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Richard P Phipps - One of the best experts on this subject based on the ideXlab platform.
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CD40 Ligand cd154 involvement in platelet transfusion reactions
Transfusion Clinique Et Biologique, 2012Co-Authors: Julie Sahler, Sherry L Spinelli, Richard P Phipps, Neil BlumbergAbstract:Abstract Platelet transfusions are commonly used treatments that occasionally lead to adverse reactions. Clinical trials, in vitro and animal studies have been performed to try to understand the causes of such reactions. Multiple studies have shown that the supernatant fraction of platelet concentrates contain prothrombotic and pro-inflammatory mediators. The origin of these mediators was first ascribed to white blood cells contaminating the platelet preparation. However, the accumulation of bioactive mediators after leukoreduction focused attention on platelets themselves during storage. Numerous cytokines, chemokines and prostaglandins are released in stored platelet concentrates. We have focused on a powerful mediator called soluble CD40 Ligand (sCD40L, formally known as CD154) as a seminal contributor to adverse reactions. sCD40L can bind and signal the surface receptor, CD40, which is present on various types of human cells including white blood cells, vascular cells and fibroblasts. Downstream results of sCD40L/CD40 signaling include pro-inflammatory cytokine and chemokine production, prothrombotic mediator release, adherence and transmigration of leukocytes to endothelium and other undesirable vascular inflammatory events. Increased plasma levels of sCD40L can be detected in conditions such as myocardial infarction, stroke, unstable angina, high cholesterol, or other cardiovascular conditions. In retrospective studies, correlations were made between increased sCD40L levels of platelet concentrates and adverse transfusion reactions. We hypothesize that transfusion of partially activated, CD40L-expressing platelets along with sCD40L into a recipient with damaged or dysfunctional vascular tissue results in a “double-hit”, thus inciting inflammation and vascular damage in the recipient.
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the platelet as an immune cell CD40 Ligand and transfusion immunomodulation
Immunologic Research, 2009Co-Authors: Neil Blumberg, Sherry L Spinelli, Charles W Francis, Mark B Taubman, Richard P PhippsAbstract:The discovery that platelets possess cell membrane, cytoplasmic, and secreted forms of the co-stimulatory molecule CD40 Ligand (CD40L, also known as CD154) has led to a revolution in the view of this anucleate, differentiated cell fragment, previously thought only to be involved in blood clotting (hemostasis). During the last decade, it has become clear that platelets function in innate and adaptive immunity and possess pro-inflammatory, as well as pro-thrombotic properties. They interact not only with other platelets and endothelial cells, but also with lymphocytes, dendritic cells, and structural cells such as fibroblasts. Soluble forms of CD40L (sCD40L) in the human circulation are almost entirely derived from platelets. Elevated levels of CD40L are associated with clinically important conditions, such as vascular disease, abnormal clotting (thrombosis), lung injury, and autoimmune disease. Each year millions of platelet transfusions are given to patients that contain large amounts of sCD40L. sCD40L in the supernatant of stored platelets can induce cytokines, chemokines, and lipid mediators by activating CD40 bearing cells. Increased levels of sCD40L in transfused blood are associated with transfusion-related acute lung injury, a potentially fatal complication, as well as more common, milder transfusion reactions such as fever and rigors. These effects come under the rubric of transfusion immunomodulation, which postulates that transfusion recipient biology, particularly immune function, is dramatically altered by transfusion of stored allogeneic blood.
