Deviation of pancreas‐infiltrating cells to Th2 by interleukin‐12 antagonist administration inhibits autoimmune diabetes

Abstract

Nonobese diabetic (NOD) mice develop spontaneous insulin-dependent diabetes mellitus (IDDM), and the pancreas-infiltrating T cells invariably show a Th1 phenotype. We demonstrated here that the interleukin (IL)-12 antagonist (p40)2 can deviate the default Th1 development of naive T cell receptor (TCR)-transgenic CD4+ cells to the Th2 pathway in vitro. Although (p40)2 does not modify the cytokine profile of polarized Th1 cells, it prevents further recruitment of CD4- cells into the Th1 subset. To study the involvement of Th1 and Th2 cells in the initiation and progression of IDDM, we targeted endogenous IL-12 by administration of (p40)2 in NOD mice. (p40)2 administration to NOD mice inhibits interferon-gamma but not IL-10 production in response to lipopolysaccharide (LPS) or to the putative autoantigen IA-2. Serum immunoglobulin isotypes determined after (p40)2 treatment indicate an increase in Th2 and a decrease in Th1 helper activity. Administration of (p40)2 from 3 weeks of age onwards, before the onset of insulitis, results in the deviation of pancreas-infiltrating CD4+ but not CD8+ cells to the Th2 phenotype as well as in the reduction of spontaneous and cyclophosphamide-accelerated IDDM. After treating NOD mice with (p40)2 from 9 weeks of age, when insulitis is well established, few Th2 and a reduced percentage of Th1 cells are found in the pancreas. This is associated with a slightly decreased incidence of spontaneous IDDM, but no protection from cyclophosphamide-accelerated IDDM. In conclusion, deviation of pancreas-infiltrating CD4+ cells to Th2 is associated with protection from IDDM. However, targeting IL-12 after the onset of insulitis, when the pancreas contains polarized Th1 cells, is not sufficient to induce an effective immune deviation able to significantly modify the course of disease.

Essential pathogenic role of endogenous IL‐18 in murine diabetes induced by multiple low doses of streptozotocin. Prevention of hyperglycemia and insulitis by a recombinant IL‐18‐binding protein: Fc construct

“…It is therefore interesting that paradoxical results have been obtained when treating NOD mice with either exogenously administered IL-12 or specific IL-12 inhibitors (monoclonal antibody, the (p40)2 antagonist); the outcome apparently depending on the time of administration during the disease development [27][28][29][30][31][32]. More concording data have recently been obtained by use of transgenic mice whose pancreatic cells constitutively express either biologically active IL-12 or the IL-12 p40 homodimer a naturally occurring antagonist of IL-12 [33,34].…”

Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains

“…However, the B6 backcrosses would not have detected a NOD-dominant gene effect, while in the NOR crosses a potentially protective effect of the NOR allele may not be sufficiently strong to be detected in the presence of all the other susceptibility alleles shared between the NOD and NOR strains. Furthermore, studies that have shown the ability of IL-12(p40) 2 to suppress diabetes development in NOD mice 21,22 utilised the recombinant form derived from B6 rather than NOD. The implications of these studies may need to be re-evaluated if either of the two amino acid replacements identified here would be found to affect binding of IL-12p75 or IL-12(p40) 2 to the IL-12 receptor.…”

Regulation of cytokine production during phagocytosis of apoptotic cells

“…IL-12 is also an important player in Tcell-mediated autoimmunity [27,28]. Specifically, IL-12 administration exacerbates autoimmune phenomena by inducing the differentiation of Th1 autoreactive cells [29,30] whereas the lack of IL-12/IL-23 p40 in genetically deficient mice or mice treated with anti-IL-12 antibody abrogated diseases in experimental models of autoimmunity such as insulin-dependent diabetes mellitus (IDDM) in NOD mice [31,32], experimental allergic encephalomyelitis (EAE) [33,34], experimental autoimmune uveitis (EAU) [35,36], and collagen-induced arthritis (CIA) [37]. Aberrant levels of IL-12 are produced by macrophages isolated from young mice prone to lupus (MRL and NZB/W) [38].…”