scholarly journals Targeting MOG to skin macrophages prevents EAE in macaques through TGFβ-induced peripheral tolerance

2019 ◽  
Author(s):  
Claire-Maëlle Fovet ◽  
Lev Stimmer ◽  
Vanessa Contreras ◽  
Philippe Horellou ◽  
Audrey Hubert ◽  
...  
Keyword(s):  
Recombinant Antibody ◽  
Specific Antigen ◽  
Autoimmune Encephalitis ◽  
Lymphocyte Activation ◽  
Peripheral Tolerance ◽  
Brain Inflammation ◽  
Macaque Model ◽  
Vaccination Scheme ◽  
Intradermal Administration ◽  
Antigen Presenting

AbstractTo study the effect of vaccination on tolerization to the myelin antigen MOG we used a macaque model of experimental autoimmune encephalitis (EAE) in which immunization with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) elicits brain inflammation and demyelination mediated by MOG-specific autoreactive CD4+ T lymphocytes and anti-MOG IgG. For antigen targeting to tolerizing antigen presenting cells, we used a recombinant antibody directed to the Dendritic Cells (DC)-Asialoglycoprotein receptor (DC-ASGPR). The intradermal administration of an anti-DC-ASGPR-MOG fusion protein, but not a control anti-DC-ASGPR-PSA (prostate specific antigen) protein, protected monkeys committed to develop EAE. Although effective treatment did not modify anti-MOG IgG production, it prevented the CD4+ T lymphocyte activation and pro-inflammatory cytokine production. Moreover, animals treated with anti-DC-ASGPR-MOG experienced a rise of MOG-specific CD4+CD25+FOXP3+CD39+ regulatory T cells as well as a TGFβ1, TGFβ2 and IL-8 upsurge after rhMOG re-immunization. Our results indicate that the pathogenicity of autoantibodies directed to MOG is mitigated in the presence of MOG-specific regulatory lymphocytes. This vaccination scheme appears suitable to treat relapsing autoimmune diseases with identified autoantigens such as that harboring anti-MOG or anti-AQP4 autoantibodies.

scholarly journals Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells

Blood ◽  
2012 ◽  
Vol 120 (24) ◽  
pp. 4772-4782 ◽  
Author(s):  
Eric F. Tewalt ◽  
Jarish N. Cohen ◽  
Sherin J. Rouhani ◽  
Cynthia J. Guidi ◽  
Hui Qiao ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cd8 T Cells ◽  
Lymphocyte Activation ◽  
Peripheral Tolerance ◽  
Lymphatic Endothelial Cells ◽  
Programmed Cell Death 1 ◽  
Tissue Antigens ◽  
High Level ◽  
Antigen Presenting

Abstract Lymphatic endothelial cells (LECs) induce peripheral tolerance by direct presentation to CD8 T cells (TCD8). We demonstrate that LECs mediate deletion only via programmed cell death-1 (PD-1) ligand 1, despite expressing ligands for the CD160, B- and T-lymphocyte attenuator, and lymphocyte activation gene-3 inhibitory pathways. LECs induce activation and proliferation of TCD8, but lack of costimulation through 4-1BB leads to rapid high-level expression of PD-1, which in turn inhibits up-regulation of the high-affinity IL-2 receptor that is necessary for TCD8 survival. Rescue of tyrosinase-specific TCD8 by interference with PD-1 or provision of costimulation results in autoimmune vitiligo, demonstrating that LECs are significant, albeit suboptimal, antigen-presenting cells. Because LECs express numerous peripheral tissue antigens, lack of costimulation coupled to rapid high-level up-regulation of inhibitory receptors may be generally important in systemic peripheral tolerance.

scholarly journals Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation

2000 ◽  
Vol 192 (7) ◽  
pp. 1027-1034 ◽  
Author(s):  
Gordon J. Freeman ◽  
Andrew J. Long ◽  
Yoshiko Iwai ◽  
Karen Bourque ◽  
Tatyana Chernova ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Peripheral Blood ◽  
Lymphocyte Activation ◽  
Antigen Presenting Cells ◽  
Peripheral Tolerance ◽  
Blood Monocytes ◽  
Activated T Cells ◽  
Antigen Presenting

PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor–mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon γ, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.

