scholarly journals Integrin-directed antibody-based immunotherapy: focus on VLA-4

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Wilson Savino ◽  
Beatriz Chaves ◽  
Adriana Cesar Bonomo ◽  
Vinicius Cotta-de-Almeida
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
Inflammatory Diseases ◽  
Heart Graft ◽  
Brain Infection ◽  
Number Of Patients ◽  
Endothelial Barriers ◽  
Activated T Lymphocytes ◽  
Leukocyte Influx

Summary One major finding of chronic inflammatory diseases of various origins is the establishment of inflammatory infiltrates, bearing different leukocyte subpopulations, including activated T lymphocytes. Integrins are among the large series of molecular interactions that have been implicated as players in both triggering and maintenance of leukocyte influx from the blood into a given organ parenchyme. Accordingly, blocking the interaction between VLA-6 integrin and laminin, experimentally abrogates heart graft rejection. Many reports have shown that VLA-4 is used by T cells to cross endothelial barriers, as well as to migrate within target tissues. In this respect, a humanized IgG4 anti-VLA-4 monoclonal antibody (specific to the α4-integrin chain of VLA-4) has been successfully applied to treat multiple sclerosis as well as inflammatory bowel disease. Anti-VLA-4 monoclonal antibody has also been applied to block transendothelial passage in other autoimmune diseases, such as rheumatoid arthritis. On this same vein is the action of such a reagent in impairing in vitro transendothial and fibronectin-driven migration of CD4+ and CD8+ T cells expressing high densities of VLA-4 from Duchenne muscular dystrophy patients, thus potentially enlarging the use of this strategy to other diseases. Yet, in a small number of patients, the use of Natalizumab has been correlated with the progressive multifocal leukoencephalopathy, a serious brain infection caused by the John Cunningham virus. This issue restricted the use of the reagent. In this respect, the development of smaller and more specific antibody reagents should be envisioned as a next-generation promising strategy.

scholarly journals Quantitative assessment of the pool size and subset distribution of cytolytic T lymphocytes within human resting or alloactivated peripheral blood T cell populations.

1983 ◽  
Vol 158 (2) ◽  
pp. 571-585 ◽  
Author(s):  
A Moretta ◽  
G Pantaleo ◽  
L Moretta ◽  
M C Mingari ◽  
J C Cerottini
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Peripheral Blood ◽  
Great Majority ◽  
T Cell Subsets ◽  
Cytolytic T Lymphocytes ◽  
Subset Distribution

In order to directly assess the distribution of cytolytic T lymphocytes (CTL) and their precursors (CTL-P) in the two major subsets of human T cells, we have used limiting dilution microculture systems to determine their frequencies. The two subsets were defined according to their reactivity (or lack thereof) with B9.4 monoclonal antibody (the specificity of which is similar, if not identical, to that of Leu 2b monoclonal antibody). Both B9+ and B9- cells obtained by sorting peripheral blood resting T cells using the fluorescence-activated cell sorter (FACS) were assayed for total CTL-P frequencies in a microculture system that allows clonal growth of every T cell. As assessed by a lectin-dependent assay, approximately 30% of peripheral blood T cells were CTP-P. In the B9+ subset (which represents 20-30% of all T cells), the CTL-P frequency was close to 100%, whereas the B9- subset had a 25-fold lower CTL-P frequency. It is thus evident that 90% and 10% of the total CTL-P in peripheral blood are confined to the B9+ or B9- T cell subsets, respectively. Analysis of the subset distribution of CTL-P directed against a given set of alloantigens confirmed these findings. CTL-P frequencies were also determined in B9+ and B9- subsets derived from T cells that had been activated in allogenic mixed leucocyte cultures (MLC). Approximately 10% of MLC T cells were CTL-P. This frequency was increased 3.5-fold in the B9+ subset, whereas the B9- subset contained only a small, although detectable number of CTL-P. Moreover, the great majority of the (operationally defined) CTL-P in MLC T cell population were found to be directed against the stimulating alloantigens, thus indicating a dramatic increase in specific CTL-P frequencies following in vitro stimulation in bulk cultures.

scholarly journals A Novel Role for IL-6 Receptor Classic Signaling: Induction of RORγt+Foxp3+ Tregs with Enhanced Suppressive Capacity

