (over)expression might have a major role in the mechanism of self-regression of skin lesions, the most distinctive clinical feature of this cutaneous lymphoma subtype.
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Mori, M., C. Manuelli, N. Pimpinelli, C. Mavilia, E. Maggi, M. Santucci, B. Bianchi, P. Cappugi, B. Giannotti, and M. E. Kadin. "CD30-CD30 Ligand Interaction in Primary Cutaneous CD30+T-Cell Lymphomas: A Clue to the Pathophysiology of Clinical Regression." Blood 94, no. 9 (November 1, 1999): 3077–83. http://dx.doi.org/10.1182/blood.v94.9.3077.421k28_3077_3083.
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Primary CD30+ cutaneous T-cell lymphomas (CTCLs) represent a spectrum of non-Hodgkin’s lymphomas (NHLs) that have been well defined at the clinical, histologic, and immunologic level. This group, which includes 2 main entities (large cell lymphoma and lymphomatoid papulosis [LyP]) and borderline cases, is characterized by the expression of CD30 antigen by neoplastic large cells at presentation, possible spontaneous regression of the skin lesions, and generally favorable clinical course. Although the functional relevance of CD30 and its natural ligand (CD30L) expression in most cases of NHL is presently undefined, previous studies indicate that CD30L is likely to mediate reduction of proliferation in CD30+ anaplastic large-cell NHL. No information is currently available concerning the expression of CD30L in primary CD30+ CTCLs. In this study, we investigated the immunophenotypic and genotypic expression of CD30 and CD30L in different developmental phases of skin lesions (growing v spontaneously regressing). By immunohistochemistry, CD30L expression was detected in regressing lesions only; by molecular analysis, the expression of CD30L was clearly higher in regressing lesions than in growing ones. CD30L, while expressed by some small lymphocytes, was most often coexpressed by CD30+neoplastic large cells, as demonstrated by 2-color immunofluorescence and by immunohistochemistry on paraffin sections. Taken together, these data suggest that CD30-CD30L interaction may play a role in the pathobiology of primary cutaneous CD30+lymphoproliferative disorders. In particular, CD30L (over)expression might have a major role in the mechanism of self-regression of skin lesions, the most distinctive clinical feature of this cutaneous lymphoma subtype.
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Gattei, Valter, Massimo Degan, Annunziata Gloghini, Angela De Iuliis, Salvatore Improta, Francesca Maria Rossi, Donatella Aldinucci, et al. "CD30 Ligand Is Frequently Expressed in Human Hematopoietic Malignancies of Myeloid and Lymphoid Origin." Blood 89, no. 6 (March 15, 1997): 2048–59. http://dx.doi.org/10.1182/blood.v89.6.2048.
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Abstract CD30 ligand (CD30L) is a type-II membrane glycoprotein capable of transducing signals leading to either cell death or proliferation through its specific counterstructure CD30. Although several lines of evidence indicate that CD30L plays a key role as a paracrine- or autocrine-acting surface molecule in the deregulated cytokine cascade of Hodgkin's disease, little is known regarding its distribution and biologic significance in other human hematopoietic malignancies. By analyzing tumor cells from 181 patients with RNA studies and immunostaining by the anti-CD30L monoclonal antibody M80, we were able to show that human hematopoietic malignancies of different lineage and maturation stage display a frequent and broad expression of the ligand. CD30L mRNA and surface protein were detected in 60% of acute myeloid leukemias (AMLs), 54% of B-lineage acute lymphoblastic leukemias (ALLs), and in a consistent fraction (68%) of B-cell lymphoproliferative disorders. In this latter group, hairy cell leukemia and high-grade B-cell non-Hodgkin's lymphoma (B-NHL) expressed a higher surface density of CD30L as compared with B-cell chronic lymphocytic leukemia and low-grade B-NHL. Purified plasmacells from a fraction of multiple myeloma patients also displayed CD30L mRNA and protein. A more restricted expression of CD30L was found in T-cell tumors that was mainly confined to neoplasms with an activated peripheral T-cell phenotype, such as T-cell prolymphocytic leukemia, peripheral T-NHL, and adult T-cell leukemia/lymphoma. In contrast, none of the T-lineage ALLs analyzed expressed the ligand. In AML, a high cellular density of CD30L was detected in French-American-British M3, M4, and M5 phenotypes, which are directly associated with the presence on tumor cells of certain surface structures, including the p55 interleukin-2 receptor α-chain, the αM (CD11b) chain of β2 integrins, and the intercellular adhesion molecule-1 (CD54). Analysis of normal hematopoietic cells evidenced that, in addition to circulating and tonsil B cells, a fraction of bone marrow myeloid precursors, erythroblasts, and subsets of megakaryocytes also express CD30L. Finally, we have shown that native CD30L expressed on primary leukemic cells is functionally active by triggering both mitogenic and antiproliferative signals on CD30+ target cells. As opposed to CD30L, only 10 of 181 primary tumors expressed CD30 mRNA or protein, rendering therefore unlikely a CD30-CD30L autocrine loop in human hematopoietic neoplasms. Taken together, our data indicate that CD30L is widely expressed from early to late stages of human hematopoiesis and suggest a regulatory role for this molecule in the interactions of normal and malignant hematopoietic cells with CD30+ immune effectors and/or microenvironmental accessory cells.
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Rottman, James B., Yi-Ling Hu, and Cynthia Willis. "Blockade of the CD30/CD30L pathway inhibits renal disease in young, SLE-prone NZB/W F1 mice (50.41)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 50.41. http://dx.doi.org/10.4049/jimmunol.182.supp.50.41.
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Abstract CD30 and CD30L are interacting members of the TNFR and TNF family, respectively. CD30 is expressed by subsets of activated T and B cells, whereas CD30L is expressed by subsets of activated T cells, macrophages and dendritic cells. The CD30 / CD30L interaction modulates T cell activation, germinal center formation and antibody isotype class switching. Given the importance of this pathway to B cell function, we tested the hypothesis that blockade of the CD30 / CD30L pathway would decrease or abrogate autoantibody formation and renal disease in the NZB/W F1 murine model of systemic lupus erythematosis (SLE). Young (5 mo) NZB/W F1 mice were treated with 300 μg CD30L blocking (M15-N297A) or blocking / depleting (M15-IgG2a) antibody weekly for 3 months during the onset of autoimmunity. Both treatments a) reduced the onset and severity of proteinuria, b) significantly decreased the severity of renal histologic scores, c) decreased glomerular immune complex and complement deposition and d) these effects were associated with reduced production of anti-DNA antibodies of the IgG, but not IgM isotype. CD30 / CD30L blockade may be a viable approach for the treatment of SLE.
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Barbieri, Alessandro, Marzia Dolcino, Elisa Tinazzi, Antonella Rigo, Giuseppe Argentino, Giuseppe Patuzzo, Andrea Ottria, Ruggero Beri, Antonio Puccetti, and Claudio Lunardi. "Characterization of CD30/CD30L+Cells in Peripheral Blood and Synovial Fluid of Patients with Rheumatoid Arthritis." Journal of Immunology Research 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/729654.
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The CD30/CD30L signalling system has been implicated in the pathogenesis of several autoimmune and inflammatory conditions. In rheumatoid arthritis (RA), soluble CD30 (sCD30) levels reflect the recruitment of CD30+T cells into the inflamed joints and correlate with a positive response to immunosuppressive therapy. The aim of our report was to clarify the role of CD30/CD30L signalling system in the pathogenesis of RA. Our analysis of the CD30L+T cell subsets in peripheral blood (PB) and synovial fluid (SF) of RA patients and of the related cytokine profiles suggests the involvement of CD30/CD30L signalling in polarization of T cells towards a Th17 phenotype with proinflammatory features. Moreover, in RA SF nearly 50% of Treg cells express CD30, probably as an attempt to downmodulate the ongoing inflammation. We also show here that the engagement of CD30L on neutrophils stimulated with CD30/Fc chimera may play a crucial role in RA inflammation since activated neutrophils release IL-8, thus potentially amplifying the local inflammatory damage. In conclusion, the results obtained suggest that the complex CD30/CD30L signalling pathway is implicated in the pathogenesis and progression of RA synovitis through a concerted action on several immune effector cells.
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Romagnani, Paola, Francesco Annunziato, Roberto Manetti, Carmelo Mavilia, Laura Lasagni, Cinzia Manuelli, Gabriella B. Vannelli, et al. "High CD30 Ligand Expression by Epithelial Cells and Hassal's Corpuscles in the Medulla of Human Thymus." Blood 91, no. 9 (May 1, 1998): 3323–32. http://dx.doi.org/10.1182/blood.v91.9.3323.
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Abstract CD30 is a member of tumor necrosis factor (TNF) receptor superfamily that is expressed by activated T cells in the presence of interleukin-4 (IL-4). Although CD30 can mediate a variety of signals, CD30-deficient mice have impaired negative selection of T cells, suggesting that at least in the context of murine thymus, CD30 is a cell death–mediating molecule. The ligand for CD30 (CD30L) is a membrane-associated glycoprotein related to TNF, which is known to be expressed mainly by activated T cells and other leukocytes. However, the nature of CD30L-expressing cells involved in the interaction with CD30+ thymocytes is unclear. We report here that in postnatal human thymus the great majority of CD30+ cells are double positive (CD4+CD8+), activated, IL-4 receptor–expressing T cells which selectively localize in the medullary areas. Moreover, many medullary epithelial cells and Hassal's corpuscles in the same thymus specimens showed unusually high expression of CD30L in comparison with other lymphoid or nonlymphoid tissues. These findings provide additional information on the nature and localization of CD30+ thymocytes and show that epithelial cells are the major holder of CD30L in the thymic medulla.
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Romagnani, Paola, Francesco Annunziato, Roberto Manetti, Carmelo Mavilia, Laura Lasagni, Cinzia Manuelli, Gabriella B. Vannelli, et al. "High CD30 Ligand Expression by Epithelial Cells and Hassal's Corpuscles in the Medulla of Human Thymus." Blood 91, no. 9 (May 1, 1998): 3323–32. http://dx.doi.org/10.1182/blood.v91.9.3323.3323_3323_3332.
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CD30 is a member of tumor necrosis factor (TNF) receptor superfamily that is expressed by activated T cells in the presence of interleukin-4 (IL-4). Although CD30 can mediate a variety of signals, CD30-deficient mice have impaired negative selection of T cells, suggesting that at least in the context of murine thymus, CD30 is a cell death–mediating molecule. The ligand for CD30 (CD30L) is a membrane-associated glycoprotein related to TNF, which is known to be expressed mainly by activated T cells and other leukocytes. However, the nature of CD30L-expressing cells involved in the interaction with CD30+ thymocytes is unclear. We report here that in postnatal human thymus the great majority of CD30+ cells are double positive (CD4+CD8+), activated, IL-4 receptor–expressing T cells which selectively localize in the medullary areas. Moreover, many medullary epithelial cells and Hassal's corpuscles in the same thymus specimens showed unusually high expression of CD30L in comparison with other lymphoid or nonlymphoid tissues. These findings provide additional information on the nature and localization of CD30+ thymocytes and show that epithelial cells are the major holder of CD30L in the thymic medulla.
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Wiley, S. R., R. G. Goodwin, and C. A. Smith. "Reverse signaling via CD30 ligand." Journal of Immunology 157, no. 8 (October 15, 1996): 3635–39. http://dx.doi.org/10.4049/jimmunol.157.8.3635.
