Failure of intravenous and intrathecal cytarabine to modify central nervous system IgG synthesis in multiple sclerosis

Tourtellotte, Wallace W.; Potvin, Alfred R.; Mendez, Mario F.; Baumhefner, Robert W.; Potvin, Janet H.; Booe, I.; Syndulko, Karl

doi:10.1002/ana.410080411

Cited by 16 publications

(11 citation statements)

References 15 publications

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“…The OCB pattern and IgG index were also unaffected in an SPMS patient who underwent two treatments of IT rituximab (Studer et al 2014). That IT antibody production is unaffected by such potent interventions as intracranial radiation (Tourtellotte et al 1980a), IT cytarabine (Tourtellotte et al 1980b), and autologous hematopoietic stem-cell transplantation (Saiz et al 2001;Nash et al 2003) is a testament to the difficulty of targeting the inflammatory process in the CNS and meninges.…”

Section: Progressive Multiple Sclerosismentioning

confidence: 99%

B-Cell Therapies in Multiple Sclerosis

Sabatino

Zamvil

Hauser

2018

Cold Spring Harb Perspect Med

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B cells play a vital function in multiple sclerosis (MS) pathogenesis through an array of effector functions. All currently approved MS disease-modifying therapies alter the frequency, phenotype, or homing of B cells in one way or another. The importance of this mechanism of action has been reinforced with the successful development and clinical testing of B-cell-depleting monoclonal antibodies that target the CD20 surface antigen. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was approved by the Food and Drug Administration (FDA) in March 2017 after pivotal trials showed dramatic reductions in inflammatory disease activity in relapsing MS as well as lessening of disability progression in primary progressive MS. These and other clinical studies place B cells at the center of the inflammatory cascade in MS and provide a launching point for development of therapies that target selective pathogenic B-cell populations.

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Section: Progressive Multiple Sclerosismentioning

confidence: 99%

B-Cell Therapies in Multiple Sclerosis

Sabatino

Zamvil

Hauser

2018

Cold Spring Harb Perspect Med

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“…Cytarabine (ara-C) is an antimetabolic agent interfering with DNA synthesis and is used in chemotherapeutic regimens for treating lymphomas. Cytotoxic levels administered in the systemic compartment do not achieve cytotoxic levels in the CSF, and reciprocally [ 93 ]. None of the 10 patients given cytarabine either systemically or intrathecally had changes in the number or pattern of CSF OCB.…”

Section: None Of the Available Ms Drugs Deplete Intrathecal Ig Synmentioning

confidence: 99%

“…CNS IgG synthesis slightly decreased (about 10%) after systemic infusion during the next month. However, CNS IgG synthesis transiently rose during the week following intrathecal administration, while at the same time CSF floating cells were low, and then all returned to their pretreatment level [ 93 ].…”

Section: None Of the Available Ms Drugs Deplete Intrathecal Ig Synmentioning

confidence: 99%

Intrathecal IgG Synthesis: A Resistant and Valuable Target for Future Multiple Sclerosis Treatments

Bonnan¹

2015

Multiple Sclerosis International

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Intrathecal IgG synthesis is a key biological feature of multiple sclerosis (MS). When acquired early, it persists over time. A growing body of evidence suggests that intrathecal Ig-secreting cells may be pathogenic either by a direct action of toxic IgG or by locally secreting bystander toxic products. Intrathecal IgG synthesis depends on the presence of CNS lymphoid organs, which are strongly linked at anatomical level to cortical subpial lesions and at clinical level to the impairment slope in progressive MS. As a consequence, targeting CNS lymphoid lesions could be a valuable new target in MS, especially during the progressive phase. As intrathecal IgGs are end-products of these lymphoid lesions, intrathecal IgG synthesis may be considered as a specific marker of the persistence of these inflammatory lesions. Here we review the effect upon intrathecal IgG synthesis of all drugs ever used in MS. Except for steroids, all these therapeutic strategies, including rituximab, failed to decrease intrathecal IgG synthesis, with the exception of a questionable incomplete action of natalizumab. Thus, IgG synthesis is a robust marker of persistent intrathecal inflammation and its complete normalization should be one of the goals in future therapeutic strategies.

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“…Silagi 33 has shown that RNA and protein synthesis were not affected in L cells exposed to lethal doses of Ara-C, and Ben-Porat et al 34 have demonstrated that Ara-C had no effect on the synthesis of pseudorabies virus structural proteins, or their movement from the cytoplasm to the nucleus, while it prevented the synthesis of viral DNA. Additionally, Tourtellotte et al 35 have shown that intravenous administration of Ara-C had no effect on de novo central nervous system immunoglobulin G synthesis in humans in spite of severe granulocytopenia and monocytopenia of 1 or 2 weeks' duration. In patients given the drug intrathecally, cytotoxic levels were maintained in the central nervous system for over 24 hours with no evidence of altered immunoglobulin synthesis or leukopenia.…”

Section: Figure 3 Effect Of Cytosine Arabinoside (Ara-c) Treatment Omentioning

confidence: 99%

Increased aortic DNA synthesis precedes renal hypertension in rats. An obligatory step?

Loeb¹,

Mandel²,

Straw³

et al. 1986

Hypertension

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SUMMARY The rate of DNA synthesis was determined in rats with developing and established twokidney, one clip renal hypertension. Rate of DNA synthesis was measured as [3 H]thymidine incorporation into DNA per hour. After stenosis of the renal artery, blood pressure increased over a 2-week period. Five days after clipping, there was an increase in the rate of aortic DNA synthesis before an increase in blood pressure was detected, whereas there was no DNA effect in sham-operated animals. This difference in [ 3 H]thymidine incorporation into aortic DNA could not be accounted for by alterations in thymidine pool sizes. The increase in DNA synthesis was still present 3 weeks after renal artery stenosis, although by that time blood pressure had plateaued. The role of DNA synthesis in the development of renal hypertension was investigated by determining whether inhibition of DNA synthesis with cytosine arabinoside could prevent the increase in blood pressure. Treatment of clipped rats with cytosine arabinoside for 5 days delayed the increase in blood pressure for more than 4 days, as compared with the effect of saline treatment in clipped rats. Although the possibility remains that some effect of cytosine arabinoside other than its effect on DNA synthesis could have influenced blood pressure, there were no differences in body weight, food intake, water intake, or urine output between cytosine arabinoside-treated and saline-treated rats with renal artery clips, and cytosine arabinoside treatment had no effect on blood pressure or body weight in normal rats. These results suggest that an increase in DNA synthesis may be an obligatory step in the genesis of renal hypertension. (Hypertension 8: 754-761, 1986) KEY WORDS • two-kidney, one clip renal hypertension muscle • cytosine arabinoside DNA synthesis * vascular smooth A LTHOUGH the pathogenesis of most clinical / \ cases of arterial hypertension is unknown, X \ . some of the sequelae are always the same. Patients exhibit a marked thickening of the arteries and resistance vessels 1 and a hyperreactivity to pressor agents. 23 The same types of changes have been observed in animal models of hypertension and are characterized by increases in the size and number of arterial

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Failure of intravenous and intrathecal cytarabine to modify central nervous system IgG synthesis in multiple sclerosis

Cited by 16 publications

References 15 publications

B-Cell Therapies in Multiple Sclerosis

B-Cell Therapies in Multiple Sclerosis

Intrathecal IgG Synthesis: A Resistant and Valuable Target for Future Multiple Sclerosis Treatments

Increased aortic DNA synthesis precedes renal hypertension in rats. An obligatory step?

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