Rituximab for the Treatment of Graves’ Orbitopathy

2011 ◽  
Vol 07 (02) ◽  
pp. 130
Author(s):  
Mario Salvi ◽  
Guia Vannucchi ◽  
Paolo Beck-Peccoz ◽  
◽  
◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Plasma Cells ◽  
Cell Function ◽  
Therapeutic Option ◽  
Therapeutic Benefit ◽  
Graves Orbitopathy

The contribution of B-cells to human autoimmune disease has recently been underscored because of the therapeutic benefit of B-cell depleting therapies. B-cells are involved in the production of autoantibodies, and in CD4+ T-cell activation, control of T-cell function, and inflammation through cytokine production. B-cells are also important antigen-presenting cells. Rituximab (RTX) has been used off-label in various autoimmune disorders and has been shown to effectively deplete mature and memory CD20+ B-cells, but not long-lived plasma cells. The rationale behind the use of RTX in Graves’ disease (GD) and Graves’ orbitopathy (GO) relies on its putative effect on pathogenic autoantibodies causing hyperthyroidism. RTX in patients with active GO has been shown to have a significant effect on the inflammatory activity and severity of GO. However, caution is suggested before proposing RTX as a novel therapeutic tool in this disease until randomized controlled trials are available. Should preliminary observations be confirmed, an optimal strategy for controlling the progression of GO would be to pursue B-cell depletion shortly after diagnosis, rather than only as an alternative therapeutic option when standard immunosuppression has failed.

Rituximab for the Treatment of Graves’ Orbitopathy

2010 ◽  
Vol 7 (2) ◽  
pp. 108
Author(s):  
Mario Salvi ◽  
Guia Vannucchi ◽  
Paolo Beck-Peccoz ◽  
◽  
◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Plasma Cells ◽  
Cell Function ◽  
Therapeutic Option ◽  
Therapeutic Benefit ◽  
Graves Orbitopathy

The contribution of B cells to human autoimmune disease has recently been underscored because of the therapeutic benefit of B-cell depleting therapies. B cells are involved in the production of autoantibodies and in CD4+ T-cell activation and control of T-cell function and inflammation, through cytokine production. B cells are also important antigen presenting cells. Rituximab (RTX) has been used off-label in various autoimmune disorders and has been shown to effectively deplete mature and memory CD20+ B cells, but not long-lived plasma cells. The rationale of RTX use in Graves’ disease (GD) and Graves’ orbitopathy (GO) relies on its putative effect on pathogenic autoantibodies causing hyperthyroidism. RTX in patients with active GO has been shown to significantly affect the inflammatory activity and severity of GO. Caution is suggested before proposing RTX as a novel therapeutic tool in this disease until randomised controlled studies are available. Should preliminary observations be confirmed, an optimal strategy for controlling the progression of GO would be to pursue B-cell depletion shortly after diagnosis and not as an additional therapeutic option when standard immunosuppression has failed.

scholarly journals 702 Dual blockade of the PD-1 checkpoint pathway and the adenosinergic negative feedback signaling pathway with a PD-1/CD73 bispecific antibody for cancer immune therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A744-A744
Author(s):  
Tingting Zhong ◽  
Zhaoliang Huang ◽  
Xinghua Pang ◽  
Na Chen ◽  
Xiaoping Jin ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Negative Feedback ◽  
Immune Suppression ◽  
Specific Antibody ◽  
Cell Activation ◽  
Immune Therapy ◽  
B Cell Activation