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Abstract CD30 ligand (CD30L), a member of the TNF family, is a type II membrane protein with a C-terminal extracellular domain that is homologous with the extracellular domains of other TNF family members. Also, like most TNF family members, the N-terminal cytoplasmic domain of CD30L is conserved across species, but not between family members, suggesting a possible biological function. Motivated by this observation, we investigated the potential for CD30L, when activated by cross-linking, to directly transduce a signal to the ligand-bearing cell. Cross-linking of CD30L by a mAb or by CD30-Fc fusion protein induced the production of IL-8 by freshly isolated neutrophils. Further, both cross-linking mechanisms produced a rapid oxidative burst. Indirect effects through CD30 were ruled out, since CD30L, but not CD30, is expressed on neutrophils. Expression of CD30L can be induced in peripheral blood T cells by cross-linking the CD3 component of the TCR. Peripheral blood T cells exposed to suboptimal concentrations of anti-CD3 increased metabolic activity, proliferated, and produced IL-6 in response to cross-linking of CD30L. These results indicate that cross-linked CD30L can transduce a signal to the ligand-bearing cell. This "reverse signaling" via CD30L taken together with previously published data concerning other ligands in the TNF family strongly suggest that, as a rule, TNF family members and their cognate receptors signal bidirectionally, blurring the distinction between ligand and receptor.
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Saraiva, Margarida, Philip Smith, Padraic G. Fallon, and Antonio Alcami. "Inhibition of Type 1 Cytokine–mediated Inflammation by a Soluble CD30 Homologue Encoded by Ectromelia (Mousepox) Virus." Journal of Experimental Medicine 196, no. 6 (September 16, 2002): 829–39. http://dx.doi.org/10.1084/jem.20020319.
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CD30 is up-regulated in several human diseases and viral infections but its role in immune regulation is poorly understood. Here, we report the expression of a functional soluble CD30 homologue, viral CD30 (vCD30), encoded by ectromelia (mousepox) virus, a poxvirus that causes a severe disease related to human smallpox. We show that vCD30 is a 12-kD secreted protein that not only binds CD30L with high affinity and prevents its interaction with CD30, but it also induces reverse signaling in cells expressing CD30L. vCD30 blocked the generation of interferon γ–producing cells in vitro and was a potent inhibitor of T helper cell (Th)1- but not Th2-mediated inflammation in vivo. The finding of a CD30 homologue encoded by ectromelia virus suggests a role for CD30 in antiviral defense. Characterization of the immunological properties of vCD30 has uncovered a role of CD30–CD30L interactions in the generation of inflammatory responses.
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Tsiagbe, Vincent, Eckhard Podack, and Yu Li. "CD30L null SJL mice exhibit reduced lymph node and spleen weights but support growth of transplantable SJL lymphoma RCS-X (48.29)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 48.29. http://dx.doi.org/10.4049/jimmunol.186.supp.48.29.
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Abstract The process by which endogenous retroviral superantigen (vSAg29) expressing SJL lymphomas (RCS) stimulate host CD4+Vβ16+ T cells, in order to elicit help (notably IL-4 and -5) for their growth, has been characterized as “reverse immune surveillance”. This response is facilitated by the high expression of an array of co-stimulating molecules on RCS cells, including B7.1, B7.2, 41BBL, CD40 and CD30. On the basis of their germinal center derivation, SJL lymphomas bear close resemblance to a subpopulation of human germinal center B cell lymphomas, such as CD30+ Hodgkin’s lymphomas. In our earlier studies, growth of transplantable SJL lymphoma (RCS-X) in vivo was inhibited by anti-CD30 mAb. While the evidence shows that this effect is indirectly on the lymphoma-responsive CD4 T cells, the mechanism of action was unclear. To shed light on the role of CD30-CD30L interactions in SJL lymphoma development, CD30L-/- were bred onto SJL background and tested for their support of transplantable lymphoma growth. A significant reduction in lymph node (17.4-54.7%) and spleen weights (21.5-38.2%) was observed for CD30 null mice, compared to wild type SJL mice. Despite this reduction in the lymphoid compartment, no reduction in lymphoma growth was observed. The results suggest that while CD30-CD30L interactions might be important for SJL lymphoma growth, other costimulating molecules might contribute significantly to the process of reverse immune surveillance in RCS lymphoma.
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Rossi, Francesca Maria, Massimo Degan, Linda Mazzocut-Zecchin, Raffaele Di Francia, Donatella Aldinucci, Antonio Pinto, and Valter Gattei. "CD30L up-regulates CD30 and IL-4 expression by T cells." FEBS Letters 508, no. 3 (November 23, 2001): 418–22. http://dx.doi.org/10.1016/s0014-5793(01)03076-9.
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Gruss, HJ, and SK Dower. "Tumor necrosis factor ligand superfamily: involvement in the pathology of malignant lymphomas." Blood 85, no. 12 (June 15, 1995): 3378–404. http://dx.doi.org/10.1182/blood.v85.12.3378.bloodjournal85123378.
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The TNF receptor superfamily members are all type I membrane glycoproteins with typical homology in the extracellular domain of variable numbers of cysteine-rich repeats (overall homologies, 25% to 30%). In contrast, the TNF ligand superfamily members (with the exception of LT alpha) are type II membrane glycoproteins with homology to TNF in the extracellular domain (overall homologies, 20%). TNF and LT alpha are trimeric proteins and are composed of beta-strands forming a beta-jellyroll. The homology of the beta-strand regions for the TNF ligand superfamily members suggest a similar beta-sandwich structure and possible trimeric or multimeric complex formation for most or all members. A genetic linkage, as evidence for evolutionary relatedness, is found by chromosomal cluster of TNFR p80, CD30, 4–1BB, and OX40 for 1p36; TNFR p60, TNFR-RP, and CD27 for 12p13; TNF, LT alpha, and LT beta for 6 (MHC locus); CD27L and 4–1BBL for 19p13; and FASL and OX40L for 1q25. Of the TNF ligand superfamily, TNF, LT alpha, and LT beta and their receptors (TNFR p60, TNFR p80, and TNFR-RP) interact in a complex fashion of cross-binding. However, the other family members presently have a one ligand/one receptor binding principle (CD27/CD27L, CD30/CD30L, CD40/CD40L, 4–1BB/4–1BBL, OX40/gp34, and FAS/FASL). In general, the members of the TNF ligand superfamily mediate interaction between different hematopoietic cells, such as T cell/B cell, T cell/monocyte, and T cell/T cell. Signals can be transduced not only through the receptors but also through at least some of the ligands. The transduced signals can be stimulatory or inhibitory depending on the target cell or the activation state. Taken together, TNF superfamily ligands show for the immune response an involvement in the induction of cytokine secretion and the upregulation of adhesion molecules, activation antigens, and costimulatory proteins, all known to amplify stimulatory and regulatory signals. On the other hand, differences in the distribution, kinetics of induction, and requirements for induction support a defined role for each of the ligands for T-cell-mediated immune responses. The shedding of members of the TNF receptor superfamily could limit the signals mediated by the corresponding ligands as a functional regulatory mechanism. Induction of cytotoxic cell death, observed for TNF, LT alpha, CD30L, CD95L, and 4–1BBL, is another common functional feature of this cytokine family. Further studies have to identify unique versus redundant biologic and physiologic functions for each of the TNF superfamily ligands.(ABSTRACT TRUNCATED AT 400 WORDS)
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Tang, Ce, Hisakata Yamada, Kensuke Shibata, Hiromi Muta, Worawidh Wajjwalku, Eckhard R. Podack, and Yasunobu Yoshikai. "A Novel Role of CD30L/CD30 Signaling by T-T Cell Interaction in Th1 Response against Mycobacterial Infection." Journal of Immunology 181, no. 9 (October 20, 2008): 6316–27. http://dx.doi.org/10.4049/jimmunol.181.9.6316.
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Williams, Joy, Jingjing Zhang, David Klug, Takeshi Nitta, Michael Kruhlak, Susan Sharrow, Larry Granger, et al. "Thymocyte autoreactivity and altered thymic epithelial development in the absence of CD28-CD80/86 and CD40-CD40L interactions (36.69)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 36.69. http://dx.doi.org/10.4049/jimmunol.184.supp.36.69.
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Abstract CD28-CD80/86 and CD40-CD40L interactions are critical to the activation of mature T cells and also have significant effects on T cell development and repertoire selection. Notably, the effects of these costimulatory interactions can be bi-directional, affecting both CD28- and CD40L-expressing T cells and the B7- and CD40-expressing cells with which these T cells interact. We have therefore analyzed development of a self-tolerant T cell repertoire as well as the development of thymic cortico-medullary structure in mice deficient for both the CD28-CD80/86 and CD40-CD40L costimulatory pathways. We find that CD4 thymocytes from CD40/CD80/CD86 KO mice respond vigorously to syngeneic antigen presenting cells, in contrast to the weak responses of thymocytes from either CD40 KO or CD80/CD86 KOs. Interestingly, we also find that the thymic medullary epithelial compartment (mTEC) is uniquely disrupted in CD40/CD80/CD86 deficient mice. The profound reduction in thymic medullary epithelial cells in CD40/CD80/CD86 deficient mice is accompanied by a significant decrease in CD4 SP thymocyte expression of several TNF family members including LTa, LTb, and CD30L. Expression of RANK-L, previously shown to be critical for development of mTEC in the embryonic and adult thymus, is unaffected in CD40/CD80/CD86 deficient thymocytes. These results indicate that thymocyte-mTEC crosstalk mediated either directly or indirectly through CD40 and B7 pathways is critical to thymic stromal development.
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Akiba, Hisaya, Yasushi Miyahira, Machiko Atsuta, Kazuyoshi Takeda, Chiyoko Nohara, Toshiro Futagawa, Hironori Matsuda, Takashi Aoki, Hideo Yagita, and Ko Okumura. "Critical Contribution of Ox40 Ligand to T Helper Cell Type 2 Differentiation in Experimental Leishmaniasis." Journal of Experimental Medicine 191, no. 2 (January 17, 2000): 375–80. http://dx.doi.org/10.1084/jem.191.2.375.
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Infection of inbred mouse strains with Leishmania major is a well characterized model for analysis of T helper (Th)1 and Th2 cell development in vivo. In this study, to address the role of costimulatory molecules CD27, CD30, 4-1BB, and OX40, which belong to the tumor necrosis factor receptor superfamily, in the development of Th1 and Th2 cells in vivo, we administered monoclonal antibody (mAb) against their ligands, CD70, CD30 ligand (L), 4-1BBL, and OX40L, to mice infected with L. major. Whereas anti-CD70, anti-CD30L, and anti–4-1BBL mAb exhibited no effect in either susceptible BALB/c or resistant C57BL/6 mice, the administration of anti-OX40L mAb abrogated progressive disease in BALB/c mice. Flow cytometric analysis indicated that OX40 was expressed on CD4+ T cells and OX40L was expressed on CD11c+ dendritic cells in the popliteal lymph nodes of L. major–infected BALB/c mice. In vitro stimulation of these CD4+ T cells showed that anti-OX40L mAb treatment resulted in substantially reduced production of Th2 cytokines. Moreover, this change in cytokine levels was associated with reduced levels of anti–L. major immunoglobulin (Ig)G1 and serum IgE. These results indicate that anti-OX40L mAb abrogated progressive leishmaniasis in BALB/c mice by suppressing the development of Th2 responses, substantiating a critical role of OX40–OX40L interaction in Th2 development in vivo.
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Gracias, Donald Tom, Amit Kumar Mehta, Hideo Yagita, and Michael Croft. "Dual Blockade of OX40 and CD30 Signaling Reduces Memory Th2-driven Lung Inflammatory Responses to House Dust Mite Allergen." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 192.2. http://dx.doi.org/10.4049/jimmunol.196.supp.192.2.
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Abstract Allergic asthma is an inflammatory disease that is induced by immune responses to airborne allergens in the lungs. Several studies have identified T cells as being important players in asthma, with Type 2 helper T cells (Th2) being a critical subset. The selective removal of pre-existing pathogenic memory Th2 cells could be a key process leading to enhanced tolerance. We have attempted to identify signaling molecules in the TNF superfamily that regulate memory Th2 cells in a house dust mite (HDM) model of allergic lung inflammation. C57BL/6J mice up-regulated OX40L to higher levels than other TNF family members measured in the lungs in response to HDM exposure. We then tested whether OX40-OX40L interactions were required for memory Th2 cell responses driven by HDM. While OX40-deficient mice displayed strongly reduced overall lung inflammation and Th2 development when challenged with HDM, therapeutic blocking of OX40L at the time of memory T cell reactivation did not result in similar inhibition of allergic responses, implying OX40L may have been important for initiation but not the memory response. Similar negative results were gained by targeting another TNF superfamily protein, CD30L, that was also up-regulated by HDM exposure. However, we observed significant reduction in airway inflammation when OX40L was simultaneously neutralized with CD30L. Dual blockade was found to target memory Th2 cell expansion and effector function but did not prevent accumulation of pTreg cells. This suggests that persisting memory responses to complex allergens are controlled by several co-stimulatory interactions, and only abrogation of signaling through multiple TNF superfamily members might promote airway tolerance.