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an association of soluble CD40 Ligand cd154 with adverse reactions to platelet transfusions
Transfusion, 2006Co-Authors: Neil Blumberg, Kelly F Gettings, Chantal K Turner, Joanna M Heal, Richard P PhippsAbstract:BACKGROUND: Removal of stored supernatant abrogates most transfusion reactions to leukoreduced platelets (PLTs), suggesting that PLT-derived soluble mediators are involved. PLTs are the primary source of soluble CD40 Ligand (sCD40L). Engagement of the receptor for CD40L induces synthesis of proinflammatory mediators including interleukin (IL)-6, IL-8, and monocyte chemotactic protein-1 (MCP-1). STUDY DESIGN AND METHODS: Supernatants from poststorage leukoreduced PLT concentrates were assayed for white cell– (IL-6, IL-8, MCP-1) and PLT-derived (sCD40L, RANTES) inflammatory mediators. These levels were correlated with clinical outcomes. RESULTS: Of 534 transfusions, there were 12 reported (2.2%) and 2 unreported reactions (0.4%)—10 febrile and 4 allergic. Transfusions with reactions had significantly higher levels of IL-6 (2.3-fold higher; p = 0.005), IL-8 (2.2-fold higher; p = 0.001), MCP-1 (2.6-fold higher; p = 0.002), and sCD40L (1.24-fold higher; p = 0.015), but not RANTES. (1.14-fold higher; p = 0.22). The vast majority (>93%) of patients transfused with mediator levels in the highest quintile had no reactions. When levels of all five mediators were summed, the reaction rates in the first through fifth quintiles increased from 1 to 7 percent (p = 0.027). All but one reaction occurred in patients with hematologic malignancies (13 reactions/380 transfusions; 3.4%; p = 0.04 vs. other diagnoses). CONCLUSIONS: These are the first data demonstrating that a PLT-derived mediator, sCD40L, is associated with adverse transfusion events. Existing clinical factors, for example, inflammation or leukopenia, may influence whether infused mediators cause reactions.
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atherosclerosis the emerging role of inflammation and the CD40 CD40 Ligand system
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Richard P PhippsAbstract:Atherosclerosis is a principal cause of death in the Westernized world. Previously, it was thought to be a disease primarily involving lipid accumulation in the arterial walls. The inflammatory cells found at the sites of fatty streaks as well as in the more advanced lesions were not considered to be principally responsible for the disease. A different view of atherosclerosis has emerged subsequently. Current concepts of this disease include involvement of the immune system and chronic inflammation as crucial elements in the initiation of endothelial cell dysfunction, in fatty streak formation, and in development of advanced lesions and eventual vessel rupture (for a recent review, see ref. 1). Atherosclerosis can now be viewed as a problem of wound healing and of chronic inflammation. Numerous reports in the past few years have demonstrated clearly that migratory immune cells, including monocytes and T lymphocytes, are key cellular elements at all stages of atherosclerosis. Most exciting and relevant to atherosclerosis as a disease of chronic inflammation are papers by Schonbeck et al. (2) and Lutgens et al. (3) appearing in this issue of PNAS. These research groups clearly show that disruption of the CD40–CD40 Ligand (L) system, a key mediator of cell communication in the immune system, prevents progression of established atherosclerotic lesions to more advanced unstable lesions. This evidence, coupled with recent studies showing that disruption of the CD40–CD40L system can retard the initiation of arterial plaque formation, provides compelling evidence for the role of chronic inflammation and elements of the immune response in atherosclerosis. Moreover, these investigations identify CD40–CD40L as key regulators of this process and recognize them as potentially important therapeutic targets.
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blockade of CD40 CD40 Ligand interactions protects against radiation induced pulmonary inflammation and fibrosis
Clinical Immunology and Immunopathology, 1998Co-Authors: Adnan Adawi, Ying Zhang, Raymond B Baggs, Philip Rubin, Jacqueline P Williams, Jacob N Finkelstein, Richard P PhippsAbstract:This study investigated whether CD40-CD40 Ligand (L) interactions are important in mediating ionizing radiation-induced lung toxicity. Radiotherapy is a key component in the management of malignant diseases and is a conditioning regimen for bone marrow transplantation. Unfortunately, radiation therapy is particularly toxic to the lung, potentially inducing a fatal pneumonitis and fibrosis, thus limiting its effectiveness. There are no therapies that protect against the development of radiation-induced lung toxicity. Using a mouse model of radiation-induced lung toxicity, a monoclonal anti-CD40L antibody (MR1) that disrupts CD40-CD40L interactions was tested for the ability to reduce lung injury. C57BL/6 mice were pretreated with either nothing, MR1, or hamster IgG 24 h prior to a single dose of 15 Gray ionizing radiation to the thorax. During the following 26 weeks, mice continued to receive MR1 or hamster IgG twice per week. MR1 protected against death from radiation pneumonitis and fibrosis and dramatically reduced lung pathology as evidenced by a limited influx of inflammatory cells, minimal collagen deposition, and septal thickening. MR1 also prevented radiation-induced pulmonary mastocytosis and blunted expression of cyclooxygenase-2, a proinflammatory enzyme responsible for prostaglandin synthesis. Disruption of CD40-CD40L interactions may offer a new mode of intervention to protect against radiation-induced pulmonary toxicity.
