Minocycline attenuates HIV‐1 infection and suppresses chronic immune activation in humanized NOD/LtsZ‐scidIL‐2Rγnull mice

More than a quarter of a century of research has established chronic immune activation and dysfunctional T cells as central features of chronic HIV infection and subsequent immunodeficiency. Consequently, the search for a new immunomodulatory therapy that could reduce immune activation and improve T‐cell function has been increased. However, the lack of small animal models for in vivo HIV study has hampered progress. In the current study, we have investigated a model of cord blood haematopoietic progenitor cells (CB‐HPCs) ‐transplanted humanized NOD/LtsZ‐scidIL‐2Rγ^null mice in which progression of HIV infection is associated with widespread chronic immune activation and inflammation. Indeed, HIV infection in humanized NSG mice caused up‐regulation of several T‐cell immune activation markers such as CD38, HLA‐DR, CD69 and co‐receptor CCR5. T‐cell exhaustion markers PD‐1 and CTLA‐4 were found to be significantly up‐regulated on T cells. Moreover, increased plasmatic levels of lipopolysaccharide, sCD14 and interleukin‐10 were also observed in infected mice. Treatment with minocycline resulted in a significant decrease of expression of cellular and plasma immune activation markers, inhibition of HIV replication and improved T‐cell counts in HIV‐infected humanized NSG mice. The study demonstrates that minocycline could be an effective, low‐cost adjunctive treatment to regulate chronic immune activation and replication of HIV.     

Impaired immune responses in diabetes mellitus: analysis of the factors and mechanisms involved. Relevance to the increased susceptibility of diabetic patients to specific infections.

The reasons why diabetic patients present with an increased susceptibility to frequent and protracted infections remain unclear. The virtual absence of epidemiological studies of the independent risk factors involved contrasts with the multitude of in vitro models focused on the metabolism and function of immune cells from diabetic patients. This review analyzes some of these models and their clinical relevance. The different levels of diabetes pathogenesis: genetic (Type 1), autoimmune (Type 1) and metabolic (Type 1 and Type 2) are responsible for immune abnormalities demonstrated in in vitro models. The participation of genetic and autoimmune factors has been mainly characterized on T lymphocyte function. The B8 DR3 haplotype is associated with several minor immunologic abnormalities in vitro. However, the high frequency of this haplotype in healthy individuals argues against its involvement in significant defects of antimicrobial immunity. Genetic deficiency of C4, present in 25% of Type 1 diabetic patients could, on the other hand, be responsible for opsonization defects against encapsulated pathogens. Several immunological abnormalities related to the autoimmune process preceding the onset of Type 1 diabetes mellitus, such as the depletion of memory CD4+ cells and the defective natural killer activity could transiently impair host defences against viral diseases. Several in vitro functional defects of the immune system have been correlated with the metabolic control of diabetic patients. This suggests the involvement of insulinopenia in some of the abnormalities observed. Insulinopenia-induced enzymatic defects have often been proposed to inhibit energy-requiring functions of phagocytes and lymphocytes. However, the relevance of this mechanism could be confined to patients with extremely severe metabolic abnormalities. The importance of systemic consequences of insulinopenia such as hyperglycaemia and ketosis has also been addressed. Usually, the defects induced in vitro by these factors are slight and require supraphysiologic concentrations of glucose or ketone bodies. Recent studies have shown abnormalities of signal transduction mechanisms in which insulinopenia itself and other factors such as circulating immune complexes could be involved. Despite numerous controversies, many in vitro studies of the immune cells of diabetic patients have demonstrated significant defects which bear quantitative similarities with abnormalities described in other immunodeficiency syndromes. Furthermore, several mechanisms have been proposed to link the different defects observed with the specific infections encountered in diabetic patients.     

Cytogenetic and genetic effects of subchronic treatments with organophosphorus insecticides

Male mice (Q strain) received 5 days a week for 7 weeks drinking water containing dichlorvos (2 ppm), dimethoate (0.6 ppm), malathion (8 ppm), methylparathion (0.15 ppm), or trichlorfon (0.5 ppm). At the end of the treatment, no chromosome damage was observed in bone marrow cells, spermatogonia, and primary spermatocytes. Dominant lethal mutation assays were performed to investigate the pre- and postimplantation foetal lethality. Only negative results were obtained.     

Evaluation of the mutagenic potential of four commercial mixtures of insecticides

Male mice (Q strain) were given a single ip injection at the maximum tolerated dose of one of four commercial mixtures of insecticides: Luxan Tue-Taons (150 g dimethoate and 150 g fenitrothion/litre), Metadipterex (210 g trichlorfon and 270 g methyldemeton/litre), Dynafos (155 g malathion, 60 g dichlorvos and 75 g carbaryl/litre) and Phosan Plus (95 g dimethoate, 100 g malathion and 100 g methoxychlor/litre). At the maximum tolerated doses, Luxan Tue-Taons (60 mg/kg), Metadipterex (15 mg/kg), Dynafos (50 mg/kg) and Phosan Plus (100 mg/kg) did not induce chromosome aberrations in bone-marrow cells, spermatogonia or primary spermatocytes of the mice. No evidence of potential genetic effects was obtained in a dominant lethal mutation assay.