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Guo, Ying, Xun Sun, Kensuke Shibata, Hisakata Yamada, Hiromi Muta, Eckhard R. Podack, and Yasunobu Yoshikai. "CD30 Is Required for Activation of a Unique Subset of Interleukin-17A-Producing γδ T Cells in Innate Immunity against Mycobacterium bovis Bacillus Calmette-Guérin Infection." Infection and Immunity 81, no. 10 (August 5, 2013): 3923–34. http://dx.doi.org/10.1128/iai.00887-13.
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ABSTRACTInterleukin-17A (IL-17A)-producing γδ T cells are known to be activated followingMycobacterium bovisbacillus Calmette-Guérin (BCG) infection. Here, we show that CD30, a member of the tumor necrosis factor (TNF) receptor superfamily, is important for activation of IL-17A-producing γδ T cells after BCG infection. Vγ1−Vγ4−γδ T cells preferentially expressing Vγ6/Vδ1 genes were identified as the major source of IL-17A in the peritoneal cavity during the early stage of BCG infection. The number of IL-17A-producing Vγ1−Vγ4−γδ T cells bearing Vγ6 increased in peritoneal exudate cells (PEC) of wild-type (WT) mice but not in those of CD30 knockout (KO) mice in response to BCG infection. Consistently, CD30 ligand (CD30L) or CD30 expression, predominantly by Vγ1−Vγ4−γδ T cells, was rapidly upregulated after BCG infection. Inhibition of CD30L/CD30 signaling byin vivoadministration of a soluble CD30 and immunoglobulin fusion protein (CD30-Ig) severely impaired activation of IL-17A-producing Vγ1−Vγ4−γδ T cells in WT mice, while stimulating CD30L/CD30 signaling byin vivoadministration of agonistic anti-CD30 monoclonal antibody (MAb) restored IL-17A production by Vγ1−Vγ4−γδ T cells in CD30L KO mice after BCG infection. These results suggest that CD30 signaling plays an important role in the activation of IL-17A-producing Vγ1−Vγ4−γδ T cells bearing Vγ6 at an early stage of BCG infection.
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Casneuf, Tineke, Andrew Lysaght, Clare LeFave, Jaime Bald, Brendan Weiss, Niels W. C. J. van de Donk, Henk M. Lokhorst, Tahamtan Ahmadi, and A. Kate Sasser. "Serum Proteomic Analysis of Multiple Myeloma Subjects Treated with Daratumumab Monotherapy." Blood 126, no. 23 (December 3, 2015): 1837. http://dx.doi.org/10.1182/blood.v126.23.1837.1837.
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Abstract Introduction: Daratumumab (DARA) is a human IgG1κ monoclonal antibody that binds with high affinity to a unique epitope on CD38. DARA monotherapy has shown promising activity in relapsed and/or refractory multiple myeloma (MM) patients with a median of 5 prior lines of therapy in two clinical studies (Study GEN501; Lokhorst HM. J Clin Oncol. 2014;32 Suppl:abstr 8513 and Study MMY2002; Lonial S. J Clin Oncol. 2015;33 Suppl:abstr LBA8512). The aim of this analysis was to identify proteins indicative of DARA's multiple mechanisms of action (MOA) and potential predictive pharmacodynamic response markers. A broad aptamer based proteomics platform (SomaSCANTM) evaluated clinical serum samples at study entry and during treatment to determine proteins and biological pathways associated with DARA MOA or clinical response. Methods: All patients were treated with 16 mg/kg DARA and whole blood samples were collected at baseline and after 8 weeks of treatment. Blood samples were processed for serum and stored frozen until batch analysis. Profiling of 1129 serum proteins was performed using the SOMAscan assay. Patients were classified based on overall best response: responders (stringent and complete responses, very good partial and partial responses), stable disease (stable disease or minimal response) and non-responders (progressive disease). Differential level testing included application of the Wilcoxon rank sum test and Limma for responder versus non-responder analysis, and ANOVA for repeated-measures with post-hoc test validation, Wilcoxon signed rank and Friedman tests for baseline versus on-treatment analysis. Results: In MMY2002 at baseline, 51 proteins were significantly different between responders and non-responders. Many have known associations with MM or CD38, and interestingly a subset is associated with T-cell biology. We recently observed that DARA induces a multi-factorial T-cell response in patients including CD8+ T-cell expansion and activation, and increased clonality. Proteins differentially expressed between responders/non-responders at baseline included tumor necrosis factor subfamily 8 (TNFSF8/CD30L), TNFSF9/CD137L, macrophage stimulating 1 (MST1), interleukin-1B (IL1B), cadherin 1 (CDH1) and cadherin 3 (CDH3). Protein profiles were evaluated at baseline and at 8 weeks (Cycle 3 Day 1) to study pharmacodynamic changes. Significant treatment-induced changes were identified in 142 proteins. Of particular interest were the 60 proteins that changed differentially over time in responders vs non-responders. Proteins associated with MM tumor load, such as beta-2-microglobulin [B2M], and immunoglobulins decreased in responders and increased in non-responders. Novel MM therapeutic targets such as signaling lymphocyte activation molecule F7 [SLAMF7] (i.e. CS1) and B-cell maturation antigen [BCMA] decreased in responders and increased in non-responders during DARA treatment. Many proteins associated with immune or T-cell response were also significantly changed by DARA treatment, including TNFRSF1B, CD163, TNFRSF25, TLR2, CCL5, IL5RA, FCGR2A, ICOS, Granzyme B, and programmed cell death ligand 1 [PD-L1] many of which were differential between responders and non-responders. Differential level testing of GEN501 samples identified a small set of proteins that were significantly altered by DARA treatment over time. Many of these proteins overlapped with those identified in the MMY2002 analysis, increasing confidence in the statistical results. Conclusions: This exploratory serum proteomic analysis identified proteins that were differentially expressed between responders and non-responders at baseline, including proteins associated with immune response and T-cell biology (TNFSF8/CD30L, TNFSF9/CD137L, IL1B). In addition, significant differential changes in protein expression between responders and non-responders after DARA treatment were seen. Many of these are associated with MM tumor load (BCMA, immunoglobulins, SLAMF7, and B2M) and decreased in responders and increased in non-responders. In addition, proteins related to T-cell activity, immune checkpoints and immune response (TNFRSF1B, CD163, TNFRSF25, TLR2, CCL5, IL5RA, FCGR2A, ICOS, Granzyme B, PD-L1) also showed changes associated with DARA treatment, supporting the recent findings that DARA induces a T-cell response in MM patients that may contribute to clinical response. Disclosures Casneuf: Janssen: Employment. Lysaght:Immuneering Corp: Employment, Other: Stockholder. LeFave:Immuneering Corp.: Employment. Bald:Janssen: Employment. Weiss:Janssen and Millennium: Consultancy; Janssen and Onclave: Research Funding. van de Donk:Janssen Pharmaceuticals: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Lokhorst:Amgen: Honoraria; Janssen: Honoraria, Research Funding; Genmab: Honoraria, Research Funding. Ahmadi:Janssen: Employment.
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Lichtenegger, Felix S., Katharina Mueller, Wolfgang Hiddemann, Dolores J. Schendel, and Marion Subklewe. "Dendritic Cells Matured with a TLR7/8 Agonist Induce T Helper 1 Cell Polarization, Activate NK Cells and Are Thus Highly Suitable for Application in Cancer Immunotherapy." Blood 118, no. 21 (November 18, 2011): 358. http://dx.doi.org/10.1182/blood.v118.21.358.358.
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Abstract Abstract 358FN2 Dendritic cells (DCs) are important regulators of the human immune response. By means of direct intercellular interactions and secretion of cytokines, they can induce a stimulatory or a regulatory response, depending on the environment in which they developed. In vitro, it is possible to imitate this process by addition of various cytokines. The aim of this study was to evaluate DCs matured by different cytokine cocktails for expression of immunostimulatory and -inhibitory molecules and correspondent activation of T helper 1 (Th1) and natural killer (NK) cells. The selection of these cocktails was guided by potential clinical application and usage in a GMP setting. We compared three different ways of DC generation from peripheral blood monocytes of healthy donors: 1) maturation by a cocktail including the TLR7/8 agonist R848 (TLR-mDCs), 2) DC generation by the standard combination of proinflammatory cytokines (IL-4, GM-CSF, IL-1β, PGE2, TNF-α, and IL-6) applied in many clinical studies so far (cc-mDCs), and 3) addition of IL-10 in order to induce a more regulatory phenotype (IL10-mDCs). The expression of a broad range of costimulatory and coinhibitory molecules (CD80, CD86, CD273, CD274, CD275, CD276, B7-H4, HVEM, CD30L, CD70, CD134L = OX40L, CD137L = 4-1BBL) on the surface of these DC populations was analyzed by FACS. Secretion of various cytokines crucial for interaction with other immune cells (IL-12p70, IL-10, TNF-α, IFN-γ, IL-2, and TGF-β) was measured by cytometric bead array after stimulation with CD40 ligand. In order to assess the functional importance of these signals, we performed in vitro polarization assays for T helper cells after co-culture with DCs and measured the in vitro stimulatory potential of the DCs for natural killer (NK) cells by CD69 upregulation and intracellular IFN-γ staining. We could show that TLR-mDCs were characterized by a predominance of costimulatory (e.g. CD80, CD86) relative to coinhibitory molecules (e.g. CD273, CD274, HVEM). When stimulated by CD40L, they displayed a cytokine profile with very high IL-12p70 and TNF-α, but little if any IL-10 production. In a co-culture with autologous T cells, the combination of these signals resulted in a strong polarization toward IFN-γ secreting Th1 cells, with little or no stimulation of Th2 and Th17 cells. The costimulatory profile of cc-mDCs, in comparison, was shifted toward a lower expression of costimulatory molecules and similar or higher expression of coinhibitory molecules (ratio of CD86 to CD273 expression around 40 compared to > 60 for TLR-mDCs, p < 0.005). No IL-12p70 and low levels of IL-10 were secreted. These signals were reflected in a less pronounced type 1 polarization of T helper cells. IL10-mDCs expressed very low levels of CD80 and CD86 and displayed a coinhibitory molecule pattern similar to cc-mDCs. Additionally, they secreted the immunoregulatory molecule IL-10 in higher amounts and did not activate T helper cells at all. As IL-12p70 is an important factor for NK cell activation, only TLR-mDCs were capable of upregulating the activation marker CD69 on NK cells and inducing significant secretion of IFN-γ. Both Th1 and NK cells play an important role in tumor defense. With this set of data, we clearly showed that TLR-mDCs, in consequence of their positive costimulatory profile and their high IL-12p70 secretion, are superior with respect to type 1 polarization of T cells and activation of NK cells. They are therefore highly suitable for application in cancer immunotherapy. This DC type will be used in a phase I/II trial for postremission therapy in patients with non-favorable AML, which will start in our clinic in 2012. Disclosures: No relevant conflicts of interest to declare.
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Gunawardana, Jay, Karolina Bednarska, Soi C. Law, Justina Lee, Muhammed Bilal Sabdia, Joshua W. D. Tobin, Simone Birch, Colm Keane, and Maher K. Gandhi. "The Tumor Microenvironment of Nodular Lymphocyte Predominant Hodgkin Lymphoma Is a Unique Immunobiological Entity Distinct from Classical Hodgkin Lymphoma." Blood 132, Supplement 1 (November 29, 2018): 4123. http://dx.doi.org/10.1182/blood-2018-99-115836.
