In vitro Evaluation of the Safety of Adalimumab for the Eye Under HTLV-1 Infection Status: A Preliminary Study

Abstract

Adalimumab (ADA), a fully human monoclonal tumor necrosis factor (TNF)-α antibody, is one of the most widely used biologics in the treatment of inflammatory diseases. However, ADA can exacerbate infectious conditions, induce paradoxical reactions such as inflammation, and cause neoplasia. Human T-cell leukemia virus type 1 (HTLV-1) is an infectious agent that induces inflammation and neoplastic infiltration in the eye. To date, numerous HTLV-1 carriers have been treated with adalimumab to suppress inflammation out of necessity, when standard anti-inflammatory drugs such as steroids and immunosuppressive agents have proven inadequate to control the inflammation. Here, we clarify the safety of adalimumab for the eye under HTLV-1 infectious conditions in vitro. We used the adult retinal pigment epithelial cell line (ARPE)-19 cell line as ocular resident cells, and used MT2 and TL-Om1 as HTLV-1-infected cells. ARPE-19 and MT2/TL-Om1 were co-cultured, and then adalimumab was administered. Production of cytokines and chemokines, TNF-α receptor (TNF-R), HTLV-1 proviral load (PVL), and apoptosis were measured to assess the effects of adalimumab. Contact between ARPE-19 and MT2/TL-Om1 produced inflammatory cytokines such as TNF, interleukin (IL)-6, IL-8 and IL-10, and transduced chemokines such as interferon-inducible protein-10 (IP-10), monocyte chemotactic protein-1 (MCP-1), monokine induced by interferon-γ (MIG), and regulated on activation, normal T cell expressed and secreted (RANTES). No inflammatory cytokines and chemokines were exacerbated by adalimumab. Expression of TNF-R on ARPE-19 and MT2/TL-Om1 cells, HTLV-1 PVLs of MT2/TL-Om1 cells, and cell growth rate and apoptotic rate of ARPE-19 were unaffected by adalimumab. In conclusion, adalimumab does not appear to exacerbate HTLV-1-associated inflammatory conditions in the eye or increase PVL in HTLV-1-infected T cells. These data suggest that adalimumab could be used safely for the eye under HTLV-1 infectious conditions from the perspective of in vitro assessment.

Safety of intraocular anti-VEGF antibody treatment under in vitro HTLV-1 infection

“…The PVL in HTLV-1–infected cells is the most commonly used biomarker for confirmation of the diagnosis and severity of HTLV-1–associated diseases ( 59 , 62 ). The effect of anti-VEGF treatment on the PVL of MT2 and TL-Om1 cells was measured after 48 h of culture with aflibercept.…”

“…An EZ1 Virus Mini kit v2.0 (Qiagen, Hilden, Germany) was used to prepare DNA from each sample in accordance with the manufacturer’s instructions. To measure HTLV-1 PVL in cells, quantitative real-time polymerase chain reaction (PCR) was used, as previously described ( 57 – 59 ). HTLV-1 Tax primer was used to determine the PVL (forward, 5’-CCCACTTCC CAGGGTTTGGA-3’; reverse, 5’-GGCCAGTAGGGCGTGA-3’) and probe (5’-FAM-CCAGTCTACGTGTTTGGA GACTGTGTACA-TAMRA-3’).…”

Mechanism of Secondary Glaucoma Development in HTLV-1 Uveitis

“…Data regarding the PVL of human tissues and cells in vivo and cells are scant. A previous investigation identified retinal pigment epithelium as a potential reservoir for HTLV-1 that contributes to the breakdown of the blood–ocular barrier, resulting in HU ( Liu et al, 2006 ; Uchida et al, 2019 ; Kurozumi-Karube et al, 2020 ). The present study therefore examined whether trabecular meshwork cells also function as reservoirs in HTLV-1-related diseases.…”

“…HTMCs were isolated from the juxtacanalicular and corneoscleral regions of human eyes. MT-2 cells were adopted as model HTLV-1-infected T cells ( Miyoshi et al, 1981 ; Yoshida et al, 1982 ), and Jurkat cells were used as HTLV-1-negative T cells as the control group ( Uchida et al, 2019 ; Yarishkin et al, 2019 ; Kurozumi-Karube et al, 2020 ). Co-cultured T cells were irradiated with 9,000 rads in all but cytometric beads assay.…”

“…According to the manufacturer’s instructions, an EZ1 Virus Mini kit v2.0 (Qiagen, Hilden, Germany) was used to prepare DNA from each sample. The HTLV-1 PVL in HTMCs was measured using quantitative real-time polymerase chain reaction (PCR), as described previously ( Fukui et al, 2017 ; Uchida et al, 2019 ; Kurozumi-Karube et al, 2020 ). PVL was quantified using the HTLV-1 Tax primer (forward, 5′-CCCACTTCCCAGGGTTTGGA-3′; reverse, 5′-GGCCAGTAGGGCGTGA-3′) and probe (5′-FAM- CCAGTCTACGTGTTTGGA GACTGTGTACA-TAMRA-3′).…”