Richard A Flavell - One of the best experts on this subject based on the ideXlab platform.
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The CD40 Ligand
Immunologic Research, 1997Co-Authors: Iqbal S Grewal, Richard A FlavellAbstract:For several years, the primary function of CD40 Ligand (CD40L) has been believed to be in regulation of contact-dependent, CD40-CD40L-mediated signals between B-and T-cells, which are essential for the regulation of thymus-dependent (TD) humoral immune responses. Recently, a flurry of reports indicate that CD40 is expressed by variety of cell types other than B-cells that include dendritic cells, follicular dendritic cells, monocytes, macrophages, fibroblasts, and endothelial cells. These studies show that CD40-CD40L interactions are important in inflammatory process. For the past few years, through the availability of CD40L-knockout mice, new data have emerged to support the belief that CD40L has many more functions than its role in TD humoral immunity. CD40L-deficient mice have provided significant information towards our understanding of the in vivo role of CD40L. The current picture that emerges indicates that CD40-CD40L interactions mediate many cell-mediated immune responses and T-cell-mediated effector functions that are required for proper functioning of the host defense system. This article focuses on the in vivo role of the CD40L in regulation of cell-mediated effector functions.
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CD40 Ligand deficient mice generate a normal primary cytotoxic t lymphocyte response but a defective humoral response to a viral infection
Journal of Virology, 1996Co-Authors: Jason K Whitmire, Iqbal S Grewal, Richard A Flavell, Mark K Slifka, Rafi AhmedAbstract:CD40 Ligand is expressed on activated T cells and interacts with CD40 on B cells and monocytes. It is not known what role CD40 Ligand plays in the generation of immune responses to viral infection. To address this issue, we examined virus-specific T- and B-cell responses in CD40 Ligand-deficient (CD40L-/-) mice following infection with lymphocytic choriomeningitis virus (LCMV). We found that primary anti-LCMV specific antibody responses were severely impaired in CD40L-/- mice, with the defect being most striking for antibody of the immunoglobulin G1 (IgG1) isotype. Interestingly, low levels of LCMV-specific antibodies of the IgG2a, IgG2b, and IgG3 isotypes were made in the CD40L-/- mice, showing that IgG1 responses are totally dependent on CD40L but that at least some IgG2a, IgG2b, and IgG3 responses can be CD40L independent. However, unlike CD40L+/+ mice, CD40L-/- mice were unable to sustain virus-specific antibody responses and showed a gradual decline in serum antibody levels over time. The CD40L-/- mice were also deficient in the generation of memory B cells. In contrast to the severely impaired humoral responses, CD40L-/- mice generated potent virus-specific CD8+ cytotoxic T-lymphocyte responses after LCMV infection and were able to clear the virus. These results show that CD40L does not play a role in generating primary virus-specific CD8+ cytotoxic T-lymphocyte responses but does affect the primary antibody response and the generation of memory B cells.