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Abstract There is proven pre-clinical and clinical efficacy of mono or combinatorial immune strategies to boost host anti-lymphoma immunity, with classical Hodgkin Lymphoma (cHL) seen as the 'poster child'. Approaches include blockade of immune-checkpoints on exhausted tumor-specific T-cells (via mAb blockade of PD-1, TIM3, LAG3, TIGIT or their ligands), activation of T-cells via mAbs agonistic to CD137, and finally modulation of FOXP3, CTLA-4 and/or LAG3 regulatory T-cells (Tregs) or immunosuppressive tumor-associated macrophages (TAMs). In contrast, studies characterizing the circulating and intra-tumoral microenvironment (TME) of the distinct but rare CD20+ Hodgkin Lymphoma entity (5-8% of HL), Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL), are minimal. Furthermore, to our knowledge no functional profiling studies comparing the host immunity of NLPHL with cHL has been performed. We compared host immunity in 29 NLPHL patients, 30 cHL patients and 10 healthy individuals, with a focus on pertinent and clinically actionable immune parameters. Paraffin-embedded tissue and paired (pre- and post-therapy) peripheral blood mononuclear cells samples were interrogated by digital multiplex hybridization (Nanostring Cancer Immune Profiling Panel) and flow cytometry. Although cytotoxic T-cell gene counts (CD8a, CD8b) were similar, compared to cHL there were higher levels of the immune effector activation marker CD137 (gene counts 439 vs. 287; P<0.01). Consistent with this, CD4 and the Treg markers LAG3, FOXP3 and CTLA-4 were lower in NLPHL (2-4 fold lower, all P<0.05), with no difference in T-helper cell activation markers CD40L and CD30L seen between tumors. TAMs and dendritic cell markers MARCO, CD36, CD68, CD163, COLEC12 and CD11b were all lower in NLPHL than cHL (all P<0.05). In line with the known 'rossette' formed around LP cells by PD-1+ T-lymphocytes, we observed strikingly elevated PD-1 and the other T-cell checkpoints TIM3 and TIGIT in NLPHL (all 2-3 fold, P<0.001). However, in line with the known gene amplification of PD-L1 on HRS cells and its presence on TAMs, gene counts of this checkpoint ligand were 2-fold higher in cHL (P<0.001). Flow cytometry profiling of immune subsets in peripheral blood showed findings consistent with findings in the TME. Specifically, there was elevation of multiple exhaustion markers within CD4, CD8, and NK immune effector cells, with a striking proportion of highly anergic dual-LAG3/PD-1 positive CD8+ T-cells. Also there was elevation of immune-suppressive monocyte/macrophages in cHL relative to NLPHL. Relative to healthy lymph nodes, there was prominent up-regulation of a range of T-cell associated exhaustion markers in both NLPHL and cHL, indicating dysregulated priming of effector immune responses and host immune homeostasis. Comparison between NLPHL and cHL illustrated that NLPHL had a myriad of features that marked its intratumoral TME as a unique immunobiological entity typified by elevated immune checkpoint markers and T-cells with a highly anergic phenotype. Put together, these findings indicate that distinct immune evasion mechanisms are operative within the TME of NLPHL, including markedly higher levels of multiple immune-checkpoints relative to cHL. In contrast, Treg subsets and immune-suppressive monocyte/macrophages were relatively lower than that seen in cHL. T-cells frequently had dual immune-checkpoint expression. The findings from this study provides a compelling pre-clinical rationale for targeting PD-1 or combinatory checkpoint inhibition in NLPHL and sets the basis for future 'chemo-free' rituximab + checkpoint inhibitor clinical trials. Disclosures Tobin: Amgen: Other: Educational Travel; Celgene: Research Funding. Birch:Medadvance: Equity Ownership. Keane:Takeda: Other: Educational Meeting; BMS: Research Funding; Roche: Other: Education Support, Speakers Bureau; Celgene: Consultancy, Research Funding; Merck: Consultancy. Gandhi:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Carbone, A., A. Gloghini, V. Zagonel, D. Aldinucci, V. Gattei, M. Degan, S. Improta, R. Sorio, S. Monfardini, and A. Pinto. "The expression of CD26 and CD40 ligand is mutually exclusive in human T- cell non-Hodgkin's lymphomas/leukemias." Blood 86, no. 12 (December 15, 1995): 4617–26. http://dx.doi.org/10.1182/blood.v86.12.4617.bloodjournal86124617.
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CD26 and CD40 ligand (CD40L) are surface molecules on human activated T lymphocytes that play a critical role in the regulation of lymphopoiesis. Both molecules are expressed on a restricted fraction of human T-cell non-Hodgkin's lymphomas (NHL)/leukemias; however, little is known about their functional and/or clinical significance in these disorders. In this study, the pattern of expression of CD40L was compared with that of the CD26 molecule. A series of 67 human T-cell NHL/leukemias and a panel of leukemia/lymphoma T-cell lines were evaluated by immunohistochemistry, flow cytometry, and RNA studies. The overall frequency of CD26+ and CD40L+ samples was rather similar (25/67 [37%] v 18/67 [27%]). However, the majority of CD26-expressing cases clustered in the lymphoblastic lymphomas (LBL)/T-acute lymphoblastic leukemias (ALL; 12/23) and CD30+ anaplastic large-cell (ALC) lymphomas (5/8), whereas CD40L+ lymphomas included a large fraction of mycosis fungoides (11/21 [52%]). CD26 and CD40L coexpression was found only in 2 myocosis fungoides cases and 1 small lymphocytic lymphoma. Thus, the expression of the two antigens was mutually exclusive in almost all T- cell lymphomas/leukemias. Accordingly, lymphoma cell lines expressed either one of the molecules or the relative amounts of CD26 and CD40L were inversely proportional. In contrast, reactive T lymphocytes from patients with non-neoplastic T-cell expansions and in vitro activated CD3+ or CD4+ normal T cells were found to coexpress CD40L and CD26. Results of a multivariate analysis showed that the expression of CD26 in T-cell LBL/ALL patients was associated to a worse outcome in terms of survival, as compared with patients with CD26- tumors (P < or = .0001). Based on our results, it can be concluded that, (1) as opposed to activated or reactive normal T cells, the expression of CD26 and of CD40L is mutually exclusive in human T-cell lymphomas/leukemias; (2) expression of CD26 is restricted to aggressive pathologic entities, such as T-cell LBL/ALL and T-cell CD30+ ALC lymphomas, whereas CD40L is expressed on slow progressing diseases such as mycosis fungoides; and (3) within the T-cell LBL/ALL group of tumors, CD26 may identify a subset of poor prognosis patients.
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de Leval, Laurence, David S. Rickman, Caroline Thielen, Aurélien de Reynies, Yen-Lin Huang, Georges Delsol, Laurence Lamant, et al. "The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells." Blood 109, no. 11 (June 1, 2007): 4952–63. http://dx.doi.org/10.1182/blood-2006-10-055145.
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Abstract The molecular alterations underlying the pathogenesis of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, unspecified (PTCL-u) are largely unknown. In order to characterize the ontogeny and molecular differences between both entities, a series of AITLs (n = 18) and PTCLs-u (n = 16) was analyzed using gene expression profiling. Unsupervised clustering correlated with the pathological classification and with CD30 expression in PTCL-u. The molecular profile of AITLs was characterized by a strong microenvironment imprint (overexpression of B-cell– and follicular dendritic cell–related genes, chemokines, and genes related to extracellular matrix and vascular biology), and overexpression of several genes characteristic of normal follicular helper T (TFH) cells (CXCL13, BCL6, PDCD1, CD40L, NFATC1). By gene set enrichment analysis, the AITL molecular signature was significantly enriched in published TFH-specific genes. The enrichment was higher for sorted AITL cells than for tissue samples. Overexpression of several TFH genes was validated by immunohistochemistry in AITLs. A few cases with molecular TFH-like features were identified among CD30− PTCLs-u. Our findings strongly support that TFH cells represent the normal counterpart of AITL, and suggest that the AITL spectrum may be wider than suspected, as a subset of CD30− PTCLs-u may derive from or be related to AITL.
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Ryan, Maureen, Ryan Lyski, Lauren Bou, Ryan Heiser, Bryan Grogan, Dave Meyer, Steven Jin, et al. "SGN-CD30C, an Investigational CD30-Directed Camptothecin Antibody-Drug Conjugate (ADC), Shows Strong Anti Tumor Activity and Superior Tolerability in Preclinical Studies." Blood 136, Supplement 1 (November 5, 2020): 41–42. http://dx.doi.org/10.1182/blood-2020-136577.
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SGN-CD30C, an investigational CD30-directed ADC, utilizes a potent novel camptothecin derivative as the cytotoxic payload. SGN-CD30C targets the same antigen as brentuximab vedotin (BV), though the payload has a different mechanism of action, namely inhibiting topoisomerase I rather than disrupting microtubules. Unlike monomethyl auristatin E, camptothecin-based therapies do not cause peripheral neuropathy clinically, suggesting that SGN-CD30C may have the potential to avoid one of the most common adverse events associated with BV. In preclinical studies, SGN-CD30C demonstrated strong monotherapy activity, inducing durable tumor regressions in multiple lymphoma models and eliciting cures in a BV-resistance tumor model (Figure 1). Moreover, SGN-CD30C exhibits many of the desirable attributes associated with BV, notably, bystander activity and CD30+ T regulatory cell (Treg) depletion. Using an admixed model of CD30+ and CD30-tumor cells, SGN-CD30C demonstrated robust anti-tumor activity in vivo, confirming SGN-CD30C can induce bystander killing of antigen-negative tumor cells in CD30-heterogeneous tumors. Additionally, SGN-CD30C depleted CD30+ Treg cells in vitro (Figure 2), suggesting it has the potential to exert activity through multiple mechanisms of action. SGN-CD30C was well-tolerated in non-human primate toxicology studies and demonstrated ~6-fold higher maximum tolerated dose when compared to BV. The primary toxicity for SGN-CD30C in non-human primates (NHP) studies was anemia due primarily to bone marrow suppression of erythropoiesis. SGN-CD30C had no effect on neutrophil counts and caused only minimal to mild decreases in platelets. The lack of significant neutropenia seen with SGN-CD30C contrasts with BV, indicating the two ADCs may have non-overlapping dose limiting toxicities. Hematology parameters show SGN-CD30C is tolerated at a 10-fold higher dose than BV with weekly dosing, suggesting SGN-CD30C may offer the potential for increased dose density. In summary, our data show SGN-CD30C is a compelling therapeutic candidate for CD30-positive malignancies. The distinct mechanism of action, strong anti-tumor activity, and enhanced tolerability provide a strong rationale to clinically investigate SGN-CD30C across the CD30-expressing lymphoma landscape. A Phase 1 clinical trial is planned to investigate SGN-CD30C in relapsed and refractory lymphoma. Disclosures Heiser: Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Grogan:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Jin:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Conerly:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company.
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de Leval, Laurence, David Rickman, Caroline Thielen, Aurélien de Reynies, Yen-Lin Huang, Georges Delsol, Laurence Lamant, et al. "The Gene Expression Profile of Nodal T-Cell Lymphomas Identifies a Molecular Link between Angioimmunoblastic T-Cell Lymphoma (AITL) and Follicular Helper T Cells (TFH), and between CD30+ Peripheral T-Cell Lymphoma and ALK-Negative Anaplastic Large Cell Lymphoma (ALCL)." Blood 108, no. 11 (November 16, 2006): 289. http://dx.doi.org/10.1182/blood.v108.11.289.289.