Conjugation of an antibody Fv fragment to a virus coat protein: cell-specific targeting of recombinant polyoma-virus-like particles

2001 ◽  
Vol 356 (3) ◽  
pp. 867-873 ◽  
Author(s):  
Kay STUBENRAUCH ◽  
Stefan GLEITER ◽  
Ulrich BRINKMANN ◽  
Rainer RUDOLPH ◽  
Hauke LILIE
Keyword(s):  
Coat Protein ◽  
Mammalian Cells ◽  
Recombinant Antibody ◽  
Specific Antigen ◽  
Antibody Fragment ◽  
Fusion Peptides ◽  
Virus Like Particles ◽  
Vector Systems ◽  
Virus Coat

The development of cell-type-specific delivery systems is highly desirable for gene-therapeutic applications. Current virus-based vector systems show broad cell specificity, which results in the need to restrict the natural tropism of these viral systems. Here we demonstrate that tumour-cell-specific virus-like particles can be functionally assembled in vitro from recombinant viral coat protein expressed in Escherichia coli. The insertion of a negatively charged peptide in the HI loop of polyoma VP1 interferes with the binding of VP1 to the natural recognition site on mammalian cells and also serves as an adapter for the coupling of antibody fragments that contain complementary charged fusion peptides. A recombinant antibody fragment of the tumour-specific anti-(Lewis Y) antibody B3 could be coupled to the mutant VP1 by engineered polyionic peptides and an additional disulphide bond. With this system an entirely recombinant cell-specific delivery system assembled in vitro could be generated that transfers genes preferentially to cells presenting the tumour-specific antigen on the cell surface.

scholarly journals Prevention of Peripheral Tolerance by a Dendritic Cell Growth Factor: Flt3 Ligand as an Adjuvant

1998 ◽  
Vol 188 (11) ◽  
pp. 2075-2082 ◽  
Author(s):  
Bali Pulendran ◽  
J.L. Smith ◽  
M. Jenkins ◽  
M. Schoenborn ◽  
E. Maraskovsky ◽  
...  
Keyword(s):  
Tolerance Induction ◽  
Cd40 Ligand ◽  
Peripheral Tolerance ◽  
Clinical Settings ◽  
Flt3 Ligand ◽  
Systemic Injection ◽  
Large Numbers ◽  
Factor Α ◽  
Antigen Presenting

Injections of soluble proteins are poorly immunogenic, and often elicit antigen-specific tolerance. The mechanism of this phenomenon has been an enduring puzzle, but it has been speculated that tolerance induction may be due to antigen presentation by poorly stimulatory, resting B cells, which lack specific immunoglobulin receptors for the protein. In contrast, adjuvants, or infectious agents, which cause the release of proinflammatory cytokines such as tumor necrosis factor α and interleukin 1β in vivo are believed to recruit and activate professional antigen-presenting cells to the site(s) of infection, thereby eliciting immunity. Here we show that administration of Flt3 ligand (FL), a cytokine capable of inducing large numbers of dendritic cells (DCs) in vivo, (a) dramatically enhances the sensitivity of antigen-specific B and T cell responses to systemic injection of a soluble protein, through a CD40–CD40 ligand–dependent mechanism; (b) influences the class of antibody produced; and (c) enables productive immune responses to otherwise tolerogenic protocols. These data support the hypothesis that the delicate balance between immunity and tolerance in vivo is pivotally controlled by DCs, and underscore the potential of FL as a vaccine adjuvant for immunotherapy in infectious disease and other clinical settings.

scholarly journals Novel Strategies for Immunotherapy in Multiple Myeloma: Previous Experience and Future Directions

2012 ◽  
Vol 2012 ◽  
pp. 1-28 ◽  
Author(s):  
Ivetta Danylesko ◽  
Katia Beider ◽  
Avichai Shimoni ◽  
Arnon Nagler
Keyword(s):  
Multiple Myeloma ◽  
Specific Antigen ◽  
Allogeneic Transplantation ◽  
Cellular Immunotherapy ◽  
Future Directions ◽  
Study Protocols ◽  
Immune Incompetence ◽  
Life Threatening ◽  
Dc Vaccines ◽  
Antigen Presenting

Multiple myeloma (MM) is a life-threatening haematological malignancy for which standard therapy is inadequate. Autologous stem cell transplantation is a relatively effective treatment, but residual malignant sites may cause relapse. Allogeneic transplantation may result in durable responses due to antitumour immunity mediated by donor lymphocytes. However, morbidity and mortality related to graft-versus-host disease remain a challenge. Recent advances in understanding the interaction between the immune system of the patient and the malignant cells are influencing the design of clinically more efficient study protocols for MM. Cellular immunotherapy using specific antigen-presenting cells (APCs), to overcome aspects of immune incompetence in MM patients, has received great attention, and numerous clinical trials have evaluated the potential for dendritic cell (DC) vaccines as a novel immunotherapeutic approach. This paper will summarize the data investigating aspects of immunity concerning MM, immunotherapy for patients with MM, and strategies, on the way, to target the plasma cell more selectively. We also include the MM antigens and their specific antibodies that are of potential use for MM humoral immunotherapy, because they have demonstrated the most promising preclinical results.