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requirement for CD40 Ligand in costimulation induction t cell activation and experimental allergic encephalomyelitis
Science, 1996Co-Authors: Iqbal S Grewal, Jian Chao Xu, Harald G Foellmer, Kate D Grewal, Fridrika Hardardottir, Jody L Baron, Charles A Janeway, Richard A FlavellAbstract:The mechanism of CD40 Ligand (CD40L)-mediated in vivo activation of CD4 + T cells was examined by investigation of the development of experimental allergic encephalomyelitis (EAE) in CD40L-deficient mice that carried a transgenic T cell receptor specific for myelin basic protein. These mice failed to develop EAE after priming with antigen, and CD4 + T cells remained quiescent and produced no interferon-γ (IFN-γ). T cells were primed to make IFN-γ and induce EAE by providing these mice with B7.1 + antigen-presenting cells (APCs). Thus, CD40L is required to induce costimulatory activity on APCs for in vivo activation of CD4 + T cells to produce IFN-γ and to evoke autoimmunity.
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a central role of CD40 Ligand in the regulation of cd4 t cell responses
Immunology Today, 1996Co-Authors: Iqbal S Grewal, Richard A FlavellAbstract:Abstract Many of the costimulatory molecules thought to be essential for T-cell activation have now been identified. The CD40-CD40 Ligand interaction is one such receptor/counter-receptor pair that has been shown to be important in B- and T-cell cognate interactions. Here Iqbal Grewal and Richard Flavell examine recent data from studies using gene knockout techniques that have helped provide a better understanding of CD40L's role in vivo , in regulation of the immune response.
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transient subversion of CD40 Ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues
Journal of Virology, 1996Co-Authors: Yiping Yang, Iqbal S Grewal, Richard A Flavell, R Schilz, James M WilsonAbstract:First-generation adenovirus vectors will have limited application in gene therapy for chronic diseases because of destructive host immune responses. Important immune effectors include CD8+ T cells, which mediate target cell destruction and ablate transgene expression, and B cells, which produce neutralizing antibodies that block effective readministration of vector. Previous studies indicated that activation of CD4+ T cells by virus capsid proteins is necessary for full realization of effector function of CD8+ T cells and B cells. In this paper, we present a strategy for preventing CD4+ T-cell activation by an adenovirus vector delivered to mouse liver and lung tissues which is based on interfering with T-cell priming via CD40 Ligand-CD40 interactions. Adenovirus transgene expression was stabilized in mice genetically deficient in CD40 Ligand (CD40L), and neutralizing antibody to adenovirus did not develop, allowing efficient readministration of vector. A transient blockade of T-cell activation with an antibody to CD40L infused into the animal at the time of adenovirus vector-mediated gene transfer led to stabilization of transgene expression and diminished production of neutralizing antibody, allowing readministration of vector. In vitro T-cell assays suggested that a block in the primary activation of CD4+ T cells was responsible for the lack of B-cell- and cytotoxic-T-cell-dependent responses. This suggests a strategy for improving the potential of adenovirus vectors based on administration of an antibody to CD40L at the time of vector administration.
Robert G Hart - One of the best experts on this subject based on the ideXlab platform.
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high sensitivity c reactive protein and soluble CD40 Ligand as indices of inflammation and platelet activation in 880 patients with nonvalvular atrial fibrillation relationship to stroke risk factors stroke risk stratification schema and prognosis
Stroke, 2007Co-Authors: Jeetesh V Patel, Elizabeth A Hughes, Robert G HartAbstract:Background and Purpose—There is now considerable evidence that atrial fibrillation is associated with an inflammatory state. We tested the hypothesis that plasma levels of C-reactive protein (CRP; an index of inflammation) and soluble CD40 Ligand (an index of platelet activation, with links to inflammation) could be related to 3 established stroke risk stratification schema (SPAF, CHADS2, and NICE), recognized stroke risk factors or other cardiovascular disease, and prognosis. Methods—We studied 880 subjects with atrial fibrillation recruited from subjects receiving aspirin 325 mg/d (alone or combined with fixed inefficacious doses of warfarin) from the Stroke Prevention in Atrial Fibrillation (SPAF) III clinical trial. CRP and soluble CD40 Ligand were measured by enzyme-linked immunosorbent assay. Results—With respect to the SPAF III stroke risk stratification criteria, those with moderate to high risk had the highest levels of CRP (Kruskal Wallis test, P0.001), but those with the highest risk had the lowest levels of soluble CD40 Ligand (P0.01). Similarly, CRP levels increased in a positive fashion with increasing stroke risk with respect to the CHADS2 and NICE risk stratification criteria, whereas soluble CD40 Ligand levels were negatively associated with stroke risk. CRP levels were higher among those patients with raised body mass index, diabetes, hypertension, ischemic heart disease, peripheral vascular disease, and recent heart failure, but not those with thromboembolism. Patients were followed-up for a mean time of 453 (standard deviation, 229) days, and all-cause mortality (log rank test, P0.001), and vascular events (P0.05), but not stroke, were more common in patients with high CRP levels. Soluble CD40 Ligand levels were not related to stroke, vascular events, or all-cause mortality. Conclusion—Among atrial fibrillation patients, CRP was positively correlated to stroke risk and related to stroke risk factors and prognosis (mortality, vascular events). Soluble CD40 Ligand levels were lowest in those at moderate to high risk of stroke and not related to prognosis. The use of CRP in risk stratification for atrial fibrillation merits further study. (Stroke. 2007;38:1229-1237.)
