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Tuftsin Combines With Remyelinating Therapy and Improves Outcomes in Models of CNS Demyelinating Disease.

ABSTRACT: Though promoting remyelination in multiple sclerosis (MS) has emerged as a promising therapeutic strategy, it does not address inflammatory signals that continue to induce neuronal damage and inhibit effectiveness of repair mechanisms. Our lab has previously characterized the immunomodulatory tetrapeptide, tuftsin, which induces an anti-inflammatory shift in microglia and macrophages. This targeted anti-inflammatory agent improves physical deficits in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we sought to determine whether tuftsin is also effective in combination with benztropine, an FDA-approved drug that stimulates remyelination, in both EAE and in the cuprizone model of demyelination. We show that combining these two agents to promote anti-inflammatory and remyelinating mechanisms alleviates symptoms in EAE and lessens pathological hallmarks in both MS models. Importantly, tuftsin is required to transform the inflammatory CNS environment normally present in EAE/MS into one of an anti-inflammatory nature, and benztropine is required in the cuprizone model to improve remyelination. Our data further support tuftsin's beneficial immunomodulatory activity in the context of EAE, and show that when studying remyelination in the absence of an autoimmune insult, tuftsin still activated microglia toward an anti-inflammatory fate, but benztropine was necessary for significant repair of the damaged myelin. Overall, tuftsin effectively combined with benztropine to significantly improve MS-like pathologies in both models.

SUBMITTER: Thompson KK

PROVIDER: S-EPMC6283261 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Tuftsin Combines With Remyelinating Therapy and Improves Outcomes in Models of CNS Demyelinating Disease.

Thompson Kaitlyn K KK Nissen Jillian C JC Pretory Amanda A Tsirka Stella E SE

Frontiers in immunology 20181128

Though promoting remyelination in multiple sclerosis (MS) has emerged as a promising therapeutic strategy, it does not address inflammatory signals that continue to induce neuronal damage and inhibit effectiveness of repair mechanisms. Our lab has previously characterized the immunomodulatory tetrapeptide, tuftsin, which induces an anti-inflammatory shift in microglia and macrophages. This targeted anti-inflammatory agent improves physical deficits in experimental autoimmune encephalomyelitis (E ...[more]

PMID: 30555470

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Project description:Background and objective The impact of COVID-19 infection and the effect of COVID-19 vaccinations on patients with demyelinating central nervous system disease in low middle income countries (LMIC's) have not been reported in detail earlier. We sought to identify risk factors associated with COVID-19 infection and the role of vaccination in order to develop management guidelines relevant to our patients. Methods A total of 621 patients from our registry that included 297 MS and 324 non MS disorders (Aquaporin- 4 antibody positive [50], Myelin oligodendrocyte glycoprotein antibody positive [81], seronegative [162] and clinically isolated syndrome [31]) were contacted. COVID-19 infection and vaccination status were queried. Patients who self reported COVID-19 infection based on a positive RT PCR report were compared with non infected patients to identify factors associated with susceptibility for COVID-19 infection. Univariate and multivariate analysis of potential risk factors included demographic and clinical features, body mass index (BMI), presence of comorbidities, absolute lymphocyte count, treatment types and vaccination status. Results Sixty seven patients with MS and 27 with non MS disorders developed COVID-19 infection. Among them 81 patients had mild infection and remained quarantined at home. All 13 patients who needed hospitalization recovered. Vaccination status was known in 582 patients among whom 69.8% had completed or taken one dose of vaccine at the time of inquiry. Majority of treated patients (61.3%) were on nonspecific immunosuppressants. In univariate analysis, presence of ≥1 comorbidity was significantly associated with COVID-19 infection in both MS (p value 0.01, OR-2.28, 95%CI- 1.18- 4.4) and non MS patients (p- 0.001, OR-4.4, 95% CI-1.88-10.24). In the latter, BMI ≥ 30 (p-0.04, OR-3.27, 95% CI- 0.98- 10.87) and EDSS score ≥ 3 (p-0.02, OR- 2.59,95% CI- 1.08- 6.23) were other significant associations. History of prior COVID-19 vaccination was associated with reduced frequency of COVID- 19 infection among MS (p- 0.001,OR- 0.24,95% CI- 0.13- 0.43) and non MS patients (p- 0.0001,OR-0.14, 95% CI- 0.058- 0.35). In multivariate analysis presence of comorbidities significantly increased and prior vaccination significantly reduced frequency of COVID-19 infection for both MS and related disorders. Concurrent disease modifying treatments showed a trend for association with infection. In the unvaccinated group, patients on disease modifying treatment were significantly at risk of infection, 81.5% unvaccinated and treated versus 18.5% who were unvaccinated and untreated (p- 0.0001, OR-10.1, 95% CI-0.56-2.11). Conclusion Frequency and severity of COVID-19 infection was low among our patient cohort. Higher rate of infection in the treated group was significantly seen among unvaccinated patients. Our preliminary results suggests that in LMIC's, where “off label therapies” with inexpensive immunosuppressives are the main disease modifying drugs, mRNA vaccinations appear safe and effective against severe COVID-19 infection.

Dataset Information

Tuftsin Combines With Remyelinating Therapy and Improves Outcomes in Models of CNS Demyelinating Disease.

Publications

Tuftsin Combines With Remyelinating Therapy and Improves Outcomes in Models of CNS Demyelinating Disease.

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