Ingham Institute for Applied Medical Research
Department of Neurology

Author Of 1 Presentation

Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0406 - The effect of cladribine upon naïve and activated CD4+ T regulatory cells in MS patients. (ID 1953)

Speakers
Presentation Number
P0406
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The administration of oral cladribine has been shown to reduce relapses and slow accumulation of disability. The Clarity study demonstrated that up to 70% of patients had a prolonged period of no relapses for some years after the second year of therapy. The cause for the prolonged period of relative remission is not entirely understood.

Objectives

To observe changes in the T cells subsets at 3, 6 and 12 months after treatment with cladribine, in particular, the effector and T regulatory cell subsets of CD4+T cells. We compared changes in 10 healthy donors (HD) and 10 patients with MS receiving cladribine over 12 months.

Methods

Blood was collected from healthy donors and MS patients (n=10/group) before treatment with Cladribine and 1, 3, 6 and 12 months after the treatment. Peripheral blood mononuclear cells (PBMC) were isolated using Ficoll and subjected to flow FACS. CD4+CD25+CD127loFoxp3+T regulatory cells (Treg) were gated into populations based on CD45RA expression, naïve Treg that express CD45RA (Population I) and activated Treg where CD45RA is lost. Most activated Treg increase expression of Foxp3 and CD25 (Population II) whereas less activated Treg do not increase CD25 and Foxp3 expression (Population III). Activated Treg migrate to sites of inflammation by expression of chemokine receptors similar to effector T cell subtypes; Th1-like (CXCR3), Th17-like (CCR6).

Results

Lymphocyte and CD4+ cell counts fell but were recovering at 12 months in MS treated with cladribine but remained stable in HD. CD4+CD25+CD127loTreg numbers fell but their proportion of CD4+T cells increased in MS treated, but remained stable in HD. The proportion of CD4+CD25+CD127loFoxp3+Treg was preserved. There were no changes in the proportion of Treg in population I, II or III. CXCR3+ cells in Population II and IV declined over 12 months, whereas CCR6+ cells in population II and IV declined at 1 and 3 months but recovered by 6 and 12 months

Conclusions

There was a drop in the CD4+ cell numbers although the proportion within lymphocyte did not change. The number of Naïve Treg (population I) dropped but not to zero and then slowly recovered. The number of activated Treg (Population II) increased by 6 months. The relative preservation of Population I may be partially responsible for the absence of autoimmune diseases that is seen in some circumstances of immune reconstitution. Whether the persistence or presence of Population II is associated with prolonged clinical response will require further study.

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