scholarly journals POS1356 PERSISTENCE OF TFH CELLS AFTER RITUXIMAB IS ASSOCIATED WITH IGG4-RELATED DISEASE RELAPSE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 960.2-960
Author(s):  
G. Mancuso ◽  
T. Jofra ◽  
M. Lanzillotta ◽  
J. Gerosa ◽  
G. DI Colo ◽  
...  
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Peripheral Blood ◽  
De Novo ◽  
Cell Depletion ◽  
P Value ◽  
B Cell Depletion ◽  
Related Disease ◽  
Tfh Cells ◽  
Igg4 Related Disease

Background:Clinical improvement after B-cell depletion with rituxmab suggests a prominent pathogenic role of B-lymphcytes in IgG4-related disease (IgG4-RD). IgG4-RD, however, relapses in most cases together with re-expansion of clonally divergent plasmablasts indicating that treatment with rituximab does not completely abrogates T follicular helper (Tfh)-cells dependent germinal center reactions leading to de-novo plasmablast differentiation.Objectives:In the present work we aim to study the effects of B-cell depletion therapy with rituximab on circulating Tfh cells and on the levels of CXCL13 - a chemotactic factor for B-lymphocytes produced by Tfh cells - in patients with IgG4-RD.Methods:Thirty patients with IgG4-RD, diagnosed according to the “Consensus Statement on the Pathology of IgG4-RD” and fulfilling the “2019 ACR/EULAR Classification Criteria” were included in the present study. Ten patients with relapsing disease were treated with the anti-CD20 monoclonal antibody rituximab (two 1g infuxions 15 days apart). Peripheral blood mononuclear cells and serum were collected before rituximab and three months after infusion. Tfh cells subsets in the peripheral blood were measured by flow cytometry and CXCL13 plasma levels were measured by ELISA assay.Results:No changes in total Tfh cells and Tfh cells subsets were observed three months after rituximab neither in absolute counts nor in percentage of CD4+ T cells. In particular, no difference in Tfh1, Tfh2, Tfh17, T follicular regulatory and highly functional Tfh cells counts was observed before and after treatment. The serum level of CXCL13 was significantly higher in active untreated IgG4-RD patients compared to healthy controls (151.94 pg/ml vs 66.98 pg/ml, p value = 0.0026), but was not affected by rituximab treatment (p value = 0.41).Conclusion:In relapsing patients with IgG4-RD rituximab does not affect circulating Tfh cells numbers and serum levels of CXCL13. Persistence of Tfh cells after rituximab and reconstitution of germinal center reactions likely drives IgG4-RD flare.References:[1]Lanzillotta M, Mancuso G, Della-Torre E. Advances in the diagnosis and management of IgG4 related disease. BMJ. 2020 Jun 16;369:m1067. doi: 10.1136/bmj.m1067. PMID: 32546500.[2]Lanzillotta M, Della-Torre E, Stone JH. Roles of Plasmablasts and B Cells in IgG4-Related Disease: Implications for Therapy and Early Treatment Outcomes. Curr Top Microbiol Immunol. 2017;401:85-92. doi: 10.1007/82_2016_58. PMID: 28091934.[3]Campochiaro C, Ramirez GA, Bozzolo EP, Lanzillotta M, Berti A, Baldissera E, Dagna L, Praderio L, Scotti R, Tresoldi M, Roveri L, Mariani A, Balzano G, Castoldi R, Doglioni C, Sabbadini MG, Della-Torre E. IgG4-related disease in Italy: clinical features and outcomes of a large cohort of patients. Scand J Rheumatol. 2016;45(2):135-45. doi: 10.3109/03009742.2015.1055796. Epub 2015 Sep 23. PMID: 26398142.[4]Mattoo H, Mahajan VS, Della-Torre E, Sekigami Y, Carruthers M, Wallace ZS, Deshpande V, Stone JH, Pillai S. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J Allergy Clin Immunol. 2014 Sep;134(3):679-87. doi: 10.1016/j.jaci.2014.03.034. Epub 2014 May 6. PMID: 24815737; PMCID: PMC4149918.Disclosure of Interests:None declared

scholarly journals B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease

2014 ◽  
Vol 74 (12) ◽  
pp. 2236-2243 ◽  
Author(s):  
Emanuel Della-Torre ◽  
Eoin Feeney ◽  
Vikram Deshpande ◽  
Hamid Mattoo ◽  
Vinay Mahajan ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Related Disease ◽  
Igg4 Related Disease ◽  
Serological Biomarkers