2019 ◽  
Vol 30 (8) ◽  
pp. 1439-1453 ◽  
Author(s):  
Julia Hagenstein ◽  
Simon Melderis ◽  
Anna Nosko ◽  
Matthias T. Warkotsch ◽  
Johannes V. Richter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Th17 Cells ◽  
Inflammatory Diseases ◽  
Double Positive ◽  
T Effector Cells ◽  
Suppressive Capacity

BackgroundNew therapies blocking the IL-6 receptor (IL-6R) have recently become available and are successfully being used to treat inflammatory diseases like arthritis. Whether IL-6 blockers may help patients with kidney inflammation currently remains unknown.MethodsTo learn more about the complex role of CD4+ T cell-intrinsic IL-6R signaling, we induced nephrotoxic nephritis, a mouse model for crescentic GN, in mice lacking T cell–specific IL-6Ra. We used adoptive transfer experiments and studies in reporter mice to analyze immune responses and Treg subpopulations.ResultsLack of IL-6Ra signaling in mouse CD4+ T cells impaired the generation of proinflammatory Th17 cells, but surprisingly did not ameliorate the course of GN. In contrast, renal damage was significantly reduced by restricting IL-6Ra deficiency to T effector cells and excluding Tregs. Detailed studies of Tregs revealed unaltered IL-10 production despite IL-6Ra deficiency. However, in vivo and in vitro, IL-6Ra classic signaling induced RORγt+Foxp3+ double-positive Tregs (biTregs), which carry the trafficking receptor CCR6 and have potent immunoregulatory properties. Indeed, lack of IL-6Ra significantly reduced Treg in vitro suppressive capacity. Finally, adoptive transfer of T cells containing IL-6Ra−/− Tregs resulted in severe aggravation of GN in mice.ConclusionsOur data refine the old paradigm, that IL-6 enhances Th17 responses and suppresses Tregs. We here provide evidence that T cell–intrinsic IL-6Ra classic signaling indeed induces the generation of Th17 cells but at the same time highly immunosuppressive RORγt+ biTregs. These results advocate caution and indicate that IL-6–directed therapies for GN need to be cell-type specific.

scholarly journals Activation of CD4+ T cells in the presence of a nondepleting monoclonal antibody to CD4 induces a Th2-type response in vitro.

1995 ◽  
Vol 182 (1) ◽  
pp. 5-13 ◽  
Author(s):  
P Stumbles ◽  
D Mason
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Primary Cultures ◽  
In Vitro Experiments ◽  
Ifn Gamma

In vitro experiments using purified rat CD4+ T cells in primary and secondary mixed leukocyte cultures (MLC) have been carried out to explore the mechanism of inhibition of cell-mediated autoimmune disease in the rat by a nondepleting monoclonal antibody (mAb) to CD4. Previous work has shown that W3/25, a mouse anti-rat CD4 mAb of immunoglobulin G1 isotype, completely prevents the development of the paralysis associated with experimental allergic encephalomyelitis (EAE) in Lewis rats, but does so without eliminating the encephalitogenic T cells. The in vitro experiments described in this study have shown that when CD4+ T cells were activated in the presence of the anti-CD4 mAb in a primary MLC, the synthesis of interferon (IFN) gamma, but not interleukin (IL) 2, was completely inhibited. After secondary stimulation, now in the absence of the mAb, the synthesis of IL-4 and IL-13 mRNA was greatly enhanced compared with that observed from CD4+ T cells derived from primary cultures in which the mAb was omitted. As IL-4 and IL-13 are known to antagonize cell-mediated immune reactions, and as EAE is cell-mediated disease, the data suggest that the W3/25 mAb controls EAE by modifying the cytokine repertoire of T cells that respond to the encephalitogen. The capacity for the mAb to suppress IFN-gamma synthesis provides, in part, an explanation for this change in cytokine production. These findings are discussed in terms of what is known of the factors that determine which cytokine genes are expressed on T cell activation. Possible implications for the evolution of T cell responses in human immunodeficiency virus infection are also discussed.

scholarly journals Alumina Ceramic Exacerbates the Inflammatory Disease by Activation of Macrophages and T Cells