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Abstract AITL and PTCL-U, the two most common forms of T-cell lymphomas in western countries, usually present as nodal disease and pursue an aggressive clinical course. AITL is commonly associated with a constellation of clinical symptoms and distinct pathological features. Conversely, PTCL-U lacks precise diagnostic criteria, and by default comprises cases not fulfilling criteria for other entities, including tumors with borderline features to ALCL and AITL. The genetic alterations and pathogenic mechanisms underlying AITL and PTCL-U are largely unknown. To determine whether the molecular signature of AITL and PTCL-U could help in distinguishing both entities and in understanding ther ontogeny, we performed gene expression profile (GEP) analysis of 15 PTCL-U tissue samples (6 CD30+ and 9 CD30−) and 19 AITL samples (including 2 sorted tumor cell suspensions) using Affymetrix HG-U133A Plus2.0 pan-genomic oligonucleotide microarrays, with comparison to that of previously published normal T-cell subsets (J Immunol173:68; J Immunol175: 7837; Blood 104: 1952). Principle component analysis (PCA, accumulated variance 95%) of all 33 tissue samples yielded three groups of tumors: one group of 12 AITLs, one group of 10 PTCLs-U and one mixed group comprising 5 AITLs (some with features borderline to PTCL-U) and 6 PTCLs-U (including 5 of 6 CD30+ tumors). The AITL molecular signature consisted of 442 genes with increased levels of expression in AITL compared to PTCL-U (t test, p<0.002), including genes encoding cell adhesion molecules, immune receptors, extracellular matrix components and several chemokines, B-cell-related and follicular dendritic cell-related genes, genes involved in endothelial and vascular biology, and several genes reported to belong to the gene expression signature of normal TFH cells (CXCL13, BCL6, PDCD1, CD40L, CD200). To specifically address the question of a molecular link beween AITL and TFH cells, we performed gene set enrichment analysis (GSEA) of our dataset using published gene sets specific of distinct normal T-cell subsets (TFH, TH1, TH2). Compared to that of PTCL-U, the molecular signature of AITL was significantly enriched in TFH-specific genes, and the enrichment was even higher for sorted AITL cells compared to AITL tissues. GSEA failed to disclose a molecular link between PTCL-U and known T-cell subsets (TH1, TH2, TFH). Compared to CD30− PTCL-U, CD30+ PTCL-U had lower expression of genes involved in TCR signalling (t test, p<0.002), and showed molecular similarities with ALK-negative ALCL. In conclusion, GEP of non-anaplastic nodal PTCL (1) segregates AITL and PTCL-U, supporting the basis for histotyping; (2) shows molecular analogies between AITL and TFH cells, strongly supporting the hypothesis of a histogenetic link; (3) suggests molecular analogies between CD30+ PTCL-U and ALK-negative ALCL.
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Carbone, A., A. Gloghini, V. Gattei, D. Aldinucci, M. Degan, P. De Paoli, V. Zagonel, and A. Pinto. "Expression of functional CD40 antigen on Reed-Sternberg cells and Hodgkin's disease cell lines." Blood 85, no. 3 (February 1, 1995): 780–89. http://dx.doi.org/10.1182/blood.v85.3.780.bloodjournal853780.
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CD40 is a member of the nerve growth factor receptor family, showing a significant homology to the Hodgkin's disease (HD)-associated antigen CD30 and is capable of transduce growth signals in a number of cell types. A series of 312 lymphoma samples, including 139 cases of HD, 32 cases of CD30+ anaplastic large cell (ALC) lymphomas, 141 cases of other non-Hodgkin's lymphomas (NHLs), and a panel of HD- or NHL-derived cell lines, were evaluated for CD40 expression by immunostaining of paraffin embedded sections, cell smears and flow cytometry. CD40 was strongly expressed with a highly distinct pattern of staining on Reed- Sternberg (RS) cells and variants in 100% (139/139) of HD cases, irrespective of their antigenic phenotype (T, B, non T-non B) and histologic subtype of HD. Conversely, CD40 was immunodetected on only one third (12/32; 37%) of ALC lymphoma cases and on 105 of 127 B-cell NHLs. The relative cell density of CD40 on HD cell lines (L-428, KM-H2, HDLM-2) as assessed by flow cytometry was significantly higher than on all other lymphoma cells analyzed. Engagement of CD40 by its soluble ligand (CD40L) enhanced both clonogenic capacity and colony cell survival of HD cell lines. Such effect was potentiated by interleukin-9 costimulation in KM-H2 cells. Finally, we have shown that in vitro rosetting of activated CD4+ T cells to HD cells (L-428) is mediated in part by the CD40/CD40L adhesion pathway. Our data indicate that CD40 is a useful antigen for immunodetection and identification of tumor cells in all subtypes of HD, and suggest that it may play a role in the regulation of RS cell expansion and the contact-dependent interactions of these cells with cytokine-producing T lymphocytes.
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Gruss, HJ, D. Hirschstein, B. Wright, D. Ulrich, MA Caligiuri, M. Barcos, L. Strockbine, RJ Armitage, and SK Dower. "Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin's disease." Blood 84, no. 7 (October 1, 1994): 2305–14. http://dx.doi.org/10.1182/blood.v84.7.2305.2305.
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Abstract CD40 was originally described as a B-cell-restricted antigen and was subsequently found to be a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 is also expressed on dendritic cells, thymic epithelium, monocytes, and some carcinoma cell lines, and plays a critical role in cell contact-dependent activation. Primary and cultured Hodgkin and Reed-Sternberg (H-RS) cells, the presumed malignant cells of Hodgkin's disease (HD); were found to express high levels of cell surface CD40. We found that recombinant CD40 ligand (CD40L) induced interleukin-8 (IL-8) secretion and enhanced IL-6, TNF, and lymphotoxin-alpha (LT-alpha/TNF-beta) release from cultured H-RS cells. These cytokines play a significant role in the clinical presentation and pathology of HD, a tumor of cytokine-producing cells. CD40L had no mitogenic activity for HD-derived cell lines. In contrast, CD40L enhanced expression of costimulatory molecules intracellular adhesion molecule-T and B7–1 on cultured H-RS cells, both of which are overexpressed on primary H-RS cells. In addition, CD40L induced a 40% to 60% reduction of the expression of the HD-associated CD30 antigen, another member of the TNF receptor superfamily. Primary and cultured H- RS cells express not only CD30, but also CD40. CD40L has pleiotropic biologic activities on H-RS cells, and the CD40-CD40L interaction might be a critical element in the deregulated cytokine network and cell contact-dependent activation cascade typical for HD.
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Gruss, HJ, D. Hirschstein, B. Wright, D. Ulrich, MA Caligiuri, M. Barcos, L. Strockbine, RJ Armitage, and SK Dower. "Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin's disease." Blood 84, no. 7 (October 1, 1994): 2305–14. http://dx.doi.org/10.1182/blood.v84.7.2305.bloodjournal8472305.
Full textAbstract:
CD40 was originally described as a B-cell-restricted antigen and was subsequently found to be a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 is also expressed on dendritic cells, thymic epithelium, monocytes, and some carcinoma cell lines, and plays a critical role in cell contact-dependent activation. Primary and cultured Hodgkin and Reed-Sternberg (H-RS) cells, the presumed malignant cells of Hodgkin's disease (HD); were found to express high levels of cell surface CD40. We found that recombinant CD40 ligand (CD40L) induced interleukin-8 (IL-8) secretion and enhanced IL-6, TNF, and lymphotoxin-alpha (LT-alpha/TNF-beta) release from cultured H-RS cells. These cytokines play a significant role in the clinical presentation and pathology of HD, a tumor of cytokine-producing cells. CD40L had no mitogenic activity for HD-derived cell lines. In contrast, CD40L enhanced expression of costimulatory molecules intracellular adhesion molecule-T and B7–1 on cultured H-RS cells, both of which are overexpressed on primary H-RS cells. In addition, CD40L induced a 40% to 60% reduction of the expression of the HD-associated CD30 antigen, another member of the TNF receptor superfamily. Primary and cultured H- RS cells express not only CD30, but also CD40. CD40L has pleiotropic biologic activities on H-RS cells, and the CD40-CD40L interaction might be a critical element in the deregulated cytokine network and cell contact-dependent activation cascade typical for HD.
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Gardell, Jennifer L., and David C. Parker. "Antigen-specific transendocytosis of CD40 ligand accompanies T cell help for B cells." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 189.4. http://dx.doi.org/10.4049/jimmunol.196.supp.189.4.
Full textAbstract:
Abstract It has been known for decades that the delivery of T cell help to B cells is antigen-specific, MHC-restricted, and depends on CD40L. However the mechanisms by which CD40L, a transmembrane cytokine, is delivered to the T cell surface and engages CD40 on antigen-presenting B cells remains to be determined. It has been thought that when a T cell recognizes an antigen-presenting B cell, CD40L expressed on the T cell surface engages with CD40 on the surface of B cells as long as the cells remain conjugated. We show for the first time that CD40L does not remain on the surface of the T cell, but is transferred to and endocytosed by B cells receiving T cell help. Transfer of CD40L is nearly absent from bystander B cells that are not presenting antigen. It was recently discovered that peptide-MHC engaged TCRs are deposited on B cells in microvesicles at the immunological synapse. Our data suggest that CD40L might be deposited in a similar manner as a secreted vesicle. CD40-engaged CD40L on vesicles could allow for sustained signaling in antigen-presenting B cells despite the brief interactions with helper T cells that occur in vivo in germinal centers.
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Steinhoff, Matthias, Michael Hummel, Ioannis Anagnostopoulos, Peter Kaudewitz, Volkhard Seitz, Chalid Assaf, Christian Sander, and Harald Stein. "Single-cell analysis of CD30+ cells in lymphomatoid papulosis demonstrates a common clonal T-cell origin." Blood 100, no. 2 (July 15, 2002): 578–84. http://dx.doi.org/10.1182/blood-2001-12-0199.
Full textAbstract:
Abstract Lymphomatoid papulosis (LyP) represents an intriguing cutaneous T-cell lymphoproliferative disorder with a histologic appearance resembling malignant lymphoma. This finding strongly contrasts with the benign clinical course of the disease. However, in 10% to 20% of cases, LyP can precede, coexist with, or follow malignant lymphoma. In these cases, the same T-cell population has been shown to be present in the LyP as well as in the associated lymphoma. In most LyP cases, there is—despite the sometimes extremely long course of the disease—no evolution of a secondary lymphoma. The investigation of these uncomplicated LyP cases for the presence of clonal T-cell receptor rearrangements has produced heterogeneous results. This might be explained by biologic or technical reasons arising from analyzing whole tissue DNA extracts. To definitively clarify whether the large atypical CD30+ cells in LyP without associated lymphoma all belong to the same clone or represent individually rearranged T cells, we analyzed the T-cell receptor–γ rearrangements of single CD30+ as well as of single CD30− cells isolated from 14 LyP lesions of 11 patients. By using this approach we could demonstrate that the CD30+ cells represent members of a single T-cell clone in all LyP cases. Moreover, in 3 patients the same CD30+ cell clone was found in anatomically and temporally separate lesions. In contrast, with only a few exceptions, the CD30− cells were polyclonal in all instances and unrelated to the CD30+ cell clone. Our results demonstrate that LyP unequivocally represents a monoclonal T-cell disorder of CD30+ cells in all instances.
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Jaiswal, A. I., and M. Croft. "CD40 ligand induction on T cell subsets by peptide-presenting B cells: implications for development of the primary T and B cell response." Journal of Immunology 159, no. 5 (September 1, 1997): 2282–91. http://dx.doi.org/10.4049/jimmunol.159.5.2282.
Full textAbstract:
Abstract Recent data suggest that CD40 ligand (CD40L)-CD40 interactions are essential for up-regulation of costimulatory activity on APC and that efficient induction of CD40L may be pivotal to the success of a CD4 T cell response. CD40L is regulated primarily by TCR signaling, but high level expression on a naive T cell appears to require additional interactions between T cell coreceptors and APC accessory molecules. The data reported here show that resting B cells presenting peptide Ag, in contrast to both dendritic cells and preactivated B cells, induce very little CD40L on naive CD4 cells, which in turn is insufficient to promote APC costimulatory activity. We also show, however, that previously activated effector T cells have enhanced responsiveness to Ag when accessory molecule help is limiting and consequently can express high levels of CD40L after interaction with resting B cells. High level CD40L expression correlated with B cell activation and up-regulation of costimulatory activity; however, blocking studies showed that CD40L was only partially responsible for these phenomena. These studies reinforce the notion that resting B cells may be tolerogenic for naive CD4 cells in part because of inefficient CD40L induction. The data also suggest that a successful primary T cell response will only occur if either the initial interaction is with a dendritic cell followed by subsequent interactions of the effector T cells with resting APC or if nonspecific inflammatory stimuli up-regulate accessory molecule expression on resting APC before an encounter with the naive T cell.
