Cardioprotective effects of the calcineurin inhibitor FK506 and the PAF receptor antagonist and free radical scavenger, EGb 761, in isolated ischemic/reperfused rat hearts.

Effects of the calcineurin inhibitor FK506, the platelet-activating factor (PAF) antagonist, and free radical scavenger Ginkgo biloba extract, EGb 761, and their combination on reperfusion-induced ventricular fibrillation (VF), ventricular tachycardia (VT), and recovery of cardiac function were studied after 30 min of global ischemia followed by 2 h of reperfusion in isolated rat hearts. In the first series of studies, rats received a daily (oral) dose of 0, 1, 5, 10, 20, or 40 mg/kg/day FK506 for 10 days. FK506 dose-dependently reduced the incidence of reperfusion-induced total (irreversible plus reversible) VF from a value of 92% for untreated animals to 92% (NS), 83% (NS), 67% (NS), 33% (p<0.05), and 25% (p<0.05), for doses of 1-40 mg/kg/day, respectively, with effects on incidence of VT showing the same pattern. FK506, between 20 and 40 mg/kg/day, also resulted in significant recovery of postischemic cardiac function. In the second series of studies, rats were treated with EGb 761 alone or in combination with FK506. Whereas no significant reduction in arrhythmias or improvement in cardiac function resulted from a single intervention of EGb 761 at 25 mg/kg/day, combined treatment of rats with 25 mg/kg/day of EGb 761 and 1 or 5 mg/kg/day of FK506 resulted in a reduction in total and irreversible VF of 92% and 92% to 42% (p<0.05) and 33% (p<0.05), 25% (p<0.05) and 8% (p<0.05), respectively, versus untreated control animals, paralleled by similar effects on the incidence of VT and accompanied by significant improvements in postischemic cardiac function. Our results demonstrate a novel cardioprotective characteristic of FK506 and suggest that combination therapy by using FK506 plus EGb 761 synergistically improves postischemic cardiac function, while reducing the incidence of reperfusion-induced VF and VT, which may expand the clinical utility of FK506 and allow therapy with FK506 at lower doses than are currently useful.

Abnormal lymphocyte subsets in Kuwaiti patients with type-1 insulin-dependent diabetes mellitus and their first-degree relatives.

Circulating lymphocyte subset imbalance is associated with type-1 insulin-dependent diabetes mellitus (IDDM). To examine the imbalance in these immunoregulatory cells in Kuwaitis with type-1 diabetes and their first-degree relatives we analysed T-lymphocyte subsets and HLA-DR expression (activation) in 18 IDDM patients with a family history of IDDM and 18 non-diabetic first-degree relatives of the IDDM patients. Both IDDM patients and their first-degree relatives showed a mild lymphopenia. Total T lymphocytes, CD3+ cells, in IDDM patients and their first-degree relatives were reduced compared to control subjects (P < 0.001). Total B lymphocytes, CD19+ cells, was increased in IDDM patients (P = 0.001), but was comparable to controls in IDDM patients' first-degree relatives. No quantitative abnormality was demonstrated in CD4+ cells in IDDM patients; however, these cells were higher in their first-degree relatives (P = 0.0089). Suppressor T lymphocytes, CD8+ cells, in first-degree relatives and controls were not significantly different; however, these cells were significantly reduced in IDDM patients (P = 0.001). The ratio of CD4+/CD8+ cells was higher in IDDM patients and their first-degree relatives compared to controls (P = 0.0007 and 0.0103, respectively). Activated T lymphocytes, HLA-DR+ CD3+ cells, were significantly increased in IDDM patients and their first-degree relatives. HLA-DR3 was the most common antigen found in IDDM patients (77% vs. 20% in controls, P = 0.00021). The second most common antigen was HLA-DR4 (55% vs. 24% in controls, P = 0.0566). However, no relationship was found in the levels of CD3+, CD4+ or CD8+ cells in patients possessing either DR3 or DR4. These results suggest that T-lymphocyte subset imbalance not only characterizes the cellular autoimmunity in the pathogenesis of IDDM but may also be significant in early pre-diabetic stages in those with a family history of IDDM.

Study of HLA class I/IL and T lymphocyte subsets in Kuwaiti vitiligo patients.

HLA polymorphisms of class I and class II MHC were investigated in 40 Kuwaiti vitiligo patients and in 40 controls using microcytotoxicity assay. HLA-B21, Cw6 and DR53 were increased significantly in patients compared to controls (P = 0.00001, 0.00001 and P = 0.0053 respectively) while HLA-A19, DR52, were significantly decreased (P = 0.00236, 0.05, respectively). Total T-cells, T4 and T8 were measured as CD2, CD4 and CD8 respectively by flow cytometry. Vitiligo patients showed significant increase in CD4 compared to controls (P = 0.03). Our findings suggest that HLA-B21 and Cw6 and DR53, are susceptible genes of vitiligo, while A19 and DR52 are protective genes in the Kuwaiti population.

Reduced levels of CD2+ cells and T-cell subsets in patients with sickle cell anaemia.

Investigation of B lymphocytes and T-lymphocyte subsets in patients with homozygous sickle cell disease (SCD) who were not in crisis and who did not demonstrate infectious complications showed these cell populations to be abnormal. The proportion of total T cells (CD2+) was significantly reduced (P = 0.002) when compared with controls. B cells (CD19+) were significantly elevated in sicklers (P = 0.029). Helper/inducer (CD4+) and suppressor/cytotoxic (CD8+) cells were significantly reduced (P = 0.019 and P = 0.0001, respectively). The average ratio of T cells/B cells in SCD patients was 3.7:1, while controls showed a ratio of 7.2:1. Since patients with SCD are abnormally susceptible to severe infections, we discussed the implications of low levels of CD4+ and CD8+ cells and the consequent cytokine imbalance in SCD patients which may lead to impairment of immunity.