Abstract:Alemtuzumab is a monoclonal antibody that binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. It is currently used as an immune reconstitution therapy in patients with relapsing–remitting multiple sclerosis. Alemtuzumab treatment is an intermittent infusion that induces long-term remission of Multiple Sclerosis also in the treatment-free period. After the robust T and B cell depletion induced by alemtuzumab, the immune syste… Show more
“…The ideal dose of DAC is a trade-off between antigen annihilation and a reduction in damaged ODC. Drug efficacy must occur with a consideration of the protection from external antigens to minimize the risk of secondary infections - sometimes with serious adverse effects - that often accompany immuno-suppressive therapies in MS [ 32 ]. Fig.…”
Background
Multiple Sclerosis (MS) represents nowadays in Europe the leading cause of non-traumatic disabilities in young adults, with more than 700,000 EU cases. Although huge strides have been made over the years, MS etiology remains partially unknown. Furthermore, the presence of various endogenous and exogenous factors can greatly influence the immune response of different individuals, making it difficult to study and understand the disease. This becomes more evident in a personalized-fashion when medical doctors have to choose the best therapy for patient well-being. In this optics, the use of stochastic models, capable of taking into consideration all the fluctuations due to unknown factors and individual variability, is highly advisable.
Results
We propose a new model to study the immune response in relapsing remitting MS (RRMS), the most common form of MS that is characterized by alternate episodes of symptom exacerbation (relapses) with periods of disease stability (remission). In this new model, both the peripheral lymph node/blood vessel and the central nervous system are explicitly represented. The model was created and analysed using Epimod, our recently developed general framework for modeling complex biological systems. Then the effectiveness of our model was shown by modeling the complex immunological mechanisms characterizing RRMS during its course and under the DAC administration.
Conclusions
Simulation results have proven the ability of the model to reproduce in silico the immune T cell balance characterizing RRMS course and the DAC effects. Furthermore, they confirmed the importance of a timely intervention on the disease course.
“…The ideal dose of DAC is a trade-off between antigen annihilation and a reduction in damaged ODC. Drug efficacy must occur with a consideration of the protection from external antigens to minimize the risk of secondary infections - sometimes with serious adverse effects - that often accompany immuno-suppressive therapies in MS [ 32 ]. Fig.…”
Background
Multiple Sclerosis (MS) represents nowadays in Europe the leading cause of non-traumatic disabilities in young adults, with more than 700,000 EU cases. Although huge strides have been made over the years, MS etiology remains partially unknown. Furthermore, the presence of various endogenous and exogenous factors can greatly influence the immune response of different individuals, making it difficult to study and understand the disease. This becomes more evident in a personalized-fashion when medical doctors have to choose the best therapy for patient well-being. In this optics, the use of stochastic models, capable of taking into consideration all the fluctuations due to unknown factors and individual variability, is highly advisable.
Results
We propose a new model to study the immune response in relapsing remitting MS (RRMS), the most common form of MS that is characterized by alternate episodes of symptom exacerbation (relapses) with periods of disease stability (remission). In this new model, both the peripheral lymph node/blood vessel and the central nervous system are explicitly represented. The model was created and analysed using Epimod, our recently developed general framework for modeling complex biological systems. Then the effectiveness of our model was shown by modeling the complex immunological mechanisms characterizing RRMS during its course and under the DAC administration.
Conclusions
Simulation results have proven the ability of the model to reproduce in silico the immune T cell balance characterizing RRMS course and the DAC effects. Furthermore, they confirmed the importance of a timely intervention on the disease course.
“… 39 On the other hand, faster repopulation of T-memory cells from the pool escaping depletion, rather than naïve T cells, may contribute to secondary autoimmunity. 40 , 41 …”
Section: Biology Of Anti-cd52 Therapymentioning
confidence: 99%
“…In the literature, there is scarce information about vaccination in patients treated with alemtuzumab. Rolla et al 41 found that despite induced B lymphopenia, alemtuzumab appeared to have no effect on immunoresponses to vaccines. RRMS patients treated with that drug maintained humoral immunomemory and an ability to develop an immunoresponse against such vaccines antidiphteria, antitetanus, antipoliomyelitis, type B anti– Haemophilus influenzae , anti meningococcus C and antipneumococcal polysaccharide.…”
“…For alemtuzumab, herpes prophylaxis with acyclovir is recommended for 2 years or until the CD4 + T cell count is at least 200 cells per microliter. An ongoing multicenter explorative phase IV study [ 242 , 243 ], aims to provide deeper insights into the immunological changes in alemtuzumab-MS treated patients and eventually identify biomarkers for treatment efficacy and safety.…”
In the past decade, the therapeutic arsenal for multiple sclerosis has expanded greatly. Newer more potent disease modifying therapies (DMTs) with varying mechanisms of actions are increasingly used early in the disease course. These newer DMTs include oral therapies (teriflunomide, dimethyl fumarate, fingolimod, siponimod, ozanimod, and cladribine) and infusion therapies (natalizumab, alemtuzumab, and ocrelizumab), and are associated with better control of disease activity and long-term outcomes in patients with MS compared to older injectable therapies (interferon beta and glatiramer acetate). However, they are associated with safety concerns and subsequent monitoring requirements. Adverse events are initially observed in phase 2 and 3 clinical trials, and further long-term data are collected in phase 3 extension studies, case series, and post-marketing reports, which highlight the need to periodically re-evaluate and adjust monitoring strategies to optimize treatment safety in an individualized approach.
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