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HendricKson, Jeanne, David R. Archer, Jennifer R. Perry, Christopher D. Hillyer, and James C. Zimring. "Berkeley Mice with Sickle Cell Disease Are Not More Immunizable to Transfused HOD Red Blood Cells Than Sickle Trait Control Mice." Blood 112, no. 11 (November 16, 2008): 292. http://dx.doi.org/10.1182/blood.v112.11.292.292.
Full textAbstract:
Abstract Background: Patients with sickle cell disease have higher rates of red blood cell (RBC) alloimmunization following transfusion than any other patient population. However, it is unclear if they are inherently more immunizable, or if the high rates of RBC alloimmunization are simply due to antigenic differences between donors/recipients and heightened transfusion frequency. Utilizing a murine model, we have previously shown that rates of alloimmunization are influenced by the inflammatory status of the recipient at the time of the transfusion. Thus, we hypothesized that sickle patients may be more immunizable, due in part to the baseline inflammation associated with their disease. Herein, we present a reductionist murine sickle model of RBC alloimmunization, and investigate the hypothesis that mice with sickle cell disease are more likely to become alloimmunized following transfusion of RBCs containing a foreign antigen than sickle trait controls. Materials/Methods: Berkeley mice (with human α and βS-globin) were determined to be homozygous (sickle cell disease) or heterozygous (sickle cell trait) by cellulose acetate electrophoresis. We generated the HOD mouse, with RBC specific expression of the model humoral antigen hen egg lysozyme (HEL) fused to the model minor histocompatibility antigen ovalbumin (OVA), linked to the cell membrane by a human blood group antigen (Duffy). The inclusion of OVA in the HOD construct allows presentation of HOD peptides from H-2b MHC; thus, Berkeley mice are able to process and present the HOD antigen. 100 microliters of packed HOD RBCs were transfused IV into mice with sickle cell disease or sickle cell trait; alloimmunization to the HEL antigen was assessed by anti-HEL IgG ELISA 2 weeks following transfusion. Given that co-stimulatory molecule expression on antigen presenting cells in part determines the response of the CD4+ T cell to the antigen being presented, we examined baseline expression of B7-1, B7-2, Ox40L, CD70, 41BBL, CD30L, and CD40 on macrophages (F480 high) and dendritic cells (CD11c high) in sickle cell disease and sickle trait mice. Results: Data for a standard curve was fit to one phase exponential association, with a non-linear best fit regression analysis (R2 of 0.96). Utilizing the OD 415 value of the anti-HEL IgG ELISA, data was combined from 3 separate experiments (n=31 mice). An unpaired two-tailed t-test showed a mean of 6.25e-5, SD 5.87e-5 for sickle disease mice, and a mean of 4.14e-5, SD 2.84e-5 for sickle trait mice, p=0.217 (see figure). Baseline co-stimulatory molecule expression of all molecules examined on macrophages and dendritic cells was similar in both sickle cell disease and sickle trait mice. Figure Figure Conclusions: Generation of the HOD mouse, containing a model humoral antigen capable of being presented by the antigen presenting cells in the Berkeley mice, allowed these studies to be performed. These data rule out the hypothesis that Berkeley mice with sickle cell disease are substantially more immunizable to a single transfusion of RBCs containing the HOD foreign antigen than are those with sickle cell trait. However, there is a large standard deviation in alloantibody response between individual mice with sickle cell disease. The varied response may be explained by differing levels of illness in individual mice; ongoing studies are investigating such a potential correlation. Clinically, many patients with sickle cell disease are transfused in times of illness (i.e. acute chest syndrome), and the possibility that illness alters alloantibody response cannot be ruled out by these studies. Furthermore, although the model was designed to be as reductionist as possible, these studies are limited by the highly heterogeneous genetic background of the Berkeley mice (including FVB/N, 129, DBA/2, C57BL/6, and Black Swiss); this diverse background likely influences response to foreign antigen and makes identifying control groups difficult. Finally, although Berkeley mice with sickle cell disease are known to have baseline inflammation associated with their disease, this does not appear to influence co-stimulatory molecule expression on their antigen presenting cells.
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Briones, Javier, Silvana Novelli, and Jorge Sierra. "T-Cell Costimulatory Molecules in Acute-Graft-Versus Host Disease: Therapeutic Implications." Bone Marrow Research 2011 (September 21, 2011): 1–7. http://dx.doi.org/10.1155/2011/976793.
Full textAbstract:
Acute Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Although this process is thought to consist of several phases, T-cell activation plays a critical role in the pathogenesis of acute GVHD. To become efficient effectors, T-cells require additional costimulation after T-cell receptor signaling. A number of molecules are involved in costimulation of T-cells such as CD28, CD40L, CD30, OX40, 4-1BB, ICOS, and LIGHT. The system is regulated by inhibitory molecules, CTLA-4, and PD-1. There is experimental evidence that those molecules are implicated in the pathogenesis of GHVD. We describe how these molecules are involved in acute GVHD and how the blockade of costimulatory molecules may have potential implications for the treatment of patients with acute GVHD.
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Maruo, S., M. Oh-hora, H. J. Ahn, S. Ono, M. Wysocka, Y. Kaneko, H. Yagita, et al. "B cells regulate CD40 ligand-induced IL-12 production in antigen-presenting cells (APC) during T cell/APC interactions." Journal of Immunology 158, no. 1 (January 1, 1997): 120–26. http://dx.doi.org/10.4049/jimmunol.158.1.120.
Full textAbstract:
Abstract Although stimulation of freshly isolated murine spleen cells with anti-CD3 mAb or Con A failed to generate IL-12 production, the same cell preparations depleted of B cells produced IL-12. Addition of normal B cells inhibited IL-12 production in a cell number-dependent manner. IL-12 production was dependent on the presence of CD4+, but not of CD8+, T cells, and inhibited by addition of anti-CD40 ligand (CD40L) mAb. Anti-CD3 or Con A stimulation induced CD40L expression only on CD4+ T cells, which was inhibited in the presence of B cells. IL-12 production was also induced by interactions between CD40L-transfected Chinese hamster ovary cells and splenocytes depleted of T and B cells, but not of APC, indicating CD40L-induced IL-12 production by APC. The involvement of CD40 molecules was examined by comparing the ability of cells from CD40-deficient (CD40 -/-) and wild-type mice (CD40 +/+) to produce IL-12. Spleen cells from CD40 -/- and CD40 +/+ mice produced comparable amounts of IL-12 in response to bacterial stimuli. However, the B cell-depleted fraction from CD40 -/- mice failed to produce IL-12 when stimulated with anti-CD3 or Con A or when cocultured with CD40L-expressing Chinese hamster ovary cells. These results indicate that CD40L expressed on activated T cells induces APC to produce IL-12 through CD40/CD40L interaction, but this pathway is competitively inhibited by CD40+ B cells incapable of producing IL-12 upon stimulation with CD40L. Thus, this might represent a novel mechanism underlying the regulation of cell-mediated and humoral immunity.
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Chakrabarty, Sagarika, James T. Snyder, Jijia Shen, Hooman Azmi, Paul Q. Hu, Qian Chen, and Jack A. Ragheb. "Human CD14hi monocytes and myeloid dendritic cells provide a cell contact–dependent costimulatory signal for early CD40 ligand expression." Blood 117, no. 5 (February 3, 2011): 1585–94. http://dx.doi.org/10.1182/blood-2008-01-130252.
Full textAbstract:
Abstract CD40L on CD4+ T cells plays a vital role in the activation of antigen-presenting cells, thus catalyzing a positive feedback loop for T-cell activation. Despite the pivotal juxtaposition of CD40L between antigen-presenting cells and T-cell activation, only a T-cell receptor stimulus is thought to be required for early CD40L surface expression. We show, for the first time, that CD40L expression on peripheral blood CD4+ T cells is highly dependent on a cell-cell interaction with CD14hiCD16− monocytes. Interactions with ICAM-1, LFA-3, and to a lesser extent CD80/CD86 contribute to this enhancement of CD40L expression but are not themselves sufficient. The contact-mediated increase in CD40L expression is dependent on new mRNA and protein synthesis. Circulating myeloid dendritic cells also possess this costimulatory activity. By contrast, CD14loCD16+ monocytes, plasmacytoid dendritic cells, B-cell lymphoma lines, and resting, activated, and Epstein-Barr virus–immortalized primary B cells all lack the capacity to up-regulate early CD40L. The latter indicates that a human B cell cannot activate its cognate T cell to deliver CD40L-mediated help. This finding has functional implications for the role of biphasic CD40L expression, suggesting that the early phase is associated with antigen-presenting cell activation, whereas the late phase is related to B-cell activation.
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Alzona, M., H. M. Jäck, R. I. Fisher, and T. M. Ellis. "CD30 defines a subset of activated human T cells that produce IFN-gamma and IL-5 and exhibit enhanced B cell helper activity." Journal of Immunology 153, no. 7 (October 1, 1994): 2861–67. http://dx.doi.org/10.4049/jimmunol.153.7.2861.
Full textAbstract:
Abstract CD30 is a lymphoid activation Ag expressed by activated B and T lymphocytes, as well as selected lymphoid malignancies. In T cells, CD30 expression is limited to a minority (15 to 25%) of activated CD45RO+ T cells. Studies were undertaken to define unique functional properties of CD30+ T cells by identifying the profile of cytokine production by CD30+ T cells, and by assessing their ability to provide help for B cell Ig production. Assessment of cytokine mRNA transcripts by reverse transcription-PCR (RT-PCR) revealed the presence of IFN-gamma mRNA transcripts only in CD30+ T cells derived from FACS purified from activated CD45RO+ T cells. IFN-gamma mRNA was present neither in the CD30- subset of activated CD45RO+ T cells, nor in activated CD45RA+ T cells. Both CD30+ and CD30- subsets expressed IL-10 and IL-2R alpha mRNAs after 3 days of activation, but neither population expressed IL-4 or IL-6 transcripts at this time. Furthermore, production of secreted IFN-gamma was significantly greater in activated CD30+CD45RO+ cells (564 +/- 250 pg/ml) than in CD30-CD45RO+ (50 +/- 33 pg/ml) or CD45RA+ (0 +/- 0) T cells. CD30+ T cells also expressed IL-5 mRNA and secreted significantly higher levels of IL-5 (320 +/- 73) than activated CD30-CD45RO+ (17 +/- 5) T cells. In contrast, CD30- T cells produced significantly higher levels of IL-2 than CD30+ T cells (1270 +/- 380 vs 450 +/- 128). Induction of IFN-gamma in CD30+ T cells was not a result of CD30 engagement by Abs used during the isolation process, although an anti-CD30 Ab (M44) known to exert agonist activity was capable of inducing IFN-gamma production by T cells when immobilized to plastic. Finally, CD30+CD4+ T cells exhibit significantly greater helper activity for B cell Ig production than CD30-CD4+ T cells. These results demonstrate that CD30 identifies a unique subset of T cells that comprise the major IFN-gamma- and IL-5-producing cells in the T cell compartment, and exhibit potent helper activity for B cell Ig production.
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Thiel, Andreas, Marco Frentsch, Joanna Listopad, Regina Stark, Alberto Sada Japp, Nadine Matzmohr, Sarah Meier, Ichiro Taniuchi, and Thomas Blankenstein. "CD40L+ CD8+ T-Cell Dependent Antitumor Immunity." Blood 124, no. 21 (December 6, 2014): 5818. http://dx.doi.org/10.1182/blood.v124.21.5818.5818.