Steady-state generation of mucosal IgA+ plasmablasts is not abrogated by B-cell depletion therapy with rituximab

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5181-5190 ◽  
Author(s):  
Henrik E. Mei ◽  
Daniela Frölich ◽  
Claudia Giesecke ◽  
Christoph Loddenkemper ◽  
Karin Reiter ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Steady State ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Ki 67

AbstractThe anti-CD20 antibody rituximab depletes human B cells from peripheral blood, but it remains controversial to what extent tissue-resident B cells are affected. In representative patients with rheumatoid arthritis, we here demonstrate that recently activated presumably short-lived plasmablasts expressing HLA-DRhigh and Ki-67 continuously circulate in peripheral blood after B-cell depletion by rituximab at 26%-119% of their initial numbers. They circulate independent of splenectomy, express immunoglobulin A (IgA), β7 integrin, and C-C motif receptor 10 (CCR10) and migrate along CCL28 gradients in vitro, suggesting their mucosal origin. These plasmablasts express somatically hypermutated VH gene rearrangements and spontaneously secrete IgA, exhibiting binding to microbial antigens. Notably, IgA+ plasmablasts and plasma cells were identified in the lamina propria of patients treated with rituximab during peripheral B-cell depletion. Although a relation of these “steady state”–like plasmablasts with rheumatoid arthritis activity could not be found, their persistence during B-cell depletion indicates that their precursors, that is, B cells resident in the mucosa are not deleted by this treatment. These data suggest that a population of mucosal B cells is self-sufficient in adult humans and not replenished by CD20+ B cells immigrating from blood, lymphoid tissue, or bone marrow, that is, B cells depleted by rituximab.

AB0033 B Cell Depletion by Rituximab in Lymphocyte Subpopupulations from Peripheral Blood in Patients with Rheumatoid Arthritis

2015 ◽  
Vol 74 (Suppl 2) ◽  
pp. 901.2-901
Author(s):  
L. Merino Meléndez ◽  
J. Lόpez Lόpez ◽  
I. Llorente ◽  
S. Castañeda Sanz ◽  
F. Herrera ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cell ◽  
Peripheral Blood ◽  
Cell Depletion ◽  
B Cell Depletion

HuMax-CD20 Fully Human Monoclonal Antibody in Follicular Lymphoma. First Human Exposure: Early Results of an Ongoing Phase I/II Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1400-1400 ◽  
Author(s):  
Anton Hagenbeek ◽  
Torben Plesner ◽  
Jan Walewski ◽  
Andrzej Hellmann ◽  
Brian K. Link ◽  
...  
Keyword(s):  
B Cells ◽  
Adverse Events ◽  
B Cell ◽  
Cell Count ◽  
Peripheral Blood ◽  
Tumor Response ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Cell Counts ◽  
Grade 3

