Immunoregulatory dysfunctions in type I diabetes: Natural and antibody-dependent cellular cytotoxic activities

Peripheral blood lymphocytes from 13 patients with established insulin-dependent diabetes mellitus (IDDM) and 2 prediabetic patients were examined for natural killer (NK) and antibody-dependent cellular cytotoxic activities (ADCC), lectin-dependent cellular cytotoxicity (LDCC), interferon- and interleukin-2-induced cytotoxicity, and concanavalin A-induced suppressor-cell activities in comparison with age-matched normal controls. IDDM patients demonstrated normal levels of NK and ADCC activities against K562 and antibody-coated SB target cells, respectively, compared to controls. IDDM patients showed normal levels of LDCC activity. Notable deviations from control values were, however, observed with diabetic lymphocytes in the following systems. Interferon-and interleukin-2-induced NK activities were significantly higher with IDDM lymphocytes than with control cells. IDDM lymphocytes precultured with concanavalin A demonstrated lower NK and ADCC activities than control cells and manifested decreased suppressor effects on the NK activity of normal allogeneic lymphocytes. Lymphocytes from one of two prediabetic patients showed increased NK, ADCC, and LDCC activities in comparison to controls. The increased interferon- and interleukin-2-induced enhancement of NK activity and reduced suppressor activity of lymphocytes from IDDM patients may be involved in the pathogenesis of the disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44848/1/10875_2004_Article_BF00915375.pd

RNAi-directed inhibition of DC-SIGN by dendritic cells: Prospects for HIV-1 therapy

Drug-resistant human immunodeficiency virus (HIV) infections are increasing globally, especially in North America. Therefore, it is logical to develop new therapies directed against HIV binding molecules on susceptible host cells in addition to current treatment modalities against virus functions. Inhibition of the viral genome can be achieved by degrading or silencing posttranslational genes using small interfering (si) ribonucleic acids (RNAs) consisting of double-stranded forms of RNA. These siRNAs usually contain 21–23 base pairs (bp) and are highly specific for the nucleotide sequence of the target messenger RNA (mRNA). These siRNAs form a complex with helicase and nuclease enzymes known as “RNA-induced silencing complex” (RISC) that leads to target RNA degradation. Thus, siRNA has become a method of selective destruction of HIV now used by various investigators around the globe. However, given the sequence divesity of the HIV genomes of infected subjects, it is difficult to target a specific HIV sequence. Therefore, targeting nonvariable HIV binding receptors on susceptible cells or other molecules of host cells that are directly or indirectly involved in HIV infections may be an interesting alternative to targeting the virus itself. Thus, the simultaneous use of siRNAs specific for HIV and host cells may be a unique, new approach to the therapy that siRNA directed at the CD4 independent attachment receptor (DC-SIGN) significantly inhibits HIV infection of dendritic cells (DCs). This effect may be mediated by modulation of p38 mitogen activated protein kinase (MAPK)