Full textAbstract:
Abstract CD40 is frequently expressed on malignant cells of different origin. Due to the observed antitumorigenic effects induced after CD40 engagement it represents an attractive target for immunotherapies. We demonstrate here that CD40L expressing tumor-specific CD8+ T-cell population can act as potent physiological CD40 agonist against CD40 expressing tumor cells. We demonstrate that in the course of cancer cell rejection high frequencies of tumor-specific CD40L+ CD8+ T cells are induced. Strikingly, in contrast to wild-type (wt), CD40L deficient CD8+ T cells were unable to prevent tumor formation in lymphopenic as well as in fully immunocompetent hosts. Apparently, in our setting CD40L expressed by CD8+ T cells is essential for cancer cell rejection. CD40L-mediated rejection does not depend on interaction with CD40+ host cells such as antigen-presenting cells but on CD40 expression by cancer cells. Our findings disclose CD40L expression by CD8+ T cells as a new antitumor effector function that should be implemented in future adoptive T-cell therapies against cancer. Disclosures No relevant conflicts of interest to declare.
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Shimoda, Michiko, Anna Bolduc, Domonica Powell, Yutetsu Ametani, Mayuko Takezaki, Stephen Nutt, Masahito Kamanaka, et al. "A critical role of dendritic cells in CD8 T cell IL-10 expression during inflammatory response triggered by CD40-activated B cells (159.16)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 159.16. http://dx.doi.org/10.4049/jimmunol.188.supp.159.16.
Full textAbstract:
Abstract CD40LBTg mice, expressing a CD40 ligand (CD40L) transgene on B cells, represent a model for human diseases where B cells aberrantly express CD40L or receive excess CD40/CD40L signaling under inflammatory conditions. Here, we show that B cells expressing transgenic CD40L are capable of priming CD8 T cells and generate strong antigen-specific cytotoxicity. Adoptively transferred SIINFEKL peptide-loaded B cells from CD40LBTg but not wild type mice were able to activate self-reactive OT-I CD8 T cells upon immunization with OVA plus alum and trigger diabetes in RIP-OVA mice by enhancing the help of endogenous self-reactive CD4 T cells. CD40L expressing B cells also trigger spontaneous activation of splenic CD8 T cells, which rapidly up-regulate PD-1, Blimp-1 and LAG-3 and lose cytotoxicity along with IL-10 expression via interaction with PDL-1hi CD11c+ dendritic cells in T cell zones. Thus, CD11c+ dendritic cells from CD40LBTg mice exhibit regulatory phenotype, which block granzyme B expression and preferentially induce IL-10 expression in activated CD8 T cells. These results demonstrate that constitutive CD40 signaling on B cells under inflammation increases the risk of breaking peripheral CD8 T cell tolerance. However, the presence of CD40-activated B cells results in PDL-1hi CD11c+ dendritic cells, which exhibit a regulatory role to dampen harmful self-reactive cytotoxicity by promoting IL-10 expression in CD8 T cells.
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Gruss, HJ, N. Boiani, DE Williams, RJ Armitage, CA Smith, and RG Goodwin. "Pleiotropic effects of the CD30 ligand on CD30-expressing cells and lymphoma cell lines." Blood 83, no. 8 (April 15, 1994): 2045–56. http://dx.doi.org/10.1182/blood.v83.8.2045.2045.
Full textAbstract:
Abstract CD30 is a member of the tumor necrosis factor receptor superfamily. CD30 was originally described as a cell surface antigen on primary and cultured Hodgkin's and Reed-Sternberg cells. In this study, recombinant human CD30 ligand was expressed on the surface of CV-1/EBNA cells and tested for biologic activities on a variety of different CD30+ human lymphoma cell lines. CD30 ligand enhanced Ig secretion of Epstein-Barr virus (EBV)-immortalized, CD30+ lymphoblastoid B-cell lines, but not Burkitt lymphoma lines. Recombinant CD30 ligand enhanced proliferation of “T-cell-like” Hodgkin's disease-derived cell lines and an adult T- cell leukemia cell line, but not “B-cell-like” Hodgkin's disease- derived cell lines, CD30+, EBV-immortalized lymphoblastoid B-cell lines, or CD30+ and EBV+ tumor B-cell non-Hodgkin's lymphoma cell lines. In addition, CD30 ligand mediated reduction of proliferation and viability, by induction of cytolytic cell death, of CD30+, large-cell anaplastic lymphoma cell lines. Two new antibodies, M44 and M67, against the CD30 antigen demonstrated similar biologic activities to the CD30 ligand. Taken together, these data demonstrate pleiotropic biologic activities of the CD30 ligand on different CD30+ lymphoma cell lines and indicate that the CD30-CD30 ligand interaction might have a pathophysiologic role in Hodgkin's and some non-Hodgkin's lymphomas.
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Gruss, HJ, N. Boiani, DE Williams, RJ Armitage, CA Smith, and RG Goodwin. "Pleiotropic effects of the CD30 ligand on CD30-expressing cells and lymphoma cell lines." Blood 83, no. 8 (April 15, 1994): 2045–56. http://dx.doi.org/10.1182/blood.v83.8.2045.bloodjournal8382045.
Full textAbstract:
CD30 is a member of the tumor necrosis factor receptor superfamily. CD30 was originally described as a cell surface antigen on primary and cultured Hodgkin's and Reed-Sternberg cells. In this study, recombinant human CD30 ligand was expressed on the surface of CV-1/EBNA cells and tested for biologic activities on a variety of different CD30+ human lymphoma cell lines. CD30 ligand enhanced Ig secretion of Epstein-Barr virus (EBV)-immortalized, CD30+ lymphoblastoid B-cell lines, but not Burkitt lymphoma lines. Recombinant CD30 ligand enhanced proliferation of “T-cell-like” Hodgkin's disease-derived cell lines and an adult T- cell leukemia cell line, but not “B-cell-like” Hodgkin's disease- derived cell lines, CD30+, EBV-immortalized lymphoblastoid B-cell lines, or CD30+ and EBV+ tumor B-cell non-Hodgkin's lymphoma cell lines. In addition, CD30 ligand mediated reduction of proliferation and viability, by induction of cytolytic cell death, of CD30+, large-cell anaplastic lymphoma cell lines. Two new antibodies, M44 and M67, against the CD30 antigen demonstrated similar biologic activities to the CD30 ligand. Taken together, these data demonstrate pleiotropic biologic activities of the CD30 ligand on different CD30+ lymphoma cell lines and indicate that the CD30-CD30 ligand interaction might have a pathophysiologic role in Hodgkin's and some non-Hodgkin's lymphomas.
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Klaus, S. J., L. M. Pinchuk, H. D. Ochs, C. L. Law, W. C. Fanslow, R. J. Armitage, and E. A. Clark. "Costimulation through CD28 enhances T cell-dependent B cell activation via CD40-CD40L interaction." Journal of Immunology 152, no. 12 (June 15, 1994): 5643–52. http://dx.doi.org/10.4049/jimmunol.152.12.5643.
Full textAbstract:
Abstract Changes in T cell helper function were analyzed when anti-CD3-activated T cells were costimulated with mAbs to the CD28 receptor (anti-CD28). T cell-dependent B cell growth and differentiation were consistently augmented if anti-CD3 stimulated-T cells were simultaneously activated with anti-CD28. Although anti-CD28 enhanced IL-2 and IL-4 production, it did not increase B cell responses solely by augmenting production of soluble lymphokines. Anti-CD28 costimulation induced increases on T cells of CD40 ligand (CD40L), known to promote B cell proliferation and Ig secretion. Because anti-CD28 promoted T cell helper functions and expression of CD40L, we examined the dependence for CD40L during T cell-dependent B cell responses. Although soluble CD40 fusion proteins only partially inhibited T cell-dependent B cell activation, we found a strict requirement for CD40L expression at initiating B cell responses. Both CD40L expression and T cell help were blocked by cyclosporin A after TCR cross-linking, and, unlike T cell proliferation, both remained cyclosporin A sensitive during CD28 costimulation. In addition, anti-CD28 could not compensate for the T cell helper deficiency of hyper IgM syndrome patients who lack functional CD40L. Thus, anti-CD28-induced T cell help is delivered via a CD40L-dependent process. The fact that cross-linking CD40 on B cells promotes expression of the B7/BB-1 ligand for CD28 suggest T and B interactions may have a reciprocal amplification mechanism.
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Mailliard, Robbie B., Shinichi Egawa, Quan Cai, Anna Kalinska, Svetlana N. Bykovskaya, Michael T. Lotze, Martien L. Kapsenberg, Walter J. Storkus, and Pawel Kalinski. "Complementary Dendritic Cell–activating Function of CD8+ and CD4+ T Cells." Journal of Experimental Medicine 195, no. 4 (February 18, 2002): 473–83. http://dx.doi.org/10.1084/jem.20011662.
Full textAbstract:
Dendritic cells (DCs) activated by CD40L-expressing CD4+ T cells act as mediators of “T helper (Th)” signals for CD8+ T lymphocytes, inducing their cytotoxic function and supporting their long-term activity. Here, we show that the optimal activation of DCs, their ability to produce high levels of bioactive interleukin (IL)-12p70 and to induce Th1-type CD4+ T cells, is supported by the complementary DC-activating signals from both CD4+ and CD8+ T cells. Cord blood– or peripheral blood–isolated naive CD8+ T cells do not express CD40L, but, in contrast to naive CD4+ T cells, they are efficient producers of IFN-γ at the earliest stages of the interaction with DCs. Naive CD8+ T cells cooperate with CD40L-expressing naive CD4+ T cells in the induction of IL-12p70 in DCs, promoting the development of primary Th1-type CD4+ T cell responses. Moreover, the recognition of major histocompatibility complex class I–presented epitopes by antigen-specific CD8+ T cells results in the TNF-α– and IFN-γ–dependent increase in the activation level of DCs and in the induction of type-1 polarized mature DCs capable of producing high levels of IL-12p70 upon a subsequent CD40 ligation. The ability of class I–restricted CD8+ T cells to coactivate and polarize DCs may support the induction of Th1-type responses against class I–presented epitopes of intracellular pathogens and contact allergens, and may have therapeutical implications in cancer and chronic infections.
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Grover, Natalie S., Anastasia Ivanova, Dominic T. Moore, Catherine Joyce Arago Cheng, Caroline Babinec, John West, Tammy Cavallo, et al. "CD30-Directed CAR-T Cells Co-Expressing CCR4 in Relapsed/Refractory Hodgkin Lymphoma and CD30+ Cutaneous T Cell Lymphoma." Blood 138, Supplement 1 (November 5, 2021): 742. http://dx.doi.org/10.1182/blood-2021-148102.
