Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


TNF Blockade Impairs the Induction of T-Cell Dependent Antibody Responses.

Salinas1,  Gabriela Franco, Rycke2,  Leen De, Brouard4,  Sophie, Jovanovic4,  Vojislav, Moizant4,  Frederique, Cantaert2,  Tineke, van der Burg3,  Mirjam

Academisch Medisch Centrum, University of Amsterdam, Amsterdam, Noord Holland, The Netherlands
Academisch Medisch Centrum, University of Amsterdam, Amsterdam, The Netherlands
Immunology, Erasmus Medical Center, Rotterdam, Netherlands
Institut de Transplantation et Recherche en Transplantation, INSERM U643, Nantes, France

Objectives:

TNFa blockade induces anti-nuclear antibodies in patients with Spondylarthritis (SpA) and Rheumatoid Arthritis. These antibodies are related to increased levels of circulating nuclear antigens, restricted to IgM autoantibodies and directed to T cell independent (TI) but not T cell dependent (TD) antigens. Based on this observation, we tested in experimental models and in arthritis patients whether TNF blockade impairs the maturation of TD humoral responses.

Methods:

Cardiac allografts from LEW.1W rats were transplanted to LEW.1A rats treated with either anti-TNF or control antibody. Alloantibodies and graft rejection were monitored for 25 days. Transplanted hearts were assessed by histology, immunohistochemistry, and qPCR. In humans, PBMCs from SpA patients treated with TNF blockade or NSAIDs were collected for ana-ly-sis of somatic hypermutation, lymphocyte phenotype, expression of costimulatory molecules and in vitro assays. After 12 weeks of treatment, both patient groups were vaccinated with a TD vaccine to Hepatitis B and a TI vaccine to S. Pneumoniae. Vaccine-specific antibody titers were determined in serum.

Results:

In the rat allotransplantation model, anti-TNF treatment at the day of transplantation inhibited the induction of IgM (p=0.004) and IgG (p=0.020) alloantibodies as well as IgG deposition in the graft (p=0.015). Accordingly, leucocyte infiltration was decreased and graft architecture was better preserved in treated animals (p=0.015), resulting in prolonged graft survival (p=0.020). In this model, TNF blockade did not affect the Th1/Th2 balance, TLR expression nor the expression of regulatory molecules like TGF-beta, IDO and FoxP3, suggesting that the beneficial clinical effects may be primarily related to the inhibition of the humoral response.

In human arthritis, the antibody response against the TD vaccine was almost completely blocked (p=0.010) during TNF blockade in SpA patients whereas TI responses were less affected. An effect on the germinal center (GC) reaction was suggested by a decreased degree of somatic hypermutation of peri-pheral B cells in SpA patients treated with anti-TNFa blockers versus controls (p=0.040). In addition, we observed an increased number of circulating memory B cells (p=0.001) but a decrease in plasmablasts (p=0.039) in anti-TNF treated patients. This was not due to an intrinsic B cell defect as B cells obtained after TNF blockade in vivo did not display defective differentiation towards plasma cells in vitro. Neither could we evidence a defective B cell activation as the post-GC B lymphocytes of anti-TNF treated patients displayed an increased expression of CD40 and HLA-DR ex vivo and a normal expression of CD80 and CD86 after TD stimulation in vitro. Further studies on the underlying mechanisms will focus on extra-follicular B cells as well as B cell migration.

Conclusion:

TNF blockade impairs the induction of humoral responses in rodents and humans, with the most pronounced effect on TD responses. Whereas the exact mechanism is currently under investigation, these data reveal a novel mechanism of action of anti-TNF with potential relevance for several fields of clinical immunology.

To cite this abstract, please use the following information:
Salinas, Gabriela Franco, Rycke, Leen De, Brouard, Sophie, Jovanovic, Vojislav, Moizant, Frederique, Cantaert, Tineke, et al; TNF Blockade Impairs the Induction of T-Cell Dependent Antibody Responses. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :753
DOI: 10.1002/art.28521

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