HEMATOPOIETIC STEM-CELL DEFECTS UNDERLYING ABNORMAL MACROPHAGE DEVELOPMENT AND MATURATION IN NOD LT MICE - DEFECTIVE REGULATION OF CYTOKINERECEPTORS AND PROTEIN-KINASE-C

The immunopathogenesis of autoimmune insulin-dependent diabetes in NOD mice entails defects in the development of macrophages (Mos) from hem atopoietic precursors. The present study analyzes the cellular and mol ecular basis underlying our previous finding that the Mo growth factor colony-stimulating factor 1 (CSF-1) promotes a reduced level of promo nocyte proliferation and Mo development from NOD bone marrow. CSF-1 st imulation of NOD marrow induced Mos to differentiate to the point that they secreted levels of tumor necrosis factor alpha equivalent to tha t of controls. However, CSF-1 failed to prime NOD Mos to completely di fferentiate in response to gamma-interferon, as shown by their decreas ed lipopolysaccharide-stimulated interleukin 1 secretion. These defect s, in turn, were associated with an inability of CSF-1 to up-regulate c-fms (CSF-1 receptor) and Ifgr (gamma-interferon receptor) expression . Even though the combination of CSF-1 and gamma-interferon up-regulat ed c-fms and Ifgr transcript levels in NOD Mos to levels induced in co ntrol Mos by CSF-1 alone, the protein kinase C activities coupled to t hese receptors remained 4-fold lower in NOD Mos than in Mos derived fr om the marrow of diabetes-resistant NON and SWR control mice. Despite expressing the diabetogenic H-2g7 haplotype, Mos derived from cytokine -stimulated marrow of the NON.H-2g7 congenic stock were functionally m ore mature than similarly derived Mos from NOD mice. Whereas diabetes resistance was abrogated in 67% of irradiated (NOD x NON)F1 females re constituted with NOD marrow, no recipients became diabetic after recon stitution with a 1:1 mixture of marrow from NOD and the congenic stock . Thus, failure to develop functionally mature monocytes may be of pat hogenic significance in NOD mice.