Reduction of inflammation and preservation of neurological function by anti-CD52 therapy in murine experimental autoimmune encephalomyelitis

Turner, Michael J.; Pang, Petti T.; Chrétien, Nathalie; Havari, Evis; LaMorte, Michael; Oliver, Jean; Pande, Nilesh; Masterjohn, Elizabeth; Carter, Karen; Reczek, David; Brondyk, William; Roberts, Bruce; Kaplan, Johanne; Siders, William

doi:10.1016/j.jneuroim.2015.05.018

Cited by 27 publications

(49 citation statements)

References 25 publications

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“…In this study mCD52‐depleting mAb also depleted T cells and inhibited the development of relapsing EAE, which is associated with reduced immune infiltration and consequent reduced demyelination and neuroprotection . The depletion profiles appeared relatively similar to that seen in hCD52 transgenic CD‐1 mice injected with alemtuzumab and SJL and C57BL/6 mice injected with the mCD52‐depleting mAb .…”

Section: Discussionsupporting

confidence: 61%

“…a,b). As alemtuzumab is administered as a set of five daily infusions in humans, five daily subcutaneous injections of mouse CD52‐mouse IgG2a mAb were administered according to instructions from the manufacturers. It was found that the relative percentages of both CD4 and CD8 T cells were now depleted by approximately 80–90% within 7 days of antibody delivery and this level of depletion persisted during an observation period of 28 days (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This was purchased from Bio X cell. Genzyme Corporation (Framingham MA) supplied the 250 μg mouse CD52 (mCD52) ‐depleting mouse IgG2a mAb . This was injected subcutaneously over 5 consecutive days .…”

Section: Methodsmentioning

confidence: 99%

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Depletion of CD52‐positive cells inhibits the development of central nervous system autoimmune disease, but deletes an immune‐tolerance promoting CD8 T‐cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis

et al. 2017

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SummaryThe objective was to determine whether CD52 lymphocyte depletion can act to promote immunological tolerance induction by way of intravenous antigen administration such that it could be used to either improve efficiency of multiple sclerosis (MS) inhibition or inhibit secondary autoimmunities that may occur following alemtuzumab use in MS. Relapsing experimental autoimmune encephalomyelitis was induced in ABH mice and immune cell depletion was therapeutically applied using mouse CD52 or CD4 (in conjunction with CD8 or CD20) depleting monoclonal antibodies. Immunological unresponsiveness was then subsequently induced using intravenous central nervous system antigens and responses were assessed clinically. A dose–response of CD4 monoclonal antibody depletion indicated that the 60–70% functional CD4 T‐cell depletion achieved in perceived failed trials in MS was perhaps too low to even stop disease in animals. However, more marked (~75–90%) physical depletion of CD4 T cells by CD4 and CD52 depleting antibodies inhibited relapsing disease. Surprisingly, in contrast to CD4 depletion, CD52 depletion blocked robust immunological unresponsiveness through a mechanism involving CD8 T cells. Although efficacy was related to the level of CD4 T‐cell depletion, the observations that CD52 depletion of CD19 B cells was less marked in lymphoid organs than in the blood provides a rationale for the rapid B‐cell hyper‐repopulation that occurs following alemtuzumab administration in MS. That B cells repopulate in the relative absence of T‐cell regulatory mechanisms that promote immune tolerance may account for the secondary B‐cell autoimmunities, which occur following alemtuzumab treatment of MS.