BackgroundCD73 (ecto-5’-nucleotidase) is an ecto-nucleotidase that dephosphorylate AMP to form adenosine. Activation of adenosine signaling pathway in immune cells leads to the suppression of effector functions, down-regulate macrophage phagocytosis, inhibit pro-inflammatory cytokine release, as well as yield aberrantly differentiated dendritic cells producing pro-tumorigenic molecules.1 In the tumor microenvironment, adenosinergic negative feedback signaling facilitated immune suppression is considered an important mechanism for immune evasion of cancer cells.2 3 Combination of CD73 and anti-PD-1 antibody has shown promising activity in suppressing tumor growth. Hence, we developed AK119, an anti- human CD73 monoclonal antibody, and AK123,a bi-specific antibody targeting both PD-1 and CD73 for immune therapy of cancer.MethodsAK119 is a humanized antibody against CD73 and AK123 is a tetrameric bi-specific antibody targeting PD-1 and CD73. Binding assays of AK119 and AK123 to antigens, and antigen expressing cells were performed by using ELISA, Fortebio, and FACS assays. In-vitro assays to investigate the activity of AK119 and AK123 to inhibit CD73 enzymatic activity in modified CellTiter-Glo assay, to induce endocytosis of CD73, and to activate B cells were performed. Assay to evaluate AK123 activity on T cell activation were additionally performed. Moreover, the activities of AK119 and AK123 to mediate ADCC, CDC in CD73 expressing cells were also evaluated.ResultsAK119 and AK123 could bind to its respective soluble or membrane antigens expressing on PBMCs, MDA-MB-231, and U87-MG cells with high affinity. Results from cell-based assays indicated that AK119 and AK123 effectively inhibited nucleotidase enzyme activity of CD73, mediated endocytosis of CD73, and induced B cell activation by upregulating CD69 and CD83 expression on B cells, and showed more robust CD73 blocking and B cell activation activities compared to leading clinical candidate targeting CD73. AK123 could also block PD-1/PD-L1 interaction and enhance T cell activation.ConclusionsIn summary, AK119 and AK123 represent good preclinical biological properties, which support its further development as an anti-cancer immunotherapy or treating other diseases.ReferencesDeaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007; 204:1257–65.Huang S, Apasov S, Koshiba M, Sitkovsky M. Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood. 1997; 90:1600–10.Novitskiy SV, Ryzhov S, Zaynagetdinov R, Goldstein AE, Huang Y, Tikhomirov OY, Blackburn MR, Biaggioni I,Carbone DP, Feoktistov I, et al. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 2008; 112:1822–31.

Cellular side of acquired immunity (B cells)

2013 ◽  
pp. 371-378
Author(s):  
Thomas Dörner ◽  
Peter E. Lipsky
Keyword(s):  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Plasma Cells ◽  
Adaptive Immune System ◽  
Adaptive Immune ◽  
B Cell Homeostasis ◽  
Anti Cd20 ◽  
Antigen Presenting

B cells have gained interest in rheumatoid arthritis (RA) beyond being the precursors of antibody-producing plasma cells since they are also a broader component of the adaptive immune system. They are capable of functioning as antigen-presenting cells for T-cell activation and can produce an array of cytokines. Disturbances of peripheral B-cell homeostasis together with the formation of ectopic lymphoid neogenesis within the inflamed synovium appears to be a characteristic of patients with RA. Enhanced generation of memory B cells and autoreactive plasma cells producing IgM-RF and ACPA-IgG antibodies together with formation of immune complexes contribute to the maintenance of RA, whereas treatment with B-cell-directed anti-CD20 and CLTA4-Ig therapy provides clinical benefit.

T cell activation by anti-CD3 antibodies: function of Fc receptors on B cell blasts, but not resting B cells, and CD18 on the responding T cells

1987 ◽  
Vol 17 (9) ◽  
pp. 1329-1335 ◽  
Author(s):  
Jonathan M. Austyn ◽  
Kenneth G. C. Smith ◽  
Peter J. Morris
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Fc Receptors

scholarly journals CD4+ T cell activation and tolerance induction in B cell knockout mice.

