Targeting plasma cells with proteasome inhibitors: possible roles in treating myasthenia gravis?

Gomez, Alejandro M.; Willcox, Nick; Molenaar, Peter; Buurman, Wim A.; Martínez‐Martínez, Pilar; Baets, Marc H. De; Losen, Mario

doi:10.1111/j.1749-6632.2012.06824.x

Cited by 38 publications

(33 citation statements)

References 74 publications

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“…Most serum autoantibodies to AChR are produced by long-lived plasma cells residing in spleen and bone marrow. These terminally differentiated cells are resistant to most non-specific immunosuppressive drugs, resulting in a delay of up to 18 months after initiation of general immunosuppressive therapy before MG patients improve [23,24]. Apoptosis of plasma cells can be induced by crosslinking FcgRIIB on the plasma cells by immune complexes [101].…”

Section: Mechanisms Of Specific Immunotherapymentioning

confidence: 99%

“…Results of a multicenter, randomized, controlled thymectomy trial are eagerly awaited [22]. Nonspecific immunosuppressive drugs mainly suppress lymphocyte activation and proliferation with little effect on long-lived plasma cells that are terminally differentiated cells and continue producing pathogenic antibodies [23,24]. Hence, the use of these drugs is hampered by delayed clinical response and undesirable side effects.…”

Section: Introductionmentioning

confidence: 99%

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AChR-specific immunosuppressive therapy of myasthenia gravis

Luo

Lindstrom

2015

Biochemical Pharmacology

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Section: Mechanisms Of Specific Immunotherapymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

AChR-specific immunosuppressive therapy of myasthenia gravis

Luo

Lindstrom

2015

Biochemical Pharmacology

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“…In hosts with preexisting humoral immune responses these regimens are slow acting and are only partially capable of depleting NAb levels. This is because NAbs are made mostly by long-lived plasma cells that do not divide, therefore immune suppressants that target proliferating cells are ineffective (8). Furthermore plasma cells lack common B-cell markers making them resistant to anti-CD20 targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

“…Several clinical trials have been conducted studying off-label uses of bortezomib. Some studies for the prevention of antibody-mediated rejection in renal transplant patients reported encouraging results, and there are also reports of positive outcomes in the treatment of autoimmune hemolytic anemia, rheumatoid arthritis, and systemic lupus erythematosus (8). …”

Section: Introductionmentioning

confidence: 99%

Bortezomib Reduces Pre-Existing Antibodies to Recombinant Immunotoxins in Mice

Manning

Mason-Osann

Onda

et al. 2015

The Journal of Immunology

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Recombinant immunotoxin (RIT) therapy is limited in patients by neutralizing antibody responses. Ninety percent of patients with normal immune systems make neutralizing antibodies after one cycle of RIT, preventing repeated dosing. Furthermore, some patients have preexisting antibodies from environmental exposure to Pseudomonas exotoxin, the component of the RIT that elicits the neutralizing antibody response. Bortezomib (B) is an FDA-approved proteasome inhibitor which selectively targets and kills plasma cells which are necessary for the neutralizing antibody response. We hypothesized B may abrogate neutralizing antibody levels, making dosing of RIT possible in mice already immune to RIT. We immunized BALB/c mice with multiple doses of SS1P, a RIT whose antibody portion targets mesothelin. Mice with elevated antibody levels were separated into groups to receive saline, B, the pentostatin/cyclophosphamide (PC) regimen, or the bortezomib/pentostatin/cyclophosphamide (BPC) combination regimen. Four weeks after finishing therapy plasma antibody levels were assayed and bone marrow was harvested. The B and PC regimens both significantly reduced antibody levels, and we observed fewer plasma cells in the bone marrow of B treated mice, but not in PC treated mice. The BPC combination regimen nearly eliminated antibodies and further reduced plasma cells in the bone marrow. The BPC combination regimen is more effective than individual regimens and may reduce antibody levels in patients with preexisting neutralizing antibodies to Pseudomonas exotoxin allowing RIT treatment.

