B and T Cell depletion mechanisms

BLyS is a member of the TNF family of proinflammatory cytokines that is expressed on monocytes and induces B cell proliferation and immunoglobulin secretion. Constitutive overexpression of BLyS protein can result in SLE-like disease in mice, and treatment with a BLyS protein antagonist or knockout models ameliorates disease progression and enhances survival. In a large subset of SLE patients, circulating levels of BLyS protein are elevated. Belimumab is a humanized monoclonal antibody to BLyS - a BLyS antagonist that induces a reduction in B cells and appears to be well tolerated. Two ongoing Phase II trials are testing its efficacy and safety in SLE and RA, respectively.

Rituximab is another monoclonal antibody therapy that leads to B cell depletion. This monoclonal antibody is directed against the CD20 receptor protein present on B lymphocytes. CD20 is expressed on B cells in intermediate stages of development - not on plasma cells - and plays a role in the differentiation of B cells into plasma cells. Rituximab appears to have no significant adverse events. It is licensed for a type of non-Hodgkins lymphoma, and is currently being tested in clinical trials for progressive and relapsing forms of MS as well as for SLE.

Epratuzumab is a monoclonal antibody to CD22, a transmembrane sialoglycoprotein expressed on the surface of mature B cells. Epratuzumab is being tested as a therapy for SLE. The precise mechanism of action of epratuzumab has not been defined but may relate to effects on B cell signaling, and may render cells more prone to apoptosis.

Alemtuzumab is a monoclonal antibody directed against the glycoprotein CD52, which is expressed on the surface of essentially all B and T lymphocytes and a majority of monocytes and macrophages as well as natural killer cells. It is used as a neoplastic drug that induces profound lymphopenia. It has US FDA approval as a second-line therapy for B cell chronic lymphocytic leukemia, but is associated with numerous and common adverse effects. It is currently being tested in clinical trials for RRMS.

Mitoxantrone is a synthetic anthracenedione (see Figure 1 and Table 2) with both antineoplastic and immunosuppressive activities.29 Unlike many small drugs, mitoxantrone is administered intravenously every 3 months, since it is poorly absorbed orally. It easily crosses the blood-brain barrier and intercalates into DNA, inhibiting DNA replication and DNA-dependent RNA synthesis; it is also a potent inhibitor of topoisomerase II, an enzyme involved in DNA repair. Mitoxantrone is thought to have a broad range of action, based mainly on preclinical studies. It is cytotoxic to both proliferating and nonproliferating human cells in vitro. It inhibits B cell, T cell, and macrophage proliferation, leading to apoptosis (patients taking mitoxantrone can have severe leukopenia). Mitoxantrone also impairs antigen presentation (by causing apoptosis of the cells involved) and decreases secretion of proinflammatory cytokines -including IL-2 and TNF-a. In MS patients, mitoxantrone has a positive impact on progression (thus the FDA approval for SPMS), relapse rate as well as MRI benefits. Mitoxantrone therapy is associated with many adverse effects, including treatment-related leukemia; however, the major limitation relates to potential cardiotoxic effects, which limits the cumulative lifetime dose.

Mycophenolate mofetil is a prodrug that is metabolized to mycophenolic acid (MPA; see Figure 1 and Table 2), an immunosuppressant that acts by reversible inhibition of IMP dehydrogenase, the rate-limiting enzyme in purine synthesis. MPA has a selective effect on Tand B cells, since their proliferation is dependent on de novo synthesis of purines (other cell types can utilize salvage pathways). MPA has a broad spectrum of action, mainly as a consequence of its suppression of Tand B cell proliferation (leukopenia is a prominent adverse reaction). Mycophenolate mofetil is approved for the prevention of allograft rejection; clinical trials are underway testing mycophenolate mofetil for MS, MG, and SLE.

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