The effects of natalizumab on the innate and adaptive immune system in the central nervous system

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Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system (CNS). Natalizumab (®Tysabri) is a humanized recombinant monoclonal antibody that binds to the alpha (α)4 chain of the α4 beta (β)1 integrin (very late activation antigen 4; VLA-4), and α4β7 integrin. Recently, two patients with MS and one patient with Crohn’s disease who were treated with natalizumab in the setting of clinical trials developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain with the polyoma virus JC. We recently showed that natalizumab decreases the numbers of CD4+ and CD8+ T lymphocytes, CD19+ B cells, and CD138+ plasma cells in the cerebrospinal fluid (CSF) of patients with MS on natalizumab therapy. In addition, we demonstrated that the cell numbers in CSF remained unchanged even 6 months after cessation of natalizumab treatment.

Introduction

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system (CNS). The egress of inflammatory cells from the peripheral blood into the CNS is considered a critical event in the pathogenesis of MS. Natalizumab (®Tysabri) was recently approved for the treatment of relapsing forms of MS. Natalizumab is a humanized recombinant monoclonal antibody that binds to the alpha (α)4 chain of the α4 beta (β)1 integrin (very late activation antigen 4; VLA-4), and α4β7 integrin [1]. Recently, two patients with MS and one patient with Crohn's disease who were treated with natalizumab in the setting of clinical trials developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain with the polyoma virus JC [2], [3], [4]. PML is almost invariably fatal, and there is currently no effective therapy [1]. Two of the three patients treated with natalizumab who developed PML died [2], [3], [4].

Our group recently showed that natalizumab decreases the numbers of CD4+ and CD8+ T lymphocytes, CD19+ B cells, and CD138+ plasma cells in the cerebrospinal fluid (CSF) of patients with MS on natalizumab therapy [5]. Interestingly, the number of CD4+ T cells and B cells was affected ten-fold more than those of other lymphocyte subsets [5], [6]. In addition, we demonstrated that the cell numbers in CSF remained unchanged even 6 month after cessation of natalizumab treatment [5]. Natalizumab has a pharmacological half-life of 11 days. Thus, the biological half-life of natalizumab far exceeds its pharmacological half-life, and the prolonged biological activity following α4 integrin antagonism cannot be explained by the presence of the drug. In peripheral blood, the number of CD4+ T cells also decreased with increasing numbers of natalizumab doses.

It is currently thought that one of the initial events in MS pathogenesis is the presentation of self or foreign antigens in secondary lymphoid organs. Activated lymphocyte have has access to the CNS, but needs to be re-activated in the CNS in order to direct cellular immune responses against CNS autoantigens. The perivascular spaces are the major antigen presenting compartment in the CNS, and hematopoetic antigen presenting cells (APC) in these spaces are absolutely required for initiation and perpetuation of CNS autoimmune disease [7], [8].

Section snippets

The effect of natalizumab therapy on leukocyte cell numbers in CSF of patients with MS

Following the recent reports on the unexpected occurrence of PML in patients treated with natalizumab [2], [3], [4], our group tested the hypothesis that treatment with natalizumab interferes with CNS immune surveillance [5], [6]. CSF JCV DNA and leukocyte phenotypes were assessed in 22 patients with MS enrolled in the SENTINEL trial and AFFIRM trial [5], [6]. One MS patient who received natalizumab at UTSW after its approval was also included [5], [6]. Six months after cessation of natalizumab

The effect of natalizumab therapy on the surface expression of CD49d on different lymphocyte subsets in patients with MS

For analysis of unbound α4 integrin (CD49d) on CD4+ and CD8+ T cells, three-color staining was performed by incubating whole blood with saturating amounts of directly conjugated monoclonal antibodies against CD49d, CD3, CD4, and CD8 (BD Biosciences) [16]. CD4+ T cells expressed significantly less unbound α4-integrin pre- and post-natalizumab therapy than CD8+ T cells [6].

These experiments provided interesting novel information on the differential effect of natalizumab on the expression of

The effect of natalizumab therapy on leukocyte cell numbers in peripheral blood of patients with MS

There was a mild leukocytosis and lymphocytosis in patients with MS treated with natalizumab. This was not surprising. It is known from pre-clinical studies that an elevation of leukocyte and lymphocyte numbers in peripheral blood is the most robust biomarker of successful α4 integrin antagonism. Six months after cessation of natalizumab, PB lymphocytes decreased significantly, but remained within normal limits [6]. The total white blood cell numbers did not change, further suggesting that

Conclusion

Our studies provide evidence that natalizumab alters the composition of the adaptive immune system in the periphery and the CNS. Following our observations on the effects of natalizumab therapy on leukocyte numbers in the CSF and peripheral blood of patients with MS treated with natalizumab, we speculated that natalizumab, in addition to blocking the entry of effector cells into the CNS, also reduces the number of antigen presenting cells (APC), and the expression of major histocompatibility

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