2020 ◽  
Vol 21 (19) ◽  
pp. 7114
Author(s):  
Seong-Min Lim ◽  
Juyoung Hwang ◽  
Hae-Bin Park ◽  
Chan Ho Park ◽  
Jun-O Jin
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Fine Particles ◽  
Inflammatory Diseases ◽  
Artificial Joints ◽  
Al2o3 Ceramic ◽  
Adaptive Immune Cells ◽  
Materials Used

(1) Background: Aluminum oxide (Al2O3) ceramic is one of the materials used for artificial joints, and it has been known that their fine particles (FPs) are provided by the wear of the ceramic. Al2O3 FPs have been shown to induce macrophage activation in vitro; however, the inflammatory effect in vivo has not been studied. (2) Methods: We examined the in vivo effect of Al2O3 FPs on the innate and adaptive immune cells in the mice. (3) Results: Al2O3 FPs promoted the activation of spleen macrophages; however, conventional dendritic cells (cDCs), plasmacytoid DCs (pDCs), and natural killer (NK) cells were not activated. In addition, increases in the CD4 and CD8 T cells was induced in the spleens of the mice treated with Al2O3 FPs, which differentiated into interferon-gamma (IFN-γ)-producing helper T1 (Th1) and cytotoxic T1 (Tc1) cells. Finally, the injection of Al2O3 FPs exacerbated dextran sulfate sodium (DSS)-induced inflammation in the colon, mediated by activated and increased number of CD4 and CD8 T cells. (4) Conclusions: These data demonstrate that FPs of Al2O3 ceramic may contribute to the exacerbation of inflammatory diseases in the patients.

scholarly journals A Novel Approach for the Treatment of T Cell Malignancies: Targeting T Cell Receptor Vβ Families

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 631
Author(s):  
Jie Wang ◽  
Katarzyna Urbanska ◽  
Prannda Sharma ◽  
Reza Nejati ◽  
Lauren Shaw ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Lymphomas ◽  
Novel Approach ◽  
T Cell Malignancies

Peripheral T cell lymphomas (PTCLs) are generally chemotherapy resistant and have a poor prognosis. The lack of targeted immunotherapeutic approaches for T cell malignancies results in part from potential risks associated with targeting broadly expressed T cell markers, namely T cell depletion and clinically significant immune compromise. The knowledge that the T cell receptor (TCR) β chain in human α/β TCRs are grouped into Vβ families that can each be targeted by a monoclonal antibody can therefore be exploited for therapeutic purposes. Here, we develop a flexible approach for targeting TCR Vβ families by engineering T cells to express a chimeric CD64 protein that acts as a high affinity immune receptor (IR). We found that CD64 IR-modified T cells can be redirected with precision to T cell targets expressing selected Vβ families by combining CD64 IR-modified T cells with a monoclonal antibody directed toward a specific TCR Vβ family in vitro and in vivo. These findings provide proof of concept that TCR Vβ-family-specific T cell lysis can be achieved using this novel combination cell–antibody platform and illuminates a path toward high precision targeting of T cell malignancies without substantial immune compromise.

scholarly journals Context-Dependent Effect of Glucocorticoids on the Proliferation, Differentiation, and Apoptosis of Regulatory T Cells: A Review of the Empirical Evidence and Clinical Applications

2019 ◽  
Vol 20 (5) ◽  
pp. 1142 ◽  
Author(s):  
Luigi Cari ◽  
Francesca De Rosa ◽  
Giuseppe Nocentini ◽  
Carlo Riccardi
Keyword(s):  
T Cells ◽  
Treg Cell ◽  
Inflammatory Diseases ◽  
Treg Cells ◽  
Cell Number ◽  
Lymphoid Tissues ◽  
Treg Number ◽  
Context Dependent

Glucocorticoids (GCs) are widely used to treat several diseases because of their powerful anti-inflammatory and immunomodulatory effects on immune cells and non-lymphoid tissues. The effects of GCs on T cells are the most relevant in this regard. In this review, we analyze how GCs modulate the survival, maturation, and differentiation of regulatory T (Treg) cell subsets into both murine models and humans. In this way, GCs change the Treg cell number with an impact on the mid-term and long-term efficacy of GC treatment. In vitro studies suggest that the GC-dependent expansion of Treg cells is relevant when they are activated. In agreement with this observation, the GC treatment of patients with established autoimmune, allergic, or (auto)inflammatory diseases causes an expansion of Treg cells. An exception to this appears to be the local GC treatment of psoriatic lesions. Moreover, the effects on Treg number in patients with multiple sclerosis are uncertain. The effects of GCs on Treg cell number in healthy/diseased subjects treated with or exposed to allergens/antigens appear to be context-dependent. Considering the relevance of this effect in the maturation of the immune system (tolerogenic response to antigens), the success of vaccination (including desensitization), and the tolerance to xenografts, the findings must be considered when planning GC treatment.