scholarly journals B7-CD28 co-stimulation modulates central tolerance via thymic clonal deletion and Treg generation through distinct mechanisms

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Masashi Watanabe ◽  
Ying Lu ◽  
Michael Breen ◽  
Richard J. Hodes
Keyword(s):  
Treg Cell ◽  
Specific Antigen ◽  
Cell Generation ◽  
Thymic Epithelial Cells ◽  
T Cell Repertoire ◽  
Cellular Mechanisms ◽  
Cell Repertoire ◽  
Clonal Deletion ◽  
Central Tolerance ◽  
Antigen Presenting

AbstractThe molecular and cellular mechanisms mediating thymic central tolerance and prevention of autoimmunity are not fully understood. Here we show that B7-CD28 co-stimulation and B7 expression by specific antigen-presenting cell (APC) types are required for clonal deletion and for regulatory T (Treg) cell generation from endogenous tissue-restricted antigen (TRA)-specific thymocytes. While B7-CD28 interaction is required for both clonal deletion and Treg induction, these two processes differ in their CD28 signaling requirements and in their dependence on B7-expressing dendritic cells, B cells, and thymic epithelial cells. Meanwhile, defective thymic clonal deletion due to altered B7-CD28 signaling results in the accumulation of mature, peripheral TRA-specific T cells capable of mediating destructive autoimmunity. Our findings thus reveal a function of B7-CD28 co-stimulation in shaping the T cell repertoire and limiting autoimmunity through both thymic clonal deletion and Treg cell generation.

scholarly journals Tissue-specific autoimmunity controlled by Aire in thymic and peripheral tolerance mechanisms

2019 ◽  
Vol 32 (2) ◽  
pp. 117-131
Author(s):  
Minoru Matsumoto ◽  
Koichi Tsuneyama ◽  
Junko Morimoto ◽  
Kazuyoshi Hosomichi ◽  
Mitsuru Matsumoto ◽  
...  
Keyword(s):  
T Cells ◽  
Type I Diabetes ◽  
Nod Mice ◽  
Peripheral Tolerance ◽  
Type I ◽  
Tolerance Mechanisms ◽  
Thymic Function ◽  
Tissue Specific ◽  
Thymic Stroma ◽  
Antigen Presenting

Abstract Tissue-specific autoimmune diseases are assumed to arise through malfunction of two checkpoints for immune tolerance: defective elimination of autoreactive T cells in the thymus and activation of these T cells by corresponding autoantigens in the periphery. However, evidence for this model and the outcome of such alterations in each or both of the tolerance mechanisms have not been sufficiently investigated. We studied these issues by expressing human AIRE (huAIRE) as a modifier of tolerance function in NOD mice wherein the defects of thymic and peripheral tolerance together cause type I diabetes (T1D). Additive huAIRE expression in the thymic stroma had no major impact on the production of diabetogenic T cells in the thymus. In contrast, huAIRE expression in peripheral antigen-presenting cells (APCs) rendered the mice resistant to T1D, while maintaining other tissue-specific autoimmune responses and antibody production against an exogenous protein antigen, because of the loss of Xcr1+ dendritic cells, an essential component for activating diabetogenic T cells in the periphery. These results contrast with our recent demonstration that huAIRE expression in both the thymic stroma and peripheral APCs resulted in the paradoxical development of muscle-specific autoimmunity. Our results reveal that tissue-specific autoimmunity is differentially controlled by a combination of thymic function and peripheral tolerance, which can be manipulated by expression of huAIRE/Aire in each or both of the tolerance mechanisms.

Experience with sipuleucel-T in metastatic castration-resistant prostate cancer (mCRPC) with visceral spread from PROCEED.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 174-174
Author(s):  
Nicholas J. Vogelzang ◽  
Philip W. Kantoff ◽  
Mark C. Scholz ◽  
Jeffrey L. Vacirca ◽  
Shaker R. Dakhil ◽  
...  
Keyword(s):  
Performance Status ◽  
Specific Antigen ◽  
Cellular Immunotherapy ◽  
Castration Resistant Prostate Cancer ◽  
Phase 3 ◽  
Castration Resistant ◽  
Visceral Metastases ◽  
Antigen Presenting ◽  
Post Hoc ◽  
Clinical Trial Information