1996 ◽  
Vol 183 (4) ◽  
pp. 1339-1344 ◽  
Author(s):  
J A Phillips ◽  
C G Romball ◽  
M V Hobbs ◽  
D N Ernst ◽  
L Shultz ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Knockout Mice ◽  
Cell Activation ◽  
Peripheral Tolerance ◽  
Cd4 T Cell ◽  
T Cell Tolerance ◽  
Cell Tolerance

B cell knockout mice microMT/microMT were used to examine the requirement for B cell antigen (Ag) presentation in the establishment of CD4+ T cell tolerance. CD4+T cells from microMT mice injected with exogenous protein Ag in adjuvant responded to in vitro challenge by transcription of cytokine mRNA, cytokine secretion, and proliferation. Peripheral tolerance could be established in microMT mice with a single dose of deaggragated protein. This tolerance was manifested by a loss of T cell proliferation and cytokine production (including both T helper cell type 1 [Th1]- and Th2-related cytokines), indicating that B cells are not required for the induction of peripheral T cell tolerance and suggesting that the dual zone tolerance theory is not applicable to all protein Ags and is not mediated through Ag presentation by B cells.

scholarly journals Immunoglobulin switch transcript production in vivo related to the site and time of antigen-specific B cell activation.

1996 ◽  
Vol 183 (5) ◽  
pp. 2303-2312 ◽  
Author(s):  
K M Toellner ◽  
A Gulbranson-Judge ◽  
D R Taylor ◽  
D M Sze ◽  
I C MacLennan
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Messenger Rna ◽  
Cell Activation ◽  
Plasma Cells ◽  
Cell Interaction ◽  
Primary Response ◽  
Antibody Responses

Immunoglobulin (Ig) class switch recombination is associated with the production and splicing of germline IgCH messenger RNA transcripts. Levels of gamma 1 transcripts in mouse spleen sections were assessed by semiquantitative analysis of reverse transcriptase polymerase chain reaction (PCR) products during primary and secondary antibody responses to chicken gamma globulin (CGG). This was correlated with the appearance of CGG-specific B cells and their growth and differentiation to plasma cells. After primary immunization with CGG, gamma 1 switch transcripts appeared after 4 d, peaked at a median of six times starting levels between 10 and 18 d after immunization, and returned to background levels before secondary immunization at 5 wk. By contrast, after secondary challenge with CGG, a sevenfold increase in transcripts occurs during the first d. The level again doubles by day 3, when it is six times that which is seen at the peak of the primary response. After day 4, there was a gradual decline over the next 2-3 wk. Within 12 h of secondary immunization, antigen-specific memory B cells appeared in the outer I zone and by 24 h entered S phase, presumably as a result of cognate interaction with primed T cells. Over the next few hours, they migrated to the edge of the red pulp, where they grew exponentially until the fourth day, when they synchronously differentiated to become plasma cells. The same pattern was seen for the migration, growth, and differentiation of virgin hapten-specific B cells when CGG-primed mice were challenged with hapten protein. The continued production of transcripts after day 3 indicates that switching also occurs in germinal centers, but in a relatively small proportion of their B cells. The impressive early production of switch transcripts during T cell-dependent antibody responses occurs in cells that are about to undergo massive clonal expansion. It is argued that Ig class switching at this time, which is associated with cognate T cell-B cell interaction in the T zone, has a major impact on the class and subclasses of Ig produced during the response.

scholarly journals B Cells in Patients With Melanoma: Implications for Treatment With Checkpoint Inhibitor Antibodies

2021 ◽  
Vol 11 ◽  
Author(s):  
Zena N. Willsmore ◽  
Robert J. Harris ◽  
Silvia Crescioli ◽  
Khuluud Hussein ◽  
Helen Kakkassery ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Response To Treatment ◽  
Cell Immunity ◽  
Cell Phenotypes

The contributions of the humoral immune response to melanoma are now widely recognized, with reports of positive prognostic value ascribed to tumor-infiltrating B cells (TIL-B) and increasing evidence of B cells as key predictors of patient response to treatment. There are disparate views as to the pro- and anti-tumor roles of B cells. B cells appear to play an integral role in forming tumor-associated tertiary lymphoid structures (TLSs) which can further modulate T cell activation. Expressed antibodies may distinctly influence tumor regulation in the tumor microenvironment, with some isotypes associated with strong anti-tumor immune response and others with progressive disease. Recently, B cells have been evaluated in the context of cancer immunotherapy. Checkpoint inhibitors (CPIs), targeting T cell effector functions, have revolutionized the management of melanoma for many patients; however, there remains a need to accurately predict treatment responders. Increasing evidence suggests that B cells may not be simple bystanders to CPI immunotherapy. Mature and differentiated B cell phenotypes are key positive correlates of CPI response. Recent evidence also points to an enrichment in activatory B cell phenotypes, and the contribution of B cells to TLS formation may facilitate induction of T cell phenotypes required for response to CPI. Contrastingly, specific B cell subsets often correlate with immune-related adverse events (irAEs) in CPI. With increased appreciation of the multifaceted role of B cell immunity, novel therapeutic strategies and biomarkers can be explored and translated into the clinic to optimize CPI immunotherapy in melanoma.