scholarly journals BINDING OF AGGREGATED γ-GLOBULIN TO ACTIVATED T LYMPHOCYTES IN THE GUINEA PIG

1974 ◽  
Vol 139 (4) ◽  
pp. 1002-1012 ◽  
Author(s):  
John A. van Boxel ◽  
David L. Rosenstreich
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Lymphocytes ◽  
Guinea Pig ◽  
Surface Membrane ◽  
Cell Populations ◽  
Cell Marker ◽  
Activated T Cells ◽  
Activated T Lymphocytes

Heat-aggregated guinea pig γ-globulin was shown to bind to the surface membrane of a subclass of guinea pig T lymphocytes. Cells of this subpopulation were identified as T lymphocytes because these cells did not stain for surface Ig (a B-cell marker) but did form spontaneous E-rosettes with rabbit erythrocytes (a T-cell marker). A strikingly high proportion of such aggregate-binding (Agg+), E-rosette-forming (E-rosette+), but surface Ig-negative (Ig-) cells were found in an inflammatory exudate. Thus purified peritoneal exudate lymphocytes (PELs) are known to consist of over 90% T cells, and 59% of these cells bound aggregates. 10% of these Agg+ Ig- E-rosette+ cells were found in draining lymph node cell populations and none in thymus cell populations. The high frequency amongst PELs suggested that these Aggregate+ Ig- E-rosette+ cells might be activated T cells as these are known to occur in high proportion in PEL populations. Confirmatory evidence for this postulate was provided by the striking increase (from 10% to 46%) of Ig- E-rosette+ cells that bound aggregates when lymph node cells were activated by antigen stimulation in vitro.

scholarly journals Role of PD-L1 in licensing immunoregulatory function of dental pulp mesenchymal stem cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rosanna Di Tinco ◽  
Giulia Bertani ◽  
Alessandra Pisciotta ◽  
Laura Bertoni ◽  
Elisa Pignatti ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Dental Pulp ◽  
Inflammatory Diseases ◽  
Activated T Cells ◽  
Indirect Contact ◽  
Inflammatory Microenvironment ◽  
Inflammatory Status ◽  
Immunomodulatory Properties

Abstract Background Dental pulp stem cells (DPSCs) are low immunogenic and hold immunomodulatory properties that, along with their well-established multi-potency, might enhance their potential application in autoimmune and inflammatory diseases. The present study focused on the ability of DPSCs to modulate the inflammatory microenvironment through PD1/PD-L1 pathway. Methods Inflammatory microenvironment was created in vitro by the activation of T cells isolated from healthy donors and rheumatoid arthritis (RA) patients with anti-CD3 and anti-CD28 antibodies. Direct and indirect co-cultures between DPSCs and PBMCs were carried out to evaluate the activation of immunomodulatory checkpoints in DPSCs and the inflammatory pattern in PBMCs. Results Our data suggest that the inflammatory stimuli trigger DPSCs immunoregulatory functions that can be exerted by both direct and indirect contact. As demonstrated by using a selective PD-L1 inhibitor, DPSCs were able to activate compensatory pathways targeting to orchestrate the inflammatory process by modulating pro-inflammatory cytokines in pre-activated T lymphocytes. The involvement of PD-L1 mechanism was also observed in autologous inflammatory status (pulpitis) and after direct exposure to pre-activated T cells from RA patients suggesting that immunomodulatory/anti-inflammatory properties are strictly related to their stemness status. Conclusions Our findings point out that the communication with the inflammatory microenvironment is essential in licensing their immunomodulatory properties.