174 Background: Trials of approved agents in mCRPC have reported shorter overall survival (OS) in men with visceral metastases (mets). The phase 3 IMPACT trial evaluated sipuleucel-T, an autologous cellular immunotherapy, in mCRPC but excluded visceral mets. PROCEED, a registry of mCRPC patients receiving sipuleucel-T, offers the first description of sipuleucel-T in patients with visceral mets. Methods: PROCEED enrolled men with mCRPC treated with sipuleucel-T biweekly x 3. Dose adjustment for organ dysfunction was unnecessary. Men were followed until death, study withdrawal, or a minimum of 3 years. OS is reported in this post-hoc subgroup analysis. Results: 1902 men received ≥1 sipuleucel-T infusion between 2011-2014. Visceral mets (n = 90) included liver (n=21), lung (n=61), and brain (n=2) involvement. Compared to patients without visceral mets (Table), men with visceral mets had poorer performance status (PS) and higher baseline prostate-specific antigen (PSA). Median OS was 20.5 and 31.2 mo in those with and without visceral mets. Patients with liver and lung mets had a median OS of 16.3 and 21.0 mo, respectively. Activation of antigen-presenting cells, a measure of immune activation and product potency, was similar in those with and without visceral mets. Conclusions: Initial observations suggest that patients with mCRPC and visceral spread can activate their immune cells to produce sipuleucel-T, but have a shorter OS than those with bone and/or lymph node spread. (NCT01306890). Clinical trial information: NCT00065442. [Table: see text]

scholarly journals Inhibition of antigen-specific T lymphocyte activation by structurally related Ir gene-controlled polymers. II. Competitive inhibition of I-E-restricted, antigen-specific T cell responses.

1984 ◽  
Vol 160 (6) ◽  
pp. 1864-1879 ◽  
Author(s):  
K L Rock ◽  
B Benacerraf
Keyword(s):  
T Cell ◽  
Antigen Processing ◽  
Competitive Inhibition ◽  
Present Report ◽  
Interleukin 2 ◽  
Lymphocyte Activation ◽  
Antigen Uptake ◽  
Accessory Cells ◽  
Antigen System ◽  
Antigen Presenting

Our previous studies have defined a highly specific competitive inhibition between a pair of structurally related antigens (GT and GAT) for antigen presentation by accessory cells. The present report investigates this phenomenon in a second antigenic system, which is controlled by a distinct Ir gene product. Two GL phi-specific, I-Ed-restricted, interleukin 2-producing T cell hybridomas were constructed. The antigenic fine specificity of these two hybrid clones was distinct. One hybrid reacted solely with GL phi while the second cross-reacted with GLleu and GLT. These latter two copolymers, as well as the antigen GL, were found to inhibit the GL phi response of the non-cross-reactive hybrid. The structurally related antigen G phi was not inhibitory for this clone's response. The cross-reactive GL phi hybrid could also be inhibited, but, in this case, G phi and not GL caused the inhibition. Reciprocal inhibitions could be demonstrated between these and other hybrids (e.g., GAT responsive), indicating a very high degree of specificity to the inhibition. The inhibition caused by the various copolymers was reversible by increasing the concentration of GL phi, This effect was localized to the antigen-presenting cell and not the T cell hybridoma. Functionally, this competition did not appear to be for antigen uptake or general antigen processing. These findings generalize the phenomenon of antigen competition to a second antigen system in the context of a second Ia molecule. The possible mechanisms accounting for the complex pattern of specificities in this system are discussed.

scholarly journals The Cell Surface Receptor SLAM Controls T Cell and Macrophage Functions

2004 ◽  
Vol 199 (9) ◽  
pp. 1255-1264 ◽  
Author(s):  
Ninghai Wang ◽  
Abhay Satoskar ◽  
William Faubion ◽  
Duncan Howie ◽  
Susumu Okamoto ◽  
...  
Keyword(s):  
T Cell ◽  
Measles Virus ◽  
Leishmania Major ◽  
Lymphocyte Activation ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Cell Surface Receptor ◽  
Mouse Macrophages ◽  
Surface Receptor ◽  
Antigen Presenting

Signaling lymphocyte activation molecule (SLAM), a glycoprotein expressed on activated lymphocytes and antigen-presenting cells, has been shown to be a coregulator of antigen-driven T cell responses and is one of the two receptors for measles virus. Here we show that T cell receptor–induced interleukin (IL)-4 secretion by SLAM−/− CD4+ cells is down-regulated, whereas interferon γ production by CD4+ T cells is only slightly up-regulated. Although SLAM controls production of IL-12, tumor necrosis factor, and nitric oxide in response to lipopolysaccharide (LPS) by macrophages, SLAM does not regulate phagocytosis and responses to peptidoglycan or CpG. Thus, SLAM acts as a coreceptor that regulates signals transduced by the major LPS receptor Toll-like receptor 4 on the surface of mouse macrophages. A defective macrophage function resulted in an inability of SLAM−/− C57Bl/6 mice to remove the parasite Leishmania major. We conclude that the coreceptor SLAM plays a central role at the interface of acquired and innate immune responses.

Sign in / Sign up

Export Citation Format

Share Document