Cellular side of acquired immunity (B cells)

2013 ◽  
Author(s):  
Thomas Dörner ◽  
Peter E. Lipsky
Keyword(s):  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Plasma Cells ◽  
Adaptive Immune System ◽  
Adaptive Immune ◽  
B Cell Homeostasis ◽  
Anti Cd20 ◽  
Antigen Presenting

B cells have gained interest in rheumatoid arthritis (RA) beyond being the precursors of antibody-producing plasma cells since they are also a broader component of the adaptive immune system. They are capable of functioning as antigen-presenting cells for T-cell activation and can produce an array of cytokines. Disturbances of peripheral B-cell homeostasis together with the formation of ectopic lymphoid neogenesis within the inflamed synovium appears to be a characteristic of patients with RA. Enhanced generation of memory B cells and autoreactive plasma cells producing IgM-RF and ACPA-IgG antibodies together with formation of immune complexes contribute to the maintenance of RA, whereas treatment with B-cell-directed anti-CD20 therapy provides clinical benefit.

Immunological Profile and Safety Evaluation in a 23-Week Single Dose Study in Cynomolgus Monkey with CHIR-12.12, a Fully Human Antagonist Anti-CD40 Antibody.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4638-4638 ◽  
Author(s):  
Ursula B. Jeffry ◽  
Mohammad Luqman ◽  
Kay Huh ◽  
Julie Klinger ◽  
Werner Frings ◽  
...  
Keyword(s):  
Single Dose ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
B Cell Depletion ◽  
Igg Antibodies ◽  
Cd40 Expression

Abstract CD40 is highly expressed in B-cell malignancies and its activation is a growth and survival signal for these cells. We have generated a novel, highly potent, fully human anti-CD40 IgG1 monoclonal antibody, CHIR-12.12 using XenoMouse® mice (Abgenix, Inc), a strain of transgenic mice expressing fully human IgG antibodies. CHIR-12.12 has at least two mechanisms of cytotoxicity in vitro: it blocks CD40-ligand mediated CD40 activation and mediates B-cell killing by ADCC. In-vitro crossreactivity studies were performed and the antibody showed cross reactivity to non-human primate but not to rodent tissue. To investigate the potential long-term toxicity of the antibody and to observe the recovery of the induced B-cell depletion, a single-dose toxicity study was conducted in cynomolgus monkeys. Three animals per sex per group (two animals per sex in control group) were given a single intravenous dose of 0, 10, or 100 mg/kg CHIR-12.12 and were monitored for 23 weeks post dosing. In addition to a detailed physical examination, samples for clinical chemistry, hematology and coagulation parameters as well as urinalysis were taken every 2 weeks. FACS analyses were performed every two weeks to monitor changes in B-cell, T-cell subpopulation and NK-cell numbers. In addition, CD40 expression and antigen saturation were measured on the remaining B-cell populations over 23 weeks. To investigate T-cell activation and T-cell function after CHIR-12.12 dosing, CD25 and CD40 expression on T-cells were monitored and at Week 23 a Mixed Lymphocyte Reaction (MLR) test was performed. The results of the study showed that a single dose of CHIR-12.12 was well tolerated and did not elicit any adverse clinical signs or effect on body weights, clinical pathology and hematology including differential blood counts. Immunophenotyping analysis showed a dramatic reduction of B-cells after dosing. The remaining B-cells mostly consist of the CD20high CD40low population, which is a population uniquely found in cynomolgus monkey blood but not in human blood (Vugmeyster et al.; Cytometry. 2003 Apr;52A). Both treatment groups showed a recovery of B-cells to normal pre-dose values in the majority of animals 19 weeks after dosing. In contrast, the average CHIR-12.12 antigen saturation level returned to pre-dose values in the low dose group after 11 weeks and in the high dose group after 19 weeks. T-cell counts (CD3, CD4 and CD8 subpopulation) showed no treatment related changes in absolute cell numbers throughout the study. No changes in T-cell activation measured by CD25 and CD40 expression were detected. T-cell responsiveness was not altered as measured by MLR. The pharmacokinetic analysis showed that, consistent with other human IgG antibodies, CHIR-12.12 had a small volume of distribution, limited to the blood volume, and was slowly eliminated from the circulation. Dose-dependency was observed with the area under serum concentration-time curve (AUC) increasing in a greater than dose-proportional fashion. Likewise, the half-life also increased with dose, ranging from 10.3 days at 10 mg/kg to 16.8 days at 100 mg/kg. In conclusion, all animals remained healthy and no evidence of immune impairment other then the expected reversible B-cell depletion was detected with a single dose of CHIR-12.12 up to 100 mg/kg. These results support the clinical development of CHIR-12.12 antibody for treatment of B-cell malignancies.