The Potential of T Cell Immunoglobulin and Mucin-Domain containing-3 (Tim-3) in Designing Novel Immunotherapy for Bladder Cancer

2021 ◽  
Vol 21 ◽  
Author(s):  
Monireh Mohsenzadegan ◽  
Parizad Bavandpour ◽  
Mohammad Reza Nowroozi ◽  
Erfan Amini ◽  
Masoumeh Kourosh-Arami ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
Checkpoint Inhibitors ◽  
Number Of Patients ◽  
Anti Cancer ◽  
Domain 3

: Targeting inhibitory receptors on T cells in the tumor sites can promote effective anti-tumor immunity in bladder cancer. Unfortunately, the main dilemma is that a large number of patients remain refractory to CTLA-4, PD-1, and PD-L1 blockade therapies. T-cell immunoglobulin and mucin domain 3 (Tim-3) is an inhibitory receptor expressed on T cells and innate immune cells. Both in vivo and in vitro data from patients with advanced cancers support the role of Tim-3 inhibition in satisfactory anti-tumor immunity. In bladder cancer, the expression level of Tim-3 significantly increases with advanced pathological grade and T stage. Therefore, rationality implies that designing novel monoclonal antibodies reactive with Tim-3 alone or in combination with other checkpoint inhibitors may indicate a favorable response in bladder cancer. Here, we aimed to investigate the possibility of targeting Tim-3 as a novel anti-cancer treatment for bladder cancer.

CD38 Expression in B-CLL Is Dynamic and Changes Due to Contact with Activating Stimuli Found within the Leukaemic Microenvironment.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2798-2798 ◽  
Author(s):  
Piers E.M. Patten ◽  
Andrea G.S. Buggins ◽  
Julie Richards ◽  
Andrew Wotherspoon ◽  
Terry John Hamblin ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Division ◽  
Mononuclear Cells ◽  
Proliferative Potential ◽  
Activated T Cells ◽  
Peripheral Blood Mononuclear ◽  
Cd38 Expression ◽  
Close Proximity ◽  
Activated T Lymphocytes

Abstract High levels of CD38 expression in B-cell chronic lymphocytic leukaemia (B-CLL) confer a poor prognosis. Although its role in B-CLL is unknown, signalling through CD38 has been implicated in cell survival, trafficking and proliferation. Since proliferation in B-CLL is thought to take place within both bone marrow (BM) and secondary lymphoid tissue, we investigated whether CD38 expression might vary in response to stimuli that occur in these tissue compartments. Firstly, we compared the percentage CD38 expression of CD5/19 cells on 35 paired PB and BM aspirate B-CLL samples. The mean CD38% was significantly higher in BM than PB in all samples (27% vs 19%, p=0.009) including samples with a PB CD38 of 7% or more (33% vs 42%, p=0.047), indicating that factors present in the BM up regulate CD38 expression. Next, CD38 expression and cell division of B-CLL peripheral blood mononuclear cells (PBMCs) were examined in an in vitro system aimed at mimicking the proliferation centre microenvironment where leukaemic cells are situated in close proximity to activated T lymphocytes. Positively selected T cells from 15 B-CLL patients were activated overnight with CD3/28 beads and subsequently cultured with autologous B-CLL PBMCs. Both the percentage of CD19+ CD38+ cells (29.9% vs 59.9%, p=0.003) and CD38 mean fluorescence intensity (75.1 vs 830.8, p=0.005) increased over the 6 day culture period. B-CLL cell division was assessed using the dye carboxyfluorescein diacetate succinimidyl ester (CFSE) in the same co-culture system. This showed that co-culture with autologous activated T-cells can result in B-CLL cell division, and is preceded by CD38 up regulation. In addition, significantly more B-CLL cells underwent at least one division from patients with an initial CD38 level of 7% or more, as compared to under 7% (24.6% vs 10.9%, p=0.031). To further investigate the relationship between B-CLL cell proliferation, CD38 expression and the role of T-cells we examined tissue sections known to contain paraimmunoblasts and other proliferating B-CLL cells. Four colour confocal microscopy using CD3, Ki67, CD38 and CD23 to label frozen B-CLL lymph nodes was employed. Large Ki67+ CD23+ cells were present in close proximity to CD3+ T-cells and these large B-CLL cells had higher CD38 expression than the surrounding small B-CLL lymphocytes. These results support the proposal that CD38 expression in B-CLL is dynamic and may reflect exposure to T-cell derived stimuli which contribute to proliferation in the BM or LN microenvironment. A possible explanation for the poorer prognosis of patients with higher CD38 expression may be that their disease has more proliferative potential.

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