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“…By inhibiting proteolysis, bortezomib disrupts several signal cascades, ultimately resulting in cell death. These effects are most relevant in plasma cells actively producing immunoglobulins and lead to a rapid reduction in Abs synthesis in patients with autoimmune diseases [112]. Bortezomib was effective in several refractory cases of anti-NMDAR encephalitis [51,52].…”

mentioning

confidence: 99%

Management of Immune-Mediated Paraneoplastic Neurological Disorders

Ayzenberg

Gold

Kleiter

2017

Neurology International Open

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AbsTR Ac TParaneoplastic neurological disorders are rare and clinically heterogeneous diseases. They can affect both the central and peripheral nervous system as well as the neuromuscular junction and muscle. Neurological deficits develop in 2/3 of cases prior to cancer diagnosis. The diagnostic approach includes screening for antineuronal antibodies and a search for the underlying tumor. A prompt tumor therapy in combination with immunotherapy is the cornerstone in the management of these diseases. Due to lack of clinical trials, treatment recommendations are based on case series and expert opinions. Highdose corticosteroids, intravenous immunoglobulins and apheresis therapies are often used in the acute stage of the disease. These therapies should be started as early as possible, e. g., during tumor screening, in order to prevent irreversible damage. Long-term treatment is mostly immunosuppressive and depends on the specific paraneoplastic syndrome. Outcomes vary depending upon the prognosis of the underlying cancer and the nature of the antineuronal antibodies. Disorders with antibodies directed against antigens on the neuronal cell surface are highly sensitive to B cell-directed therapies and mostly associated with a favorable outcome. A thorough review of published data on actual treatment recommendation is provided along with discussion of currently not validated, but potentially effective new therapies. E264Ayzenberg I et al. Management of Immune-mediated Paraneoplastic … Neurology International Open 2017; 1: E264-E274 course, treatment response and prognosis of PNS [2,3]. Depending on tumor association, obligate and facultative paraneoplastic Abs are differentiated (Tab. 1).Clinically, the following PNS exist [3,4]: A. In the central nervous system: ▪ Encephalomyelitis (incl. brainstem encephalitis) ▪ Limbic encephalitis ▪ Subacute cerebellar degeneration ▪ Opsoclonus-myoclonus syndrome ▪ Optic neuritis/neuromyelitis optica ▪ Myelopathy/myelitis ▪ Stiff person syndrome ▶Table 1 Paraneoplastic antibodies: associated neurological syndromes and tumors. Target antigen clinical presentation# Association with tumorObligate paraneoplastic Abs (directed against intracellular antigens; tumor association > 95 %) In this review we discuss the diagnosis and management of PNS. With regard to facultative paraneoplastic syndromes which are more frequently of autoimmune origin, such as neuromyelitis optica or myasthenia gravis, the reader should refer to pertinent reviews [5,6]. Diagnostic and Pathogenetic Significance of Antibodies to Intracellular and Surface AntigensAntibodies (Abs) to intracellular antigens or so-called "classical" Abs are almost always tumor-associated (exception: GAD-Abs). They can be associated with various tumors and a variety of neurological conditions [7]. However, a direct pathogenetic significance of these Abs has not yet been demonstrated. Abs to intracellular antigens serve as useful diagnostic markers in the targeted tumor search in PNS. Here, cell-mediated immune responses play a major p...

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Targeting plasma cells with proteasome inhibitors: possible roles in treating myasthenia gravis?

Cited by 38 publications

References 74 publications

AChR-specific immunosuppressive therapy of myasthenia gravis

AChR-specific immunosuppressive therapy of myasthenia gravis

Bortezomib Reduces Pre-Existing Antibodies to Recombinant Immunotoxins in Mice

Management of Immune-Mediated Paraneoplastic Neurological Disorders

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