Anti-T cell immunoglobulin and mucin domain-2 monoclonal antibody exacerbates collagen-induced arthritis by stimulating B cells (1)
The T cell immunoglobulin and mucin domain (TIM) family has recently been implicated in the regulation of T cell activation and immune responses. Four proteins (TIM-1, -2, -3, and -4) have been identified in mice and three proteins (TIM-1, -3, and -4) have been found in humansTIM-1 and TIM-3 have polymorphism at the protein level, represented by BALB/c-type and B6-type. TIM-2 was also identified as a ligand for semaphoring 4A (Sema4A), which was expressed on activated macrophages, B cells, T helper (Th) 2 cells, and dendritic cells.
DBA/1 mice were immunized intradermally at the base of the tail with 200 μg of bovine type II collagen in 0.05 M acetic acid, emulsified in CFA. Twenty-one days after primary immunization, some groups of mice were boosted in the same way with 200 μg of CII in 0.05 M acetic acid, emulsified in incomplete Freund’s adjuvant (IFA). The immunized mice were intraperitoneally administered with 300 μg of anti-TIM-2 mAbs every three days from day 0 to day 42, or day 0, 2, 5, 8, 11, 14, and 17 for the early phase, or day 15, 17, 20, 23, 26, 29, and 32 for the late phase.
Anti-TIM-2 mAb (RMT2-14) administration resulted in significantly more severe arthritis than the control IgG-treated mice in CIA. In the early phase, administration of RMT2-14 (P < 0.05 on day 17 to 27 and day 37 to 39) and RMT2-25 (P < 0.05 on day 32 to 39) significantly enhanced the development of CIA as compared with control IgG. In the late phase, administration of RMT2-14, RMT2-25, or RMT2-26 did not affect the disease severity.
Denatured CII-specific proliferative response and production of IFN-γ and IL-17 were almost comparable between the anti-TIM-2 mAb-treated mice and the control IgG-treated mice.
RMT2-14 mAb treatment increased anti-CII IgG2a and IgG2b antibody levels on day 16 and 24 but not IgG1. Similarly, RMT2-25 increased anti-CII antibody levels of IgG1, 2a and 2b on day 32 but RMT2-26 failed.
Supernatants from purified splenic B-cells culture with the RMT2-14 and RMT2-25 showed higher IgG2b/λ and IgG3/κ levels as compared with the control IgG and RMT-2-26 cultures.
The administration of TIM-2-Ig at the induction phase or just before disease onset reduced the severity of experimental autoimmune encephalomyelitis (EAE), which is a Th17-mediated autoimmune disease model. The mechanism for such differential roles of TIM-2 in EAE and Th1-mediated disease of CIA is presently unknown.