Peter Libby - One of the best experts on this subject based on the ideXlab platform.
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effect of atorvastatin on risk of recurrent cardiovascular events after an acute coronary syndrome associated with high soluble CD40 Ligand in the myocardial ischemia reduction with aggressive cholesterol lowering miracl study
Circulation, 2004Co-Authors: Scott Kinlay, Gregory G Schwartz, Anders G Olsson, Nader Rifai, William J Sasiela, Michael Szarek, Peter Ganz, Peter LibbyAbstract:Background - Patients with acute coronary syndromes have elevated plasma levels of the proinflammatory, prothrombotic cytokine CD40 Ligand (sCD40L). Statins inhibit CD40L signaling in vitro, but th ...
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elevated plasma levels of the atherogenic mediator soluble CD40 Ligand in diabetic patients a novel target of thiazolidinediones
Circulation, 2003Co-Authors: Nerea Varo, Peter Libby, Rebecca Nuzzo, David Vicent, Alfonso Callepascual, Maria Rosa Bernal, Arturo Fernandezcruz, Aristidis Veves, Petr Jarolim, Jose Javier VaroAbstract:Background— Considerable evidence implicates the proinflammatory cytokine CD40 Ligand (CD40L) in atherosclerosis and accumulating data link type 1 and 2 diabetes, conditions associated with accelerated atherosclerosis, to inflammation. This study therefore evaluated the hypothesis that diabetic patients have elevated plasma levels of soluble CD40L (sCD40L) and that treatment with the insulin-sensitizing thiazolidinediones lowers this index of inflammation. Methods and Results— Subjects with type 1 (n=49) or type 2 diabetes (n=48) had higher (P<0.001) sCD40L plasma levels (6.56±3.27 and 6.67±2.90 ng/mL, respectively) compared with age-matched control groups (1.40±2.21 and 1.32±2.68 ng/mL, respectively). Multiple regression analysis demonstrated a significant (P<0.001) association between plasma sCD40L and type 1 as well as type 2 diabetes, independent of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, blood pressure, body mass index, gender, C-re...
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CD154 (CD40 Ligand).
The International Journal of Biochemistry & Cell Biology, 2000Co-Authors: Uwe Schönbeck, François Mach, Peter LibbyAbstract:CD40 Ligand, a type II transmembrane protein recently renamed CD154, was originally considered restricted to activated T lymphocytes, functioning as a mediator of T cell-dependent B cell activation, proliferation, and differentiation. However, the spectrum of CD154 expression and function has broadened considerably during recent years, establishing new roles as a central mediator of immunity and inflammation for this member of the tumor necrosis factor (TNF) gene superfamily. The emerging picture indicates that ligation of the receptor CD40 via CD154, most potently in its trimeric form, functions in two ways. CD154 modulates physiologic processes, such as T cell-mediated effector functions and general immune responses required for appropriate host defense, but also triggers the expression of pro-inflammatory mediators, such as cytokines, adhesion molecules, and matrix degrading activities, all of which are associated with the pathogenesis of chronic inflammatory diseases, e.g., autoimmune disorders, arthritis, atherosclerosis, and cancer. Accordingly, CD40/CD154 interactions have advanced as a potential therapeutic target for these diseases, whereby two opposing strategies, interruption as well as enhancement of CD40 signaling, are explored for beneficial outcomes.