Abstract HuMax-CD20 is a fully human monoclonal IgG1 antibody targeting a unique extracellular epitope of the CD20 molecule on B-cells. HuMax-CD20 stops growth of engrafted B-cell tumors in SCID mouse tumor models more efficiently than Rituximab®, and i.v. infusion of HuMax-CD20 in cynomolgus monkeys has led to profound, long lasting, dose-dependent B-cell depletion. A total of 40 patients with CD20+ relapsed or refractory follicular non-Hodgkin’s lymphoma grade I-II will be enrolled in this open-label, dose-escalating, international, multi-center clinical trial. Cohorts of 10 patients will receive i.v. infusions at doses of either 300, 500, 700 or 1000 mg once weekly for 4 weeks. The patients are followed for 12 months. Patients receive oral acetaminophen and i.v. antihistamin before infusion. In case of adverse events of CTC grade 3 or higher, i.v. glucocorticosteroids are given. The endpoints are CT scan verified tumor response according to the Cheson criteria, B-cell depletion in peripheral blood and lymph nodes, time to next anti-lymphoma treatment, duration of response, BCL2 conversion, pharmacokinetics, and adverse events. Tumor and bone marrow biopsies and CT scans are assessed centrally. The first 17 patients treated with HuMax-CD20 are the subject of this report. Mean age is 60 years. In the 300 mg group all 10 patients have received all 4 infusions. Seven patients have been enrolled in the 500 mg group; three of them have received 4 infusions, two have received 3 infusions, and two patients have received 2 infusions. Baseline B-cell count was in the range of 11-382 x 106 cells per L with a median of 114 x 106. One week after the first infusion the median B-cell count available in 16 patients was 8 x 106 cells per L with a range of 0–19 x 106. In six of the 16 patients no B-cells were detected. B-cell counts measured one week after the 4th infusion are available for 10 patients. Eight patients had no detectable B-cells, one patient had 11 x 106 and one had 34 x 106 cells per L. B-cell counts eight weeks after the 4th infusion are available for two patients. No B-cells were detectable in these two patients. No dose limiting toxicity has been reported with administration of 300 or 500 mg. One serious adverse event assessed as not related to HuMax-CD20 has been reported in the 300 mg group. Infusion related adverse events have primarily been seen during the first infusion of HuMax-CD20. The events have, as expected, predominantly been signs and symptoms of cytokine release, e.g. pruritus, dyspnoea, rigors/chills, nausea, hypotension, urticaria, fatigue, fever and rash. In 15 of the 17 patients, 51 adverse events have been reported. Nine adverse events were CTC grade 3, 16 were grade 2, and 26 events were grade 1. In conclusion, this analysis based on preliminary data for the first 17 patients treated with HuMax-CD20 demonstrated significant depletion of peripheral blood B-cells and a favorable safety profile. An updated report of results for all 40 patients including preliminary tumor response data will be presented.

scholarly journals Expansion of Activated Peripheral Blood Memory B Cells in Rheumatoid Arthritis, Impact of B Cell Depletion Therapy, and Biomarkers of Response

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0128269 ◽  
Author(s):  
Diana G. Adlowitz ◽  
Jennifer Barnard ◽  
Jamie N. Biear ◽  
Christopher Cistrone ◽  
Teresa Owen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Memory B Cells ◽  
Cell Depletion ◽  
B Cell Depletion

Comparison of B Cell Depletion Mediated by Intravenous (IV) Rituxan® and Rituxan Given Subcutaneous (SC) In Cynomolgus Monkeys

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3980-3980 ◽  
Author(s):  
Christopher J Del Nagro ◽  
Cheng Ping Mao ◽  
Martin Brovarney ◽  
Karim Dabbagh ◽  
Herbert Birnboeck ◽  
...  
Keyword(s):  
B Cell ◽  
Peripheral Blood ◽  
The Body ◽  
Cell Depletion ◽  
Lymphoid Tissues ◽  
Target Coverage ◽  
Chimeric Mouse ◽  
B Cell Depletion ◽  
Cynomolgus Monkeys ◽  
Trough Concentrations

