Spleen cells of non-obese diabetic mice fed with pig splenocytes display modified proliferation and reduced aggressiveness in vitro against pig islet cells

A new means of modifying xenogeneic reaction to pig islet cells, which involves pre-feeding with pig spleen cells, was investigated for the first time in the non-obese diabetic (NOD) mouse. Compared with controls, mice fed with pig spleen cells displayed much higher splenocyte proliferation in response to pig spleen and islet cells (p < 0.0001). This enhanced proliferation was specific for the species providing the fed cells. Positive relationships (p < 0.01) were found between increased splenocyte proliferation in response to pig spleen or islet cells and the number of cells per feeding or the number of daily feedings. Concomitantly, while co-incubation with splenocytes from control mice led to inhibition of both basal and stimulated insulin releases from pig islet cells (p < 0.001), this aggressiveness was abolished (p < 0.001) after co-culture with splenocytes from mice fed with pig spleen cells. The proliferative responses of splenocytes from fed or control mice to pig islet or spleen cells were abolished after removal of plastic-adherent cells, indicating that the major indirect pathway of T-cell activation was unchanged by pig spleen cell feeding. The main T-splenocyte subsets involved were restricted to MHC class II as they did not proliferate in the presence of monoclonal antibodies (mAbs) directed at I-A molecules. In mice fed with pig spleen cells, as well as in control mice, the blocking of CD4 + T cells with mAbs led to abolition of proliferation (p < 0.002), while the blocking of CD8 + led to a less marked effect. However, an increase in the blocking effect of anti-CD8 mAbs was noted in mice fed with pig spleen cells (p < 0.02). In control mice, the main splenocyte subset involved during proliferation in response to pig islet cells was Th1, since interferon γ (IFNγ) production increased significantly (p < 0.01) while that of interleukin-10 (IL-10) increased only slightly. The main change observed in mice fed with pig spleen cells was a marked increase in basal IL-10 production (p < 0.01) and the basal IL-10/IFNγ ratio (p < 0.001). It seems likely that feeding with pig spleen cells shifted the Th1/Th2 balance towards a dominance of Th2-type class II-restricted CD4 + T cells, which may have been conducive to activating CD8 + suppressor T cells. In any event, oral administration of pig cells modified xenogeneic cellular response, which may have implications for xenografts of pig islets. In a more general sense, physiological feeding of cells from xenogeneic species would appear to have certain effects on the immune system. [Diabetologia (1998) 41: 955–962]