SPLEEN-CELLS OF NONOBESE 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 contro ls, mice fed with pig spleen cells displayed much higher splenocyte pr oliferation in response to pig spleen and islet cells (p < 0.0001). Th is enhanced proliferation was specific for the species providing the f ed cells. Positive relationships (p < 0.01) were found between increas ed splenocyte proliferation in response to pig spleen or islet cells a nd the number of cells per feeding or the number of daily feedings. Co ncomitantly, while co-incubation with splenocytes from control mice le d 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 cell s. 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 a ctivation was unchanged by pig spleen cell feeding. The main T-splenoc yte subsets involved were restricted to MHC class II as they did not p roliferate in the presence of monoclonal antibodies (mAbs) directed at I-A molecules. In mice fed with pig spleen cells, as well as in contr ol mice, the blocking of CD4 + T cells with mAbs led to abolition of p roliferation (p < 0.002), while the blocking of CD8 + led to a less ma rked effect. However, an increase in the blocking effect of anti-CD8 m Abs was noted in mice fed with pig spleen cells (p < 0.02). In control mice, the main splenocyte subset involved during proliferation in res ponse to pig islet cells was Th1, since interferon gamma (IFN gamma) p roduction 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 product ion (p < 0.01) and the basal IL-10/IFN gamma, ratio (p < 0.001). It se ems likely that feeding with pig spleen cells shifted the Th1/Th2 bala nce 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 ce llular response, which may have implications for xenografts of pig isl ets. In a more general sense, physiological feeding of cells from xeno geneic species would appear to have certain effects on the immune syst em.