Full textAbstract:
Abstract Chimeric antigen receptor T cells targeting CD30 (CD30.CAR-T) have shown high response rates, including some durable remissions, in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (HL) (Ramos et al., JCO 2020). However, some patients are non-responders or eventually relapse after therapy. Because CD30 expression is retained in relapsing tumors, recurrence may be due to the insufficient persistence of CAR-Ts within the highly immunosuppressive tumor microenvironment of HL. We therefore reasoned that with enhanced trafficking to the tumor site, CD30.CAR-Ts would have increased opportunities to eliminate tumors before inhibitory mechanisms become predominant. This is especially relevant for HL, where Hodgkin Reed Sternberg (HRS) cells produce CCL17 (thymus and activation-regulated chemokine) to create a physical and inhibitory barrier to cytotoxic T cells. We have previously shown that CD30.CAR-Ts co-expressing the cognate receptor for CCL17, CCR4 (CCR4.CD30.CAR-Ts), have improved tumor homing and anti-lymphoma activity compared with CD30.CAR-Ts that do not express CCR4 (Di Stasi et al., Blood 2009). CCR4.CD30.CAR-Ts should also be more effective in CD30+ cutaneous T-cell lymphomas (CTCL) due to enhanced trafficking to the skin. We present the preliminary results of a clinical trial assessing the safety (primary objective) of this novel strategy and its efficacy compared to CD30.CAR-Ts lacking CCR4 in patients with r/r HL and CD30+ CTCL (NCT03602157). CCR4.CD30.CAR-Ts are infused in patients in a dose escalation fashion (DL1=2x10 7 CAR-Ts/m 2, DL3=5x10 7 CAR-Ts/m 2, DL5=1x10 8 CAR-Ts/m 2,). To provide definitive conclusions on the role of CAR-T tumor homing, after completion of each dose level, patients receive the dose of CCR4.CD30.CAR-Ts established to be safe in the prior DL, combined with a fixed dose of CD30.CAR-Ts (1x10 8 CAR-Ts/m 2) (DL2, DL4, DL6). All patients receive lymphodepletion with 3 days of bendamustine 70 mg/m 2 and fludarabine 30 mg/m 2. Key inclusion criteria are age ≥ 18 years and r/r HL or CTCL having failed ≥2 prior therapies. At the time of data cut off (8/1/2021), 6 patients were treated on DL1, 3 patients on DL2, and 3 patients on DL3. The median age is 43.5 (range 27-75) with a median of 5.5 prior lines of therapy (range 2-10). Ten patients had HL and 2 patients had CTCL. All patients had received prior brentuximab vedotin. Eleven patients received prior checkpoint inhibitors, 9 had prior autologous stem cell transplant, and 5 had prior allogeneic stem cell transplant. The treatment was well tolerated with no dose limiting toxicities observed. Two patients had grade 2 cytokine release syndrome (CRS) which resolved with tocilizumab, and 1 had self-limiting grade 1 CRS. None of the treated patients developed immune effector cell-associated neurotoxicity syndrome. All of the 8 patients with HL who have had disease assessment have responded with 6 complete responses (CR) (75%) and 2 partial responses (PR). Five patients are in remission to date, with one patient still in CR at 2.5 years post treatment. Two patients with HL have responses pending at time of data cut off. Among the 2 patients with CTCL, 1 patient had stable disease and went on to receive alternative therapy and 1 patient had progressive disease. At a median follow up of 12.7 months, the median progression free survival (PFS) for all 10 evaluable patients is 5.2 months and the median PFS for HL patients has not been reached. The median overall survival for all patients has not been reached. Plasma CCL17, a biomarker of disease response for HL, was reduced by 83±15% by week 2 post infusion in patients treated with CCR4.CD30.CAR-Ts as compared to 52±38% in patients on our previous trial that had received CD30.CAR-Ts lacking CCR4 (p=0.02). In a HL patient on DL1 biopsied 3 weeks post infusion, we found markedly enriched CAR-T signals at the tumor site (14.4 x10 5 copies/ug of DNA) as compared to the signals found at the same time point in the peripheral blood (4.3 x10 5 copies/ug of DNA). Our data confirm the safety of CCR4.CD30.CAR-Ts as well as their promising efficacy in patients with r/r HL. Interestingly, responses are already seen at the lowest dose level, suggesting that early tumor homing driven by CCR4 may allow more fitted cells to better exploit their antitumor potential. Our data serve as a proof of concept for future modifications of CAR-T cells to improve their localization to disease sites. Figure 1 Figure 1. Disclosures Grover: Kite: Other: Advisory Board; Tessa: Consultancy; ADC: Other: Advisory Board; Novartis: Consultancy; Genentech: Research Funding. Morrison: Vesselon: Consultancy. Dittus: BeiGene: Other: Advisory Board; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding. Dotti: Tessa: Patents & Royalties: Approach for CD30.CAR-T Cells for Hodgkin Lymphoma. Serody: Tessa: Patents & Royalties: Approach for CD30.CAR-T Cells for Hodgkin Lymphoma. Savoldo: Tessa: Patents & Royalties: Approach for CD30.CAR-T Cells for Hodgkin Lymphoma.
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Whitmire, Jason K., Richard A. Flavell, Iqbal S. Grewal, Christian P. Larsen, Thomas C. Pearson, and Rafi Ahmed. "CD40-CD40 Ligand Costimulation Is Required for Generating Antiviral CD4 T Cell Responses But Is Dispensable for CD8 T Cell Responses." Journal of Immunology 163, no. 6 (September 15, 1999): 3194–201. http://dx.doi.org/10.4049/jimmunol.163.6.3194.
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Abstract This study documents a striking dichotomy between CD4 and CD8 T cells in terms of their requirements for CD40-CD40 ligand (CD40L) costimulation. CD40L-deficient (−/−) mice made potent virus-specific CD8 T cell responses to dominant as well as subdominant epitopes following infection with lymphocytic choriomeningitis virus. In contrast, in the very same mice, virus-specific CD4 T cell responses were severely compromised. There were 10-fold fewer virus-specific CD4 T cells in CD40L−/− mice compared with those in CD40L+/+ mice, and this inhibition was seen for both Th1 (IFN-γ, IL-2) and Th2 (IL-4) responses. An in vivo functional consequence of this Th cell defect was the inability of CD40L−/− mice to control a chronic lymphocytic choriomeningitis virus infection. This study highlights the importance of CD40-CD40L interactions in generating virus-specific CD4 T cell responses and in resolving chronic viral infection.
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Schattner, Elaine J., John Mascarenhas, Inna Reyfman, Mary Koshy, Caroline Woo, Steven M. Friedman, and Mary K. Crow. "Chronic Lymphocytic Leukemia B Cells Can Express CD40 Ligand and Demonstrate T-Cell Type Costimulatory Capacity." Blood 91, no. 8 (April 15, 1998): 2689–97. http://dx.doi.org/10.1182/blood.v91.8.2689.2689_2689_2697.
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Chronic lymphocytic leukemia (CLL) is characterized by a clonal expansion of CD5+ B cells in the peripheral blood. Associated immune aberrations include abnormal Th-cell function and pathogenic autoantibodies. Under most circumstances, CLL B cells do not proliferate in culture and express a limited repertoire of surface antigens, including CD19, CD20, CD23, CD27, CD40, and CD70. In this report, we demonstrate that freshly isolated B cells from a subset of CLL cases constitutively express CD40 ligand (CD40L, CD154), a member of the tumor necrosis factor family which is normally expressed by activated CD4+ T cells and mediates T-cell–dependent B-cell proliferation and antibody production. The degree of CD40L expression varied considerably among the CLL cases examined. CD40L was detected in purified CLL B cells by immunofluorescence flow cytometry, by RT-PCR, and by immunoprecipitation. To demonstrate that CD40L in the CLL B cells is functional, we used irradiated CLL cells to stimulate IgG production by target, nonmalignant B cells in coculture. The CLL B cells induced IgG production by normal B cells to a similar degree as did purified T cells in a process which was partially inhibited by monoclonal antibody to CD40L. This is one of the first reports of CD40L expression in a B-cell tumor. The data suggest that CD40L in the tumor cells may be a factor in the generation of pathologic antibodies by normal B cells in some patients with CLL.
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Martin, James M., Hong Wu, and Stefan K. Barta. "CD30+ T-cell lymphoproliferative disorders." Chinese Clinical Oncology 8, no. 1 (February 2019): 4. http://dx.doi.org/10.21037/cco.2018.09.06.
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Stout, R. D., J. Suttles, J. Xu, I. S. Grewal, and R. A. Flavell. "Impaired T cell-mediated macrophage activation in CD40 ligand-deficient mice." Journal of Immunology 156, no. 1 (January 1, 1996): 8–11. http://dx.doi.org/10.4049/jimmunol.156.1.8.
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Abstract The expression of the ligand for CD40 (CD40L) is critical for induction of T cell-dependent Ab responses. To examine how critical the expression of CD40L is for induction of cell-mediated immune responses, the ability of T cells from CD40L knockout mice to activate macrophage effector function was assessed. CD4+ T cells from CD40L-knockout mice were fourfold less effective than +/+ T cells in activating the nitric oxide response in allogeneic macrophages. CD40L-knockout T cells that were fixed with paraformaldehyde after a 6-h activation period, a time point at which CD40L dominates the macrophage-activating capability of the T cell, could activate neither macrophage production of inflammatory cytokines (TNF-alpha) nor generation of reactive nitrogen intermediates. After 24 h of activation, however, both CD40L-knockout and +/+ T cells could induce similar but weak responses from the macrophages. This study demonstrates that animals deficient in CD40L expression display a deficiency in T cell-dependent macrophage-mediated immune responses.
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Koguchi, Yoshinobu, Timothy J. Thauland, Mark K. Slifka, and David C. Parker. "Preformed CD40 ligand exists in secretory lysosomes in effector and memory CD4+ T cells and is quickly expressed on the cell surface in an antigen-specific manner." Blood 110, no. 7 (October 1, 2007): 2520–27. http://dx.doi.org/10.1182/blood-2007-03-081299.
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CD40 ligand (CD40L) is an essential effector cytokine for macrophage activation, dendritic cell licensing, and T-cell–dependent antibody responses. Although CD40L is known to be made de novo following antigen recognition, several reports have described surface mobilization of preformed, intracellular CD40L in certain CD4+ effector T cells. Here we show that rapid surface expression of preformed CD40L following antigen recognition is a general property of both effector and memory CD4+ T cells, including in vitro and in vivo activated T-cell–receptor transgenic T cells, memory phenotype CD4+ T cells from pathogen-free naive mice, and polyclonal virus–specific effector and memory T cells. Intracellular CD40L is stored in secretory lysosomes, and colocalizes more strongly with Fas ligand than with CTLA-4, two other molecules that are delivered to the cell surface following antigen recognition. Stimulated surface expression of preformed CD40L is found in memory CD4+ T cells from CD40-deficient mice, indicating that it does not depend on CD40-induced internalization for delivery to the secretory compartment. We suggest that delivery of preformed CD40L to antigen-presenting cells (APCs) could enable antigen-specific activation of APCs in transient interactions that are too brief to permit de novo synthesis of CD40L.
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Peng, S. L., J. M. McNiff, M. P. Madaio, J. Ma, M. J. Owen, R. A. Flavell, A. C. Hayday, and J. Craft. "alpha beta T cell regulation and CD40 ligand dependence in murine systemic autoimmunity." Journal of Immunology 158, no. 5 (March 1, 1997): 2464–70. http://dx.doi.org/10.4049/jimmunol.158.5.2464.
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Abstract To explore the mechanisms by which alpha beta T cells and gamma delta T cells regulate systemic autoimmunity, lupus-prone mice were rendered deficient in CD40 ligand and/or alpha beta T cells by intercrossing CD40L -/- and TCR-alpha -/- knockouts, generating CD40L-intact or -deficient (CD40L+ or CD40L-), alpha beta T cell-intact or -deficient (alpha beta+ or alpha beta-) MRL-lpr/lpr animals. As expected, CD40L+ alpha beta+ mice developed high titer autoantibodies along with severe renal and cutaneous disease. CD40L+ alpha beta- animals developed lower levels of autoantibodies, accompanied by less severe or delayed renal and cutaneous disease. CD40L- alpha beta+ mice developed even lower titers of autoantibodies and less severe renal disease yet developed cutaneous lesions indistinguishable from those of CD40L+ alpha beta+ disease. Most surprisingly, CD40L- alpha beta- animals developed higher levels of some autoantibodies than did CD40L- alpha beta+ mice and developed renal disease similar in severity to CD40L+ alpha beta- counterparts; however, they failed to develop skin disease. Thus, disruption of CD40L and alpha beta T cells provides a novel dissection of the physiology and pathology of murine lupus; while these data confirm previous findings demonstrating a role for CD40L-dependent, alpha beta T cell-dependent mechanisms in autoantibody production and renal disease in murine lupus, they also: 1) establish that alpha beta T cells may drive autoimmune skin disease by a CD40L-independent mechanism; 2) identify a role for CD40L in non-alpha beta T cell-dependent autoantibody production and autoimmune skin disease; and 3) suggest a role for alpha beta T cells in the down-regulation of autoimmunity driven by other T cells. Thus, both alpha beta and non-alpha beta T cells, such as gamma delta T cells, regulate systemic autoimmunity by CD40L-dependent and -independent mechanisms.