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1.
Clin Exp Immunol ; 217(1): 15-30, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38642912

RESUMO

B and T cells collaborate to drive autoimmune disease (AID). Historically, B- and T-cell (B-T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B-cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab, or ofatumumab. Refractory AID is a significant problem for patients with incomplete BCD with a greater frequency of IgD-CD27+ switched memory B cells, CD19+CD20- B cells, and plasma cells that are not directly targeted by anti-CD20 antibodies, whereas most lymphoid tissue plasma cells express CD19. Furthermore, B-T-cell collaboration is predominant in lymphoid tissues and at sites of inflammation such as the joint and kidney, where BCD may be inefficient, due to limited access to key effector cells. In the treatment of cancer, chimeric antigen receptor (CAR) T-cell therapy and T-cell engagers (TCE) that recruit T cells to induce B-cell cytotoxicity have delivered promising results for anti-CD19 CAR T-cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab, or epcoritamab. Limited evidence suggests that anti-CD19 CAR T-cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B-T-cell collaboration toward overcoming rituximab-resistant AID.


Assuntos
Doenças Autoimunes , Linfócitos B , Imunoterapia Adotiva , Linfócitos T , Humanos , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Linfócitos B/imunologia , Linfócitos T/imunologia , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Rituximab/uso terapêutico , Comunicação Celular/imunologia , Animais
2.
Rheumatology (Oxford) ; 61(7): 2894-2904, 2022 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34788412

RESUMO

OBJECTIVES: To investigate key factors that may contribute to the variability of rituximab-mediated peripheral and renal B cell depletion (BCD) in SLE. METHODS: We analysed: (i) CD19+ B cell counts in patients with SLE before and 1, 2, 3 and 6 months after treatment with rituximab, comparing them with RA patients; (ii) the presence of B cells in renal biopsies after rituximab therapy; (iii) whether the duration of BCD correlated with patient demographics and B cell expression of CD20 and FcγRIIb; and (iv) the effect of B cell activation factor (BAFF) on the efficiency of rituximab and obinutuzumab at inducing BCD in whole blood assays, in vitro. RESULTS: In SLE (n = 71), the duration of BCD was shorter compared with RA (n = 27). B cells were detectable in renal biopsy samples (n = 6) after treatment with rituximab in all patients with poor response while peripheral blood B cells remained low or undetectable in the same patients. There were no significant relationships between peripheral BCD and patient age, disease duration, serum C3 levels or the level of expression of B cell surface proteins CD20 and FcγRIIb. Obinutuzumab was more efficient than rituximab at inducing BCD in whole blood assays, regardless of excess BAFF. CONCLUSIONS: BCD in SLE is less efficient than in RA. Renal B cell presence following rituximab treatment was associated with poor outcomes. No significant relationships between any measured B cell related, clinical or laboratory parameters and the efficiency of BCD by rituximab was found. Obinutuzumab was superior to rituximab at inducing BCD.


Assuntos
Lúpus Eritematoso Sistêmico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD20 , Linfócitos B , Humanos , Rituximab/farmacologia , Rituximab/uso terapêutico
3.
Biologicals ; 69: 1-14, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33288390

RESUMO

Systemic Lupus Erythematosus (SLE) is an autoimmune inflammatory condition with a wide spectrum of disease manifestations and severities, resulting in significant morbidity and mortality. The aetiopathogenesis of SLE is complex. Young women and certain ethnicities are commonly affected, suggesting a significant hormonal and genetic influence. Diverse immunological abnormalities have been described. A characteristic abnormality is the presence of autoantibodies, implicating a central role for B cells in disease pathogenesis and/or perpetuation. Whilst conventional therapies have improved outcomes, a great unmet need remains. Recently, biological therapies are being explored. B-cell depletion therapy with rituximab has been in use off-label for nearly two decades. Inconsistent results between uncontrolled and controlled studies have raised doubts about its efficacy. In this review, we will focus on B cell abnormalities and the rationale behind B-cell depletion therapy with anti-CD20 monoclonal antibody (mAb), rituximab, will be explored including an evaluation of clinical and trial experience. Finally, we will discuss the mechanistic basis for considering alternative anti-CD20 mAbs.


Assuntos
Anticorpos Monoclonais , Lúpus Eritematoso Sistêmico , Rituximab , Anticorpos Monoclonais/uso terapêutico , Antígenos CD20 , Linfócitos B , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Rituximab/uso terapêutico
4.
Front Oncol ; 13: 1156743, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37342197

RESUMO

Background: Patient-derived xenograft (PDX) models involve the engraftment of tumour tissue in immunocompromised mice and represent an important pre-clinical oncology research method. A limitation of non-small cell lung cancer (NSCLC) PDX model derivation in NOD-scid IL2Rgammanull (NSG) mice is that a subset of initial engraftments are of lymphocytic, rather than tumour origin. Methods: The immunophenotype of lymphoproliferations arising in the lung TRACERx PDX pipeline were characterised. To present the histology data herein, we developed a Python-based tool for generating patient-level pathology overview figures from whole-slide image files; PATHOverview is available on GitHub (https://github.com/EpiCENTR-Lab/PATHOverview). Results: Lymphoproliferations occurred in 17.8% of lung adenocarcinoma and 10% of lung squamous cell carcinoma transplantations, despite none of these patients having a prior or subsequent clinical history of lymphoproliferative disease. Lymphoproliferations were predominantly human CD20+ B cells and had the immunophenotype expected for post-transplantation diffuse large B cell lymphoma with plasma cell features. All lymphoproliferations expressed Epstein-Barr-encoded RNAs (EBER). Analysis of immunoglobulin light chain gene rearrangements in three tumours where multiple tumour regions had resulted in lymphoproliferations suggested that each had independent clonal origins. Discussion: Overall, these data suggest that B cell clones with lymphoproliferative potential are present within primary NSCLC tumours, and that these are under continuous immune surveillance. Since these cells can be expanded following transplantation into NSG mice, our data highlight the value of quality control measures to identify lymphoproliferations within xenograft pipelines and support the incorporation of strategies to minimise lymphoproliferations during the early stages of xenograft establishment pipelines.

5.
BMJ Case Rep ; 13(4)2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32269047

RESUMO

This report highlights the importance of tailored treatment strategies in severe systemic lupus erythematosus (SLE) flares driving the life-threatening condition, macrophage activation syndrome (MAS). We report the case of a 42-year-old woman with active systemic lupus erythematosus (SLE) who was diagnosed with MAS within 3 days of onset of lethargy, rash, joint pain and significant cytopenias. This early diagnosis meant that her condition was managed with less intensive immunosuppression with only modest doses of steroids and mycophenolate mofetil.


Assuntos
Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Síndrome de Ativação Macrofágica/tratamento farmacológico , Síndrome de Ativação Macrofágica/etiologia , Ácido Micofenólico/uso terapêutico , Prednisolona/uso terapêutico , Adulto , Diagnóstico Diferencial , Quimioterapia Combinada , Inibidores Enzimáticos/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos
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