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Section: Discussionsupporting

confidence: 61%

Section: Resultsmentioning

confidence: 99%

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Depletion of CD52‐positive cells inhibits the development of central nervous system autoimmune disease, but deletes an immune‐tolerance promoting CD8 T‐cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis

et al. 2017

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“…Administration of anti-muCD52 not only reduces the number of circulating T lymphocytes, but also reduces the number of infiltrating T lymphocytes in the CNS of EAE mice, decreases the number of MOGreactive CD4 T cells and overall cytokine production and strongly inhibited the development of CNS inflammation and concomitant demyelination and axonal damage. Electrophysiological assessment showed preservation of axonal conductance in the spinal cord suggesting that anti-CD52 therapy may help to preserve CNS integrity [41]. Taken all together, these results demonstrate the robust general and local immunosuppressive action of anti-muCD52 treatment in several models of EAE and parallel the long term control of disease observed in the majority of RRMS patients treated with alemtuzumab.…”

Section: Experimental Autoimmune Encephalomyelitissupporting

confidence: 54%

Alemtuzumab for multiple sclerosis: the new concept of immunomodulation

Gallo¹,

Centonze

Marrosu

2017

Mult Scler Demyelinating Disord

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Alemtuzumab (Lemtrada®) is a humanized anti-CD52 IgG1 monoclonal antibody that depletes CD52-expressing cells from the circulation. Robust clinical and radiologic data, derived from clinical trials and long-term observational studies, indicate that alemtuzumab induces a marked immunosuppression related to the depletion of circulating T and B lymphocytes. However, recent advances suggest that the long-term clinical effects of alemtuzumab are probably due to unique qualitative changes in the process of lymphocyte repopulation of the immune system. This leads to a particular rebalancing of the immune system. In this paper we review the immunomodulatory mechanisms underlying the therapeutic effect of alemtuzumab in pre-clinical models and in patients with relapsing remitting multiple sclerosis (RRMS), and stress the importance of a monoclonal antibody-based immunosuppression for treating the severe forms of RRMS. Alemtuzumab has many features of the ideal immunomodulatory drug: rapid biological and clinical actions and and long-lasting benefit. Alemtuzumab can be used as rescue therapy or as first line drug in severe-onset MS. Thus, the availability of alemtuzumab constitutes a significant step forward in the therapy of MS.

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“…These models have proven useful in developing and understanding currently approved DMTs including natalizumab (10), fingolimod (25), dimethylfumarate (24) or alemtuzumab (129). These models have proven useful in developing and understanding currently approved DMTs including natalizumab (10), fingolimod (25), dimethylfumarate (24) or alemtuzumab (129).…”

Section: Experimental Autoimmune Encephalomyelitismentioning

confidence: 99%

Multiple sclerosis animal models: a clinical and histopathological perspective

et al. 2017

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There is a broad consensus that multiple sclerosis (MS) represents more than an inflammatory disease: it harbors several characteristic aspects of a classical neurodegenerative disorder, that is, damage to axons, synapses and nerve cell bodies. While we are equipped with appropriate therapeutic options to prevent immune-cell driven relapses, effective therapeutic options to prevent the progressing neurodegeneration are still missing. In this review article, we will discuss to what extent pathology of the progressive disease stage can be modeled in MS animal models. While acute and relapsing-remitting forms of experimental autoimmune encephalomyelitis (EAE), which are T cell dependent, are aptly suited to model relapsing-remitting phases of MS, other EAE models, especially the secondary progressive EAE stage in Biozzi ABH mice is better representing the secondary progressive phase of MS, which is refractory to many immune therapies. Besides EAE, the cuprizone model is rapidly gaining popularity to study the formation and progression of demyelinating CNS lesions without T cell involvement. Here, we discuss these two non-popular MS models. It is our aim to point out the pathological hallmarks of MS, and discuss which pathological aspects of the disease can be best studied in the various animal models available.

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Reduction of inflammation and preservation of neurological function by anti-CD52 therapy in murine experimental autoimmune encephalomyelitis

Cited by 27 publications

References 25 publications

Depletion of CD52‐positive cells inhibits the development of central nervous system autoimmune disease, but deletes an immune‐tolerance promoting CD8 T‐cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis

Depletion of CD52‐positive cells inhibits the development of central nervous system autoimmune disease, but deletes an immune‐tolerance promoting CD8 T‐cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis

Alemtuzumab for multiple sclerosis: the new concept of immunomodulation

Multiple sclerosis animal models: a clinical and histopathological perspective

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