| dc.description.abstracteng | Multiple sclerosis (MS) is considered to be a T cell-mediated demyelinating disease. However, there is increasing evidence for the involvement of B cells and plasma cells in MS pathogenesis: for instance, B cells and plasma cells are present in MS lesions and a subgroup of early active demyelinating lesions is characterized by immunoglobulin and complement depositions. Natalizumab is a humanized monoclonal antibody approved for the treatment of relapsing-remitting MS. It hinders the transmigration of immune cells into the CNS by blocking the interaction between the α4 chain (CD49d) of integrins and their ligands. Although natalizumab is an effective drug with a pronounced reduction of the relapse rate, some patients do not respond to the therapy. Histopathology after natalizumab therapy has not been investigated. Moreover, therapeutic effects of anti-α4 integrin antibody therapy in animals were only investigated in a T cell-dependent but not B cell-dependent mouse model of MS with no detailed characterization of the inflammatory infiltrate.
The first aim of the study was to characterize the lesional pathology with a focus on inflammatory cells in natalizumab-treated patients and to compare the histology with MS patients who had no prior natalizumab therapy as well as to correlate the inflammatory cells after natalizumab treatment with clinical and therapy-related data. The second aim of the study was to investigate therapy effects of a natalizumab analogon (PS/2 antibody) in a B cell-dependent mouse model of MS (OSE) and to compare the findings with human data.
Histological analysis showed that inflammatory infiltrates in CNS lesions of natalizumab treated patients were mainly composed of macrophages, T cells and some B cells and plasma cells. T cell numbers were not significantly reduced as compared to MS patients without natalizumab treatment. However, plasma cell numbers were significantly increased in active demyelinating as well as in inactive demyelinated lesions after natalizumab therapy. Plasma cell numbers tended to be higher and T cells lower when natalizumab was still pharmacologically active as compared to later time points. Higher plasma cell numbers did not correlate with the disease duration or the therapy duration.
Therapy with the natalizumab-analogon PS/2 antibody in OSE mice increased leukocyte numbers in the blood and resulted in a partial internalization of CD49d-antibody complexes in T- and B cells. Treatment improved the clinical outcome and decreased spinal cord demyelination and inflammatory cells of all investigated immune cell subsets if given early in the disease course. However, PS/2 antibody therapy was not effective when given late in the disease course. Moreover, no evidence for a rebound activity was observed after therapy discontinuation. The therapeutic effects of PS/2 antibody injections were independent of the Fc fragment of the antibody, since F(ab’)2 injections showed the same beneficial effects as the intact antibody.
In conclusion, although natalizumab is an effective drug for MS it could be shown that therapy with natalizumab does not completely prevent immune cells from entering the CNS. Plasma cell numbers were even increased after natalizumab therapy as compared to controls. Due to the important role also for B cells / plasma cells in MS pathogenesis, these findings could be of therapeutic relevance.
Natalizumab analogon therapy is effective in a B cell-dependent mouse model of MS. PS/2 antibody treatment in the OSE model showed comparable peripheral effects as in MS patients treated with natalizumab. In contrast to human studies, where an increase of plasma cells after natalizumab therapy was observed, all investigated inflammatory cell subsets including T- and B cells, plasma cells and macrophages were decreased after natalizumab analogon therapy. My studies confirm that the therapeutic effect is mediated by antibody binding and leads to a partial antibody-receptor internalization. | de |