Vedolizumab does not reduce the CD4+:CD8+ ratio in the CSF of healthy volunteers

Vedolizumab (VDZ) (previous versions MLN0002, MLN02, LDP-02) is a gut-selective integrin antagonist in phase 3 development for treatment of ulcerative colitis (UC) and Crohn's disease (CD). VDZ binds to the GI-homing integrin α4β7, antagonizing its interaction with MAdCAM-1 and thereby preventing migration of memory T lymphocytes into the GI tract. Natalizumab (NTZ), an integrin antagonist that binds to 2 integrins, α4β7 and α4β1, is approved for the treatment of multiple sclerosis (MS) and CD, and is believed to exert its pharmacologic effect by blocking migration of white blood cells (WBCs) into the central nervous system (CNS) and GI tract. NTZ is associated with progressive multifocal leukoencephalopathy (PML), believed to be caused by NTZ's inhibition of WBC migration into the CNS. NTZ decreases WBCs and helper (CD4+) and cytotoxic (CD8+) T lymphocytes, and reduces the CD4+:CD8+ ratio to <1 in the cerebrospinal fluid (CSF) of MS patients. VDZ does not decrease WBCs, or CD4+ and CD8+ T lymphocytes, or the CD4+:CD8+ ratio in the CSF of rhesus monkeys. We hypothesized that VDZ would not alter CSF lymphocyte counts in humans. Our objective was to study the effects of VDZ on the CD4+:CD8+ lymphocyte ratio and cell counts in CSF of healthy volunteers. Healthy subjects ages 18-45 underwent lumbar puncture (LP) before and after receiving a single 450 mg dose of VDZ. Each subject served as his/her own control. Approximately 15 mL CSF was obtained from each subject for immunophenotyping. CSF samples were included for analyses only if they met the following criteria: ≤10 RBCs/μL per sample (to minimize peripheral blood contamination), negative CSF culture result, adequate T-lymphocyte numbers in each flow cytometry sample, and no detection of serum antibodies to VDZ. 14 subjects underwent LP and 13 were eligible for analysis. Mean (SE) CD4+:CD8+ ratios were 3.59 (0.273) at baseline and 3.60 (0.265) post-VDZ. The mean ratio difference (SE; 90% CI) pre- and post-VDZ was 0.01 (0.197; -0.337, 0.363). No subject had a postdose CD4+:CD8+ ratio <1. No significant changes in CSF % CD4+ and % CD8+ T lymphocytes were observed after VDZ dosing: mean % CD4+ predose, 75%; postdose, 74%; mean % CD8+ predose, 22%; postdose, 22%. These data show that VDZ does not affect CSF CD4+ and CD8+ cell counts or the CD4+:CD8+ ratio in healthy volunteers. These results are consistent with VDZ's lack of effect on both physiologic CNS immune surveillance and pathologic CNS inflammation in monkeys. VDZ's gut selectivity, including lack of observed effect on lymphocytes in the brain, may translate to a lower risk of opportunistic infections of the CNS such as PML.