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Effects of natalizumab treatment on Foxp3+ T regulatory cells.

Stenner MP, Waschbisch A, Buck D, Doerck S, Einsele H, Toyka KV, Wiendl H - PLoS ONE (2008)

Bottom Line: Natalizumab does not alter the suppressive capacity of CD4+CD25(high)CD127(low)Foxp3+ Tregs under in vitro conditions.We provide a first detailed analysis of Natalizumab effects on the regulatory T cell population.We further the understanding of the mechanisms of action of Natalizumab by demonstrating that unlike other immunomodulatory drugs the beneficial therapeutic effects of the monoclonal antibody are largely independent of alterations in Treg frequency or function.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Julius-Maximilians University, Wuerzburg, Germany.

ABSTRACT

Background: Natalizumab, a monoclonal humanized antibody targeting the alpha-4 chain of very late activation antigen 4 (VLA-4) exerts impressive therapeutic effects in patients with relapsing-remitting multiple sclerosis. Our objective was to study impacts of Natalizumab therapy on Foxp3+ T regulatory cells (Tregs) in multiple sclerosis (MS) patients.

Methodology: A combined approach of in vitro and ex vivo experiments using T cells isolated from the peripheral blood of healthy donors and Natalizumab treated MS patients was chosen. We determined binding of Natalizumab and its effects on the frequency, transmigratory behaviour and suppressive function of Tregs.

Principal findings: Binding of Natalizumab and expression of CD49d (alpha-4 chain of VLA-4) differed between non-regulatory and regulatory cells. Albeit Foxp3+ Tregs had lower levels of CD49d, Natalizumab blocked the transmigration of Foxp3+ Tregs similar to non-regulatory T cells. The frequency of peripheral blood Tregs was unaffected by Natalizumab treatment. Natalizumab does not alter the suppressive capacity of CD4+CD25(high)CD127(low)Foxp3+ Tregs under in vitro conditions. Furthermore, the impaired function of Tregs in MS patients is not restored by Natalizumab treatment.

Conclusions: We provide a first detailed analysis of Natalizumab effects on the regulatory T cell population. Our prospective study shows that Foxp3+ Tregs express lower levels of VLA-4 and bind less Natalizumab. We further the understanding of the mechanisms of action of Natalizumab by demonstrating that unlike other immunomodulatory drugs the beneficial therapeutic effects of the monoclonal antibody are largely independent of alterations in Treg frequency or function.

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Frequency and mRNA of CD4+Foxp3+ T regulatory cells are not altered by Natalizumab therapy.(A) The frequency of CD4+Foxp3+ Tregs was determined by flow cytometry before and 30 days after the first infusion. (B) Foxp3 mRNA expression levels as analyzed by real-time PCR before and 3 months after initiation of therapy (n = 5).
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pone-0003319-g003: Frequency and mRNA of CD4+Foxp3+ T regulatory cells are not altered by Natalizumab therapy.(A) The frequency of CD4+Foxp3+ Tregs was determined by flow cytometry before and 30 days after the first infusion. (B) Foxp3 mRNA expression levels as analyzed by real-time PCR before and 3 months after initiation of therapy (n = 5).

Mentions: VLA-4 blockade is associated with an increase of the absolute lymphocyte numbers in the peripheral blood of MS patients [2], [3], however, flow cytometrical analysis of Foxp3+ T regulatory cells in patients treated with Natalizumab demonstrated that Treg frequency was not significantly affected by therapy 30 days after Natalizumab application (n = 15, Figure 3a). In accordance with our protein data, mRNA analysis of FOXP3 expression levels on PBMC before and 3 months after the first infusion yielded comparable results (n = 5, Figure 3b).


Effects of natalizumab treatment on Foxp3+ T regulatory cells.

Stenner MP, Waschbisch A, Buck D, Doerck S, Einsele H, Toyka KV, Wiendl H - PLoS ONE (2008)

Frequency and mRNA of CD4+Foxp3+ T regulatory cells are not altered by Natalizumab therapy.(A) The frequency of CD4+Foxp3+ Tregs was determined by flow cytometry before and 30 days after the first infusion. (B) Foxp3 mRNA expression levels as analyzed by real-time PCR before and 3 months after initiation of therapy (n = 5).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553177&req=5

pone-0003319-g003: Frequency and mRNA of CD4+Foxp3+ T regulatory cells are not altered by Natalizumab therapy.(A) The frequency of CD4+Foxp3+ Tregs was determined by flow cytometry before and 30 days after the first infusion. (B) Foxp3 mRNA expression levels as analyzed by real-time PCR before and 3 months after initiation of therapy (n = 5).
Mentions: VLA-4 blockade is associated with an increase of the absolute lymphocyte numbers in the peripheral blood of MS patients [2], [3], however, flow cytometrical analysis of Foxp3+ T regulatory cells in patients treated with Natalizumab demonstrated that Treg frequency was not significantly affected by therapy 30 days after Natalizumab application (n = 15, Figure 3a). In accordance with our protein data, mRNA analysis of FOXP3 expression levels on PBMC before and 3 months after the first infusion yielded comparable results (n = 5, Figure 3b).

Bottom Line: Natalizumab does not alter the suppressive capacity of CD4+CD25(high)CD127(low)Foxp3+ Tregs under in vitro conditions.We provide a first detailed analysis of Natalizumab effects on the regulatory T cell population.We further the understanding of the mechanisms of action of Natalizumab by demonstrating that unlike other immunomodulatory drugs the beneficial therapeutic effects of the monoclonal antibody are largely independent of alterations in Treg frequency or function.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Julius-Maximilians University, Wuerzburg, Germany.

ABSTRACT

Background: Natalizumab, a monoclonal humanized antibody targeting the alpha-4 chain of very late activation antigen 4 (VLA-4) exerts impressive therapeutic effects in patients with relapsing-remitting multiple sclerosis. Our objective was to study impacts of Natalizumab therapy on Foxp3+ T regulatory cells (Tregs) in multiple sclerosis (MS) patients.

Methodology: A combined approach of in vitro and ex vivo experiments using T cells isolated from the peripheral blood of healthy donors and Natalizumab treated MS patients was chosen. We determined binding of Natalizumab and its effects on the frequency, transmigratory behaviour and suppressive function of Tregs.

Principal findings: Binding of Natalizumab and expression of CD49d (alpha-4 chain of VLA-4) differed between non-regulatory and regulatory cells. Albeit Foxp3+ Tregs had lower levels of CD49d, Natalizumab blocked the transmigration of Foxp3+ Tregs similar to non-regulatory T cells. The frequency of peripheral blood Tregs was unaffected by Natalizumab treatment. Natalizumab does not alter the suppressive capacity of CD4+CD25(high)CD127(low)Foxp3+ Tregs under in vitro conditions. Furthermore, the impaired function of Tregs in MS patients is not restored by Natalizumab treatment.

Conclusions: We provide a first detailed analysis of Natalizumab effects on the regulatory T cell population. Our prospective study shows that Foxp3+ Tregs express lower levels of VLA-4 and bind less Natalizumab. We further the understanding of the mechanisms of action of Natalizumab by demonstrating that unlike other immunomodulatory drugs the beneficial therapeutic effects of the monoclonal antibody are largely independent of alterations in Treg frequency or function.

Show MeSH
Related in: MedlinePlus