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Notes: The specificity of the recognition of type II collagen (CII) by T cells in the DBA/1 mouse was analysed using fragments of chick and rat CII obtained by cyanogen bromide (CB) cleavage. Firstly DBA/1 mice were immunized with chick CB fragments 5, 8, 9, 10, 11 and 12. Ten days later the draining lymph node cells were cultured with rat and mouse CII and the proliferative response was determined by incorporation of [3H]thymidine All peptides were capable of triggering T cells recognizing rat CII but only CB9 immunized mice responded well to mouse CII. Secondly, lymph node cells from CBA/1 mice immunized with rat and mouse CII were cultured with the CB fragments including rat CB10 and CB11, and the proliferative response was determined. After immunization with rat CH, the response was strongly dominated by T cells recognizing CB11 with equal responses against chick and rat CB11. After immunization with mouse CH only rat CB10 gave a strong response. It is concluded that several epitopes on the CH molecule can be recognized by T cells in the DBA/1 mouse and that most of these epitopes are shared by rat and chick CH but not mouse CH. These epitopes exhibit strong immunodominance. In mice immunized with intact heterologous CH, the immunodominant response is directed against one or more epitopes on the CB11 fragment present on several heterologous CH but apparently not on mouse CH. In mice immunized with autologous CH the immunodominant response is directed against one or more epitopes on the CBl0 fragment present on rat and mouse CH. They are either absent in chick CH or located in the carboxyterminal end of the CB10 fragment where a cyanogen bromide cleavage site is present in chick CH but not in rat CH. These results suggest that the proposed importance of CBH in collagen-induced arthritis is due to activation of T cells reactive with heterologous CH only. These cells may be important for the induction of the strong auto-antibody-response after immunization with heterologous CH. Structures of importance for direct T cell involvement in the arthritic process and recognized by autoreactive T cells are suggested to be found on CB10.

Notes: Abstract Cultured rat synovial cells generate PGE2 upon stimulation with a factor derived from rate polymorphonuclear cells (Prostaglandins27, 697, 1984). E-5110 inhibited PGE2 generation by the synovial cells. The IC50 values (μM) for inhibition of PGE2 generation were 0.026 for E-5110, 0.008 for indomethacin, 0.112 for piroxicam, 0.003 for R-830, 0.667 for BW-755C and 2.05 for benoxaprofen. Calcium ionophore A-23187-stimulated LTB4 generation by human neutrophils was inhibited by E-5110 with an IC50 value of 0.20 μM, which was similar to NDGA. The inhibition of LTB4 by E-5110 was more potent than that of R-830, BW-755C or benoxaprofen. E-5110 also inhibited superoxide generation by human neutrophils stimulated with opsonized zymosan, f-Met-Leu-Phe and phorbol myristate acetate. These results indicate that E-5110 is a potent dual inhibitor that suppresses superoxide generation.

Notes: Abstract The antiinflammatory activity of a novel pyrrolidone derivative E-5110 was investigated using anti-inflammatory, analgesic and antipyretic animal models in comparison to indomethacin (IND) and piroxicam (PIR). The acute antiinflammatory activity of E-5110 on carrageenin paw edema was similar to IND, and half of PIR. E-5110 inhibited the pleural exudate volume and leucocyte infiltration in a reversed passive Arthus reaction more potent than IND. The chronic inflammatory responses in the established adjuvant- and type II collagen-induced arthritis were suppressed by E-5110 similar to IND and PIR. The analgesic potency of E-5110 was similar to IND and PIR, but the antipyretic activity of E-5110 was more potent than that of IND, and slightly more potent than that of PIR. The ulcerogenic effect of E-5110 on rat gastric mucosa was less than that of the reference drugs.