T Cell Pathway Deficiencies in Chronic Lymphocityc Leukemia: Partial Restoration with OKT3/IL-2 Activation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4692-4692
Author(s):  
Mauro Di Ianni ◽  
Lorenzo Moretti ◽  
Beatrice Del Papa ◽  
Maria De Ioanni ◽  
Adelmo Terenzi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Activated T Cells ◽  
Mutational Status ◽  
The Impact

Abstract As Chronic Lymphocytic Leukemia (CLL) is associated with several defects in the T cell compartment, the impact of tumour burden on the autologous immune system was studied. Gene expression profiles (using Applied Biosystem Human Genome Microarray) identified 237 genes with significantly increased expression and 221 genes with significantly decreased expression (p<0.05) in CD3+ cells from CLL patients compared with healthy donors. Panther software analysis identified 34/237 upregulated genes and 26/221 downregulated genes that were involved in specific pathways, mainly cell differentiation and proliferation, survival, apoptosis, cytoskeleton formation, vesicle trafficking and T cell activation. The 26 dowregulated genes included Zap70, a member of the syk family protein tyrosine kinase, which is involved in T-cell activation. Zap-70 results were validated by mRNA quantification by RT-PCR (−1.77 fold in comparison with healthy controls) and by flow-cytometric analysis (Mean Intensity Fluorescence=33±12 vs 80±23.62 in controls, p<0.05). To test the hypothesis that activation with OKT3 /IL-2 could bypass these T cell deficiencies, activated T cells from 20 patients with CLL were tested in vitro for cytotoxicity (using the 51chromium release assay) against mutated and unmutated (according to IgVH mutational status) autologous B cells, DAUDI, K562 and P815 cell lines. After 10 days’ culture, the T cell count remained unchanged; CD8 cells expanded more than CD4; TCR spectratyping analysis indicated no differences in TCR repertoires. Activation restored the ZAP-70 mRNA (+1.67 fold). The 51chromium release cytotoxicity assay showed an index > 30% in 5/20 patients. The other 15 were partially cytotoxic against P815, K562 and Daudi. Cell line analysis in all 20 confirmed prevalently T cell-mediated cytotoxicity and poor NK/LAK activity. Cytotoxicity did not correlate with B cell mutational status. We tested the cytotoxic activity of autologous activated T cells in NOD/SCID mice co-transplanted with leukaemic B cells. Only activated T cells exerting cytotoxicity vs autologous B-cell CLL prevent CLL in human-mouse chimera, as confirmed by PCR and FACS analysis which visualised only CD3+ cells. In conclusion, in patients with CLL, activating autologous T cells with OKT3 /IL-2 bypasses, at least in part, the T cell immunological deficiencies. These in vitro and in vivo findings might serve to throw light on new mechanisms that could be exploited in immunotherapy designed to exert disease control.

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