Abstract Abstract 3980 Rituximab (MabThera)® is a chimeric mouse/human monoclonal antibody recognizing the B cell specific trans-membrane protein CD20. Rituximab's CD20 specific binding facilitates the prolonged depletion of both malignant and endogenous CD20+ B cells. Rituximab is currently FDA approved for monotherapy and combinatorial therapies in the treatment of multiple forms of Non Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL) and Diffuse Large B cell Lymphomas (DLBCL), as well as for the treatment of moderate to severe rheumatoid arthritis patients who are refractory to TNF antagonists (in combination with methotrexate, MTX). As with most large protein based biologics, the proto-typical route of administration of rituximab is by intravenous (IV) infusion. Following delivery to the circulation, rituximab distributes into both primary and secondary lymphoid tissues throughout the body. This distribution is essential to full target coverage of CD20+ cells and therefore critical for the efficacy in targeting those cells for depletion. For other monoclonal antibodies in other clinical settings, the conversion from IV to SC administration has resulted in an improved tolerability with less infusion-related reactions, shorter administration times, an increased patient-convenience and an improved cost-effectiveness. These advantages are anticipated for the SC administration of rituximab as well. Here we describe the results of an IV/SC pharmacokinetic/pharmacodynamic (PKPD) cynomolgus monkey study comparing the traditional IV infusion of rituximab to a novel SC dosing route of rituximab administration using an SC formulation of rituximab containing recombinant human hyaluronidase (rHuPH20). rHuPH20 transiently degrades the local interstitial matrix component, hyaluronan, at the SC injection site, acting as a permeation enhancer and allowing SC administration of high volumes. Cynomolgus monkeys were treated twice, one week apart, with the rituximab SC formulation or with IV rituximab (2 × 10 mg/kg IV or SC). CD20 target coverage and depth of distal lymph node B-cell depletion was measured 7 days later, while the prolonged target coverage and duration of peripheral blood B-cell depletion was evaluated over an extended two month period. The results indicate similar rituximab trough concentrations in serum as well as similar B-cell depletion efficacy in both peripheral blood and distal secondary lymphoid tissue after IV and SC dosing. In conclusion, the results of the study suggest that the SC versus IV dosing routes do not influence the non-clinical efficacy in this B cell depletion model given that similar trough concentrations of rituximab are reached with both administration routes. Disclosures: Del Nagro: Genentech/Roche: Employment. Mao:Roche: Employment. Dabbagh:Roche: Consultancy, Employment. Birnboeck:Roche: Consultancy, Employment. Richter:Roche: Employment.

B Cell Depletion Therapy Normalizes Circulating Follicular Th Cells in Primary Sjögren Syndrome

2016 ◽  
Vol 44 (1) ◽  
pp. 49-58 ◽  
Author(s):  
Gwenny M. Verstappen ◽  
Frans G.M. Kroese ◽  
Petra M. Meiners ◽  
Odilia B. Corneth ◽  
Minke G. Huitema ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Activity ◽  
B Cell ◽  
Th17 Cells ◽  
Serum Levels ◽  
Cd4 T Cell ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Tfh Cells ◽  
Primary Sjögren Syndrome

Objective.To assess the effect of B cell depletion therapy on effector CD4+ T cell homeostasis and its relation to objective measures of disease activity in patients with primary Sjögren syndrome (pSS).Methods.Twenty-four patients with pSS treated with rituximab (RTX) and 24 healthy controls (HC) were included. Frequencies of circulating effector CD4+ T cell subsets were examined by flow cytometry at baseline and 16, 24, 36, and 48 weeks after the first RTX infusion. Th1, Th2, follicular Th (TFH), and Th17 cells were discerned based on surface marker expression patterns. Additionally, intracellular cytokine staining was performed for interferon-γ, interleukin (IL)-4, IL-21, and IL-17 and serum levels of these cytokines were analyzed.Results.In patients with pSS, frequencies of circulating TFH cells and Th17 cells were increased at baseline compared with HC, whereas frequencies of Th1 and Th2 cells were unchanged. B cell depletion therapy resulted in a pronounced decrease in circulating TFH cells, whereas Th17 cells were only slightly lowered. Frequencies of IL-21–producing and IL-17–producing CD4+ T cells and serum levels of IL-21 and IL-17 were also reduced. Importantly, the decrease in circulating TFH cells was associated with lower systemic disease activity over time, as measured by the European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index scores and serum IgG levels.Conclusion.B cell depletion therapy in patients with pSS results in normalization of the elevated levels of circulating TFH cells. This reduction is associated with improved objective clinical disease activity measures. Our observations illustrate the pivotal role of the crosstalk between B cells and TFH cells in the pathogenesis of pSS.

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