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functional CD40 Ligand is expressed on human vascular endothelial cells smooth muscle cells and macrophages implications for CD40 CD40 Ligand signaling in atherosclerosis
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: François Mach, Uwe Schönbeck, Jean Yves Bonnefoy, Galina K Sukhova, Todd Bourcier, Jordan S Pober, Peter LibbyAbstract:Increasing evidence supports involvement of inflammation and immunity in atherogenesis. We report here that CD40 Ligand (CD40L), an immunoregulatory signaling molecule heretofore considered largely restricted to recently activated CD4+ T lymphocytes, is expressed by human vascular endothelial cells (EC), smooth muscle cells (SMC), and human macrophages in vitro, and is coexpressed with its receptor CD40 on all three cells types in human atherosclerotic lesions in situ. Cultured human vascular EC, SMC, and human macrophages all constitutively expressed CD40L mRNA as well as protein. Stimulation with interleukin 1β, tumor necrosis factor α, or interferon γ increased surface levels and de novo synthesis of CD40L on all three cell types. CD40L expressed on EC, SMC, and macrophages exhibited biological activity, as it induced B7.2 expression on B cells. Human vascular SMC also constitutively expressed CD40, the receptor for CD40L, and through CD40 signaling, human recombinant CD40L induced expression of proinflammatory cytokines in these cells, identifying SMC as a target for CD40L. Human atherosclerotic lesions (n = 8) showed expression of immunoreactive CD40L on EC, SMC, and macrophages, while normal arterial tissues (n = 5) contained no CD40L. In atheroma CD40L+ cells often also expressed CD40. These observations establish human vascular EC, SMC, and human macrophages as a novel source of CD40L, and point to T cell-independent CD40 signaling, and a broader function of this pathway in regulation of nonimmune cells, as illustrated here by potential autocrine and paracrine activation during atherogenesis.
Iqbal S Grewal - One of the best experts on this subject based on the ideXlab platform.
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The CD40 Ligand
Immunologic Research, 1997Co-Authors: Iqbal S Grewal, Richard A FlavellAbstract:For several years, the primary function of CD40 Ligand (CD40L) has been believed to be in regulation of contact-dependent, CD40-CD40L-mediated signals between B-and T-cells, which are essential for the regulation of thymus-dependent (TD) humoral immune responses. Recently, a flurry of reports indicate that CD40 is expressed by variety of cell types other than B-cells that include dendritic cells, follicular dendritic cells, monocytes, macrophages, fibroblasts, and endothelial cells. These studies show that CD40-CD40L interactions are important in inflammatory process. For the past few years, through the availability of CD40L-knockout mice, new data have emerged to support the belief that CD40L has many more functions than its role in TD humoral immunity. CD40L-deficient mice have provided significant information towards our understanding of the in vivo role of CD40L. The current picture that emerges indicates that CD40-CD40L interactions mediate many cell-mediated immune responses and T-cell-mediated effector functions that are required for proper functioning of the host defense system. This article focuses on the in vivo role of the CD40L in regulation of cell-mediated effector functions.
