Antitumor and immune-modulatory efficacy of dual-treatment based on levamisole and/or taurine in Ehrlich ascites carcinoma-bearing mice.

Many alternative and complementary therapies for cancer have been reported. The objective of the present work is to examine antitumor and immune-modulatory properties of dual-treatment based on levamisole (Lms) and/or taurine (Tau) in Ehrlich ascites carcinoma-bearing mice. In the current study, Lms (10 mg/kg; subcutaneously) and Tau (640 mg/kg; intragastrically) was administered alone or as a dual-treatment. Lms or Tau was administered in combination with cyclophosphamide (CTX) (100 mg/kg; intraperitoneal) in mice bearing Ehrlich ascites carcinoma. Treatment with CTX or (Lms plus Tau) significantly reduced the ascitic tumor cell count, percentage of tumor cell viability while elevated the tumor inhibition rate and apoptosis percentage compared to non-treated animals. Dual-treatment (Lms and CTX) or (Tau and CTX) significantly potentiated the reduction of the ascitic tumor cell count, viability and augmented the tumor inhibition rate and apoptosis percentage compared to CTX-treated mice. Dual-treatment of (Lms plus Tau), (Lms plus CTX) or (Tau plus CTX) altered splenocytes immunological profile of CD3+CD4+, CD3+CD8+, CD4+CD25+ and CD11b+Ly6G+ cells in order to achieve better immune surveillance against tumor cells. In conclusion, dual-treatments based on Lms and/or Tau are promising therapies for cancer, not only due to its abilities to induce apoptosis in the tumor cells and modulate the immune response against them, but also due to its capabilities to potentiate the chemotherapy anticancer efficacy and minimize its adverse effects.

Increased levels of type 1 interferon in a type 1 diabetic mouse model induce the elimination of B cells from the periphery by apoptosis and increase their retention in the spleen.

BACKGROUND: The autoimmune disease type 1 diabetes mellitus (T1D) is associated with a defect in the immune response, which increases susceptibility to infection. We recently demonstrated that prolonged elevated levels of type 1 interferon (IFN) induce lymphocyte exhaustion during T1D. AIMS: In the present study, we further investigated the effect of blocking the type I IFN receptor signaling pathway on diabetic dyslipidemia, in which an abnormal lipid profile leads to the exhaustion of B cells and alteration of their distribution and functions. METHODS: T1D was induced in a mouse model by an intraperitoneal injection of a single dose (60 mg/kg) of streptozotocin (STZ). Three groups of mice were examined: a non-diabetic control group, a diabetic group and a diabetic group treated with an anti-IFN (alpha, beta and omega) receptor 1 (IFNAR1) blocking antibody to block type I IFN signaling. RESULTS: We observed that induction of T1D was accompanied by a marked destruction of ß cells and a reduction in the insulin levels in the diabetic group. Diabetic mice exhibited many changes, including alterations in their lipid profiles, expansion of splenic B cells, increased caspase-3, -8 and -9 activity, and apoptosis in peripheral B cells. Blocking type 1 IFN signaling in diabetic mice significantly returned the insulin and lipid profiles to normal levels, subsequently restored the B cell distribution, and rescued the peripheral B cells from apoptosis. CONCLUSION: Our data suggest the potential role of type I IFN in mediating diabetic dyslipidemia and an exhausted state of B cells during T1D.

Blocking type I interferon signaling rescues lymphocytes from oxidative stress, exhaustion, and apoptosis in a streptozotocin-induced mouse model of type I diabetes.

Elevated levels of type I interferon (IFN) during type 1 diabetes mellitus (T1D) are associated with a defective immune response. In the present study, we investigated whether blocking type I IFN signaling during streptozotocin- (STZ-) induced T1D in mice improves lymphocyte proliferation and escape from continuous apoptosis. Three groups of mice were examined: diabetic mice, type I IFN signaling-incompetent diabetic mice, and control nondiabetic mice. We first found that diabetes induction was accompanied by an elevation in the plasma levels of reactive oxygen species (ROS), hydroperoxide, malondialdehyde (MDN), and the proinflammatory cytokines IL-1 α, IL-1 ß, IL-6, and CXCL10. Blocking type 1 IFN signaling in diabetic mice significantly decreased the levels of oxidative stress and proinflammatory cytokines. In addition, lymphocytes from diabetic mice exhibited a marked reduction in their proliferative capacity, increased apoptosis, upregulation of the exhaustion marker PD-1, and aberrant phosphorylation of STAT1, STAT2, AKT and I κ B- α. Interestingly, following the blocking of type I IFN signaling in diabetic mice, the lymphocytes exhibited restored proliferative capacity, decreased apoptosis, normal expression of PD-1, and normal phosphorylation of STAT1, STAT2, AKT and I κ B- α. Our data suggest that elevated levels of type I IFN during T1D trigger lymphocyte exhaustion and a defective lymphocyte-medicated immune response.