Treatment with neutralizing antibodies specific for IL-1beta prevents cyclophosphamide-induced diabetes in nonobese diabetic mice.

Interleukin-1 (IL-1) has been shown to be involved in the pathogenesis of IDDM, but it is not clear which form, IL-1alpha or IL-1beta, is predominantly implicated. In this study, we have evaluated the contribution of IL-1beta by treating diabetes-prone nonobese diabetic (NOD) mice with specific neutralizing antibodies. First, we assessed the neutralizing potential of these antibodies in C57BL/6 mice under acute septic shock by measuring IL-1beta in sera 4 h after lipopolysaccharide injection. One milligram and 0.1 mg of anti-IL-1beta antibodies (Abs) were capable of neutralizing the IL-1beta produced, and the effect persisted for at least 5 days. Second, we evaluated the role of IL-1beta in the cyclophosphamide (CY)-accelerated model of diabetes. Nondiabetic male NOD mice were injected with 200 mg/kg CY and treated twice weekly with anti-IL-1beta Ab. The incidence of diabetes reached 76 and 100% in the control groups treated with 0.25 and 0.1 mg rabbit IgG, respectively. In contrast, only 34% of mice treated with 0.25 mg of anti-IL-1beta Ab became diabetic. In the group treated with 0.1 mg of anti-IL-1beta Ab, 89% of the mice became diabetic in the same period of time, demonstrating that the protective effect was dose dependent. Our results show that IL-1beta is a critical effector molecule in this model of IDDM and that its specific inhibition could be an attractive target for therapeutic intervention.

[Ambulatory measurement of Korotkoff sounds timing (QKD interval) in a normal population]. / Mesure ambulatoire du temps d'apparition des bruits de Korotkoff (intervalle QKD) dans une population normale.

Ambulatory monitoring of Korotkoff sounds appearance time (QKD interval) was performed during 24 hours in 131 normal subjects (85 males, 46 females, aged 14-78 years, mean 36 +/- 15 years) with a new device (Diasys 200RK, Novacor-France). This device allows simultaneous measurements of blood pressure, heart rate and QKD interval at programmed intervals, every 15 minutes in this study. For each patient we calculated the average 24th QKD interval, the QKD interval for a systolic BP of 100 mmHg and a heart rate of 60 bt/min (QKD: 100-60), and the slope (S) of the variations of the QKD interval against systolic BP and pulse pressure (PP). Results are presented for each 10 years age group (mean +/- SD).

Analysis of susceptibility of NOD mice to spontaneous and experimentally induced thyroiditis.

Beside diabetes, non-obese diabetic (NOD) mice develop sporadic lymphoid infiltration of the thyroid gland, mimicking Hashimoto's thyroiditis. We have examined the prevalence of those manifestations in NOD mice, the influence of the major histocompatibility complex (MHC) and the association with autoantibodies. The incidence at 1 year is of 14.3% in wild-type NOD mice versus 19.6% in congenic NOD.H2k mice. The moderate, but statistically significant difference, based on the analysis of 161 NOD and 169 NOD.H2k mice, suggests that MHC genes partially control spontaneous NOD thyroiditis. Autoantibodies against thyroglobulin (Tg) are mouse specific and their presence correlates closely with thyroiditis. The strong correlation between cellular and humoral anomalies therefore resembles Hashimoto's thyroiditis. NOD and NOD.H2k mice actively immunized against Tg develop severe chronic lesions with epithelium necrosis and interstitial tissue fibrosis. Most interestingly, those lesions do not regress spontaneously as in CBA/J mice. Paradoxically, the response to Tg of lymph node cells from NOD mice is weaker both in proliferation and cytokine production. The defect is most evident for interferon-gamma-producing T cells and is reflected in the marked deficit in IgG2a antibodies. Thus a moderate anti-Tg response seems to favor chronicity of thyroiditis. In conclusion, NOD and NOD.H2k mice offer a unique opportunity of analyzing the factors leading to immune chronicity in a genetic context which promotes autoimmune endocrinopathies.

Non-obese diabetic (NOD) mice are genetically susceptible to experimental autoimmune prostatitis (EAP).

Rodents develop inflammatory, non-infectious, prostatitis upon autoimmuniz-ation with male accessory gland (MAG) extracts in complete Freund's adjuvant (CFA). Although there appears to be differences among strains, with respect to susceptibility to induction, specific details are not known about the genetic bases of such differences. Because NOD mice have inherited a genetic predisposition to autoimmune lesions affecting, apart from the islets of Langerhans, a large array of secretory glands such as salivary glands, thyroid, parathyroids and adrenal cortex, we selected this strain to assess the influence of inherited genes upon experimentally-induced autoimmune prostatitis (EAP). Indeed, MAG extracts injected into young NOD males in association with CFA cause a severe inflammatory reaction in the prostate, accompanied by a humoral and T cell-mediated response. NOD mice develop a more aggressive form of EAP than Wistar rats, the strain of reference used to establish the model. In NOD mice, disease begins earlier, affects 100% of the animals, does not require boosting and leads to florid infiltrates circumscribed to lateral and dorsal prostatic lobes. Immune mice develop a T cell-mediated response to MAG assessed by in vitro proliferation and accompanied by the release of IFN-gamma, whereas IL-4 is not detectable in the same culture super-natants. To assess the influence of the NOD background genes upon EAP susceptibility, we tested C57BL/6.H2(g7) mice in parallel. NOD mice are considerably more susceptible to EAP induction than congenic C57BL/6.H2(g7) mice. Both strains demonstrate a detectable humoral and cell-mediated response against MAG, but the histopathological manifestations are considerably more dramatic in NOD than in the C57BL/6.H2(g7) strain. Our results thus support the notion that NOD mice have background genes which favour severe autoimmune manifestations, irrespective of the target tissue.

Effect of SR 27417 on the binding of [3H]PAF to rabbit and human platelets and human polymorphonuclear leukocytes.

SR 27417, the first member of a newly developed PAF antagonist series, fully and competitively displaced [3H]PAF from its high-affinity binding sites on washed rabbit and human platelets with Ki values of 57 +/- 0.02 and 50 +/- 0.8 pM (n = 3), respectively. Studies carried out in parallel demonstrated that SR 27417 was 5-7-times more potent than C16-PAF itself and more than 50-60-fold as active as the best synthetic PAF antagonist yet described. Additionally, SR 27417 selectively and competitively inhibited the specific binding of [3H]WEB-2086, a selective PAF receptor antagonist to its high-affinity receptors on washed rabbit platelets (IC50 = 0.18 +/- 0.01 nM). On human polymorphonuclear leukocytes, [3H]PAF bound to two classes of specific binding sites with high (KD = 0.31 +/- 0.05 nM; Bmax = 1.2 +/- 0.07 fmol/10(6) cells) and low affinity (KD = 11.1 +/- 1.5 nM; Bmax = 13.7 +/- 0.8 fmol/10(6) cells). On these cells, SR 27417 selectively inhibited the specific binding of [3H]PAF to its high- and low-affinity receptors (IC50 values of 0.17 +/- 0.02 and 6.9 +/- 0.7 nM, respectively) and displayed the same inhibitory pattern as that already reported on platelets. In conclusion, SR 27417 can be considered as the most potent PAF receptor antagonist described to date.