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CD40 Ligand deficient mice generate a normal primary cytotoxic t lymphocyte response but a defective humoral response to a viral infection
Journal of Virology, 1996Co-Authors: Jason K Whitmire, Iqbal S Grewal, Richard A Flavell, Mark K Slifka, Rafi AhmedAbstract:CD40 Ligand is expressed on activated T cells and interacts with CD40 on B cells and monocytes. It is not known what role CD40 Ligand plays in the generation of immune responses to viral infection. To address this issue, we examined virus-specific T- and B-cell responses in CD40 Ligand-deficient (CD40L-/-) mice following infection with lymphocytic choriomeningitis virus (LCMV). We found that primary anti-LCMV specific antibody responses were severely impaired in CD40L-/- mice, with the defect being most striking for antibody of the immunoglobulin G1 (IgG1) isotype. Interestingly, low levels of LCMV-specific antibodies of the IgG2a, IgG2b, and IgG3 isotypes were made in the CD40L-/- mice, showing that IgG1 responses are totally dependent on CD40L but that at least some IgG2a, IgG2b, and IgG3 responses can be CD40L independent. However, unlike CD40L+/+ mice, CD40L-/- mice were unable to sustain virus-specific antibody responses and showed a gradual decline in serum antibody levels over time. The CD40L-/- mice were also deficient in the generation of memory B cells. In contrast to the severely impaired humoral responses, CD40L-/- mice generated potent virus-specific CD8+ cytotoxic T-lymphocyte responses after LCMV infection and were able to clear the virus. These results show that CD40L does not play a role in generating primary virus-specific CD8+ cytotoxic T-lymphocyte responses but does affect the primary antibody response and the generation of memory B cells.
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requirement for CD40 Ligand in costimulation induction t cell activation and experimental allergic encephalomyelitis
Science, 1996Co-Authors: Iqbal S Grewal, Jian Chao Xu, Harald G Foellmer, Kate D Grewal, Fridrika Hardardottir, Jody L Baron, Charles A Janeway, Richard A FlavellAbstract:The mechanism of CD40 Ligand (CD40L)-mediated in vivo activation of CD4 + T cells was examined by investigation of the development of experimental allergic encephalomyelitis (EAE) in CD40L-deficient mice that carried a transgenic T cell receptor specific for myelin basic protein. These mice failed to develop EAE after priming with antigen, and CD4 + T cells remained quiescent and produced no interferon-γ (IFN-γ). T cells were primed to make IFN-γ and induce EAE by providing these mice with B7.1 + antigen-presenting cells (APCs). Thus, CD40L is required to induce costimulatory activity on APCs for in vivo activation of CD4 + T cells to produce IFN-γ and to evoke autoimmunity.
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a central role of CD40 Ligand in the regulation of cd4 t cell responses
Immunology Today, 1996Co-Authors: Iqbal S Grewal, Richard A FlavellAbstract:Abstract Many of the costimulatory molecules thought to be essential for T-cell activation have now been identified. The CD40-CD40 Ligand interaction is one such receptor/counter-receptor pair that has been shown to be important in B- and T-cell cognate interactions. Here Iqbal Grewal and Richard Flavell examine recent data from studies using gene knockout techniques that have helped provide a better understanding of CD40L's role in vivo , in regulation of the immune response.
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transient subversion of CD40 Ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues
Journal of Virology, 1996Co-Authors: Yiping Yang, Iqbal S Grewal, Richard A Flavell, R Schilz, James M WilsonAbstract:First-generation adenovirus vectors will have limited application in gene therapy for chronic diseases because of destructive host immune responses. Important immune effectors include CD8+ T cells, which mediate target cell destruction and ablate transgene expression, and B cells, which produce neutralizing antibodies that block effective readministration of vector. Previous studies indicated that activation of CD4+ T cells by virus capsid proteins is necessary for full realization of effector function of CD8+ T cells and B cells. In this paper, we present a strategy for preventing CD4+ T-cell activation by an adenovirus vector delivered to mouse liver and lung tissues which is based on interfering with T-cell priming via CD40 Ligand-CD40 interactions. Adenovirus transgene expression was stabilized in mice genetically deficient in CD40 Ligand (CD40L), and neutralizing antibody to adenovirus did not develop, allowing efficient readministration of vector. A transient blockade of T-cell activation with an antibody to CD40L infused into the animal at the time of adenovirus vector-mediated gene transfer led to stabilization of transgene expression and diminished production of neutralizing antibody, allowing readministration of vector. In vitro T-cell assays suggested that a block in the primary activation of CD4+ T cells was responsible for the lack of B-cell- and cytotoxic-T-cell-dependent responses. This suggests a strategy for improving the potential of adenovirus vectors based on administration of an antibody to CD40L at the time of vector administration.