PubMed · 5592133
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M Spidla, I Latković, Z Kalafatić, I Simonović. 1967. [Acute suppurative thyroiditis].. https://pubmed.ncbi.nlm.nih.gov/5592133/
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Cytokine-induced neutrophil chemoattractant (CINC), a member of the IL-8 superfamily of chemokines, is one rat homologue of the three human GRO proteins. Neutralizing Abs against CINC have been shown previously to be efficacious in several models of inflammation, indicating that CINC is an important proinflammatory mediator in vivo. By introducing the N-terminal mutation delta1-5,ELR>AAR into CINC, we have developed a rat alpha-chemokine receptor antagonist (ra) analogous to a previously described mutant of human IL-8. Bacterially expressed CINCra had no chemotactic activity itself, but completely blocked the activity of physiologic concentrations of CINC when used as an antagonist in vitro. Inhibition by CINCra was specific, since it had approximately 10-fold less antagonist activity on the related, but distinct rat alpha-chemokine macrophage-inflammatory protein 2. When coinjected with zymosan into the peritoneal cavities of Lewis rats, 100 microg of CINCra inhibited neutrophil influx by approximately 40%, which was comparable with inhibition caused by polyclonal anti-CINC Abs.
Injection of parental spleen cells into BDF1 mice results in a graft-vs-host disease (GVHD), the nature of which is critically dependent on the parental haplotype. B6-->BDF1 mice develop a Th1-mediated immunosuppressive lethal GVHD, whereas DBA/2-->BDF1 mice develop a Th2-dependent chronic GVHD, characterized by autoantibody production and glomerulonephritis. In this study we show that neutralizing endogenous IL-12 for a brief period during the initiation of acute GVHD in B6-->BDF1 mice not only confers long term protection from the acute disease, but also permits full repopulation of the recipient with donor B6 lymphocytes. Antibody-treated animals showed normal T cell proliferation in response to Con A stimulation and remained healthy throughout the study. Splenocytes from such mice showed reduced in vitro production of IFN-gamma and enhanced production of IL-5 and IL-10, suggesting a permanent switch from a Th1 to a Th2 cytokine response, comparable to that associated with chronic GVHD in DBA/2-->BDF1 mice. In contrast to DBA/2-->BDF1 mice, however, anti-IL-12-treated B6-->BDF1 mice displayed only mild B cell hyper-responsiveness, as evidenced by a modest increase in serum IgG and IgE levels and moderate levels of anti-dsDNA Abs. Importantly, however, anti-IL-12-treated B6-->BDF1 mice showed no evidence of immune complex-mediated glomerulonephritis. These results demonstrate that neutralizing IL-12 is an effective means of preventing acute GVHD and does not result in the development of chronic GVHD, which might otherwise limit its application.
Autoimmune diabetes is caused by the CD4(+), T helper 1 (Th1) cell-mediated apoptosis of insulin-producing beta cells. We have previously shown that Th2 T cells bearing the same T cell receptor (TCR) as the diabetogenic Th1 T cells invade islets in neonatal nonobese diabetic (NOD) mice but fail to cause disease. Moreover, when mixed in excess and cotransferred with Th1 T cells, Th2 T cells could not protect NOD neonates from Th1-mediated diabetes. We have now found, to our great surprise, the same Th2 T cells that produced a harmless insulitis in neonatal NOD mice produced intense and generalized pancreatitis and insulitis associated with islet cell necrosis, abscess formation, and subsequent diabetes when transferred into immunocompromised NOD.scid mice. These lesions resembled allergic inflamation and contained a large eosinophilic infiltrate. Moreover, the Th2-mediated destruction of islet cells was mediated by local interleukin-10 (IL-10) production but not by IL-4. These findings indicate that under certain conditions Th2 T cells may not produce a benign or protective insulitis but rather acute pathology and disease. Additionally, these results lead us to question the feasibility of Th2-based therapy in type I diabetes, especially in immunosuppressed recipients of islet cell transplants.