Potentiation, immune system

As some of the toxicity observed with DPP-8/9 inhibitors 4 and 7 in predinical species suggested a potential immune system role, we hypothesized that the immunological effects observed with historical DPP-4 inhibitors [14] might be due to inhibition of DPP-8/9 instead of DPP-4 as initially reported. Sure enough, when these historical compounds were assayed at DPP-8/9 and DPP-4, they possessed more potent intrinsic inhibition at DPP-8/9 than at DPP-4 [20]. Furthermore, we demonstrated that DPP-8/9 inhibitor 7 is able to attenuate proliferation and IL-2 release in human in vitro models of T-cell activation, while a selective DPP-4 inhibitor does not. Recent tissue distribution studies also suggest a role for DPP-8 in the immune system [25]. 

Chinese Herbal Medicines. Many traditional Chinese medicines have been screened for radioprotective activity in experimental animals. In one study of more than a thousand Chinese herbs, a number of agents increased the survival rate of dogs exposed to a lethal dose of y-rays by 30—40%, and some symptoms of radiation injury were ameHorated. These effects are potentially related to stimulation of the hemopoietic and immune systems (130). Extracts of five Chinese dmg plants, as weU as aspirin, effectively protected mice exposed to 7.5—8.0 Gy (750—800 rad) of y-radiation, and increased survival rates by 8—50% (131). Several Chinese traditional medicines, adininistered ip before or after irradiation, protected against Hpid peroxidation in a variety of mouse tissues, including BM, Hver, and spleen, as weU as in mouse Hver microsomal suspensions irradiated in vitro (132). 

The prophylactic stimulation of the immune system using vaccines and bacterins is time-consuming. Of even greater value would be the abiUty to activate the system to combat a disease attack already underway, or to be able to increase the response to abnormal cells and neutralize neoplasia in any organ of the body. Several compounds, some unique entities and some already in use for other purposes, have shown potential utiUty as such nonspecific immune stimulants. 

In addition to their endocrine disrupting properties, it must be appreciated that many of the chemicals in question possess more general toxic properties, which may be potentiated by metabolism by the organism. Several PAHs, PCBs and PCDDs are carcinogenic, while certain phthalate esters can enhance the excretion of zinc, potentially leading to zinc deficiency. Zinc, an essential element, plays a vital role in spermatogenesis and mature T-cell production. Deficiency may result in abnormalities of the male reproductive system, depletion of spermatogenesis and suppression of the immune system. 

The other global environmental problem, stratospheric ozone depletion, was less controversial and more imminent. The U.S. Senate Committee Report supporting the Clean Air Act Amendments of 1990 states, Destruction of the ozone layer is caused primarily by the release into the atmosphere of chlorofluorocarbons (CFCs) and similar manufactured substances—persistent chemicals that rise into the stratosphere where they catalyze the destruction of stratospheric ozone. A decrease in stratospheric ozone will allow more ultraviolet (UV) radiation to reach Earth, resulting in increased rates of disease in humans, including increased incidence of skin cancer, cataracts, and, potentially, suppression of the immune system. Increased UV radiation has also been shown to damage crops and marine resources."... 

Acute infection with Hetpes simplex viruses (HSV) results in painful rashes on skin and mucous membranes. HSV-1 mainly causes cold sores around the mouth (hetpes labialis) or eyes (keratitis), whereas infection by HSV-2 mostly results in sores in the genital or anal area. Less frequently, HSV also causes severe infections in newborns or potentially fatal encephalitis. HSV remains latent and can be reactivated by stress, suppression of the immune system or other infections. 

For patients with leukemia, the transfer of siRNA-based strategies into clinical applicability will certainly be both frustrating and time-consuming and many hurdles still have to be overcome in order to realize the therapeutic potential of siRNAs. Efficient delivery of siRNA into the leukemic stem cell and their unknown influence of the patient s immune system are the most challenging issues that need to be addressed. 

Dioxins have effects similar to and potentially even more far-reaching than those of DDT, because they apparently affect a wide variety of species. Predatory birds are especially susceptible, and there is growing evidence that humans may be at risk. Tests have shown that when the concentration of dioxins in the blood of laboratory animals reaches a critical level, reproductive and immune-system defects result. Moreover, recent data indicate that the concentration of dioxins in the blood of the average U.S. resident has nearly reached that level. A major reason is that dioxins are hydrophobic, so they accumulate in fatty tissue rather than being readily processed and excreted from the body. 

It is suggested that altered cells which could be potentially malignant are recognized by the immune system and eliminated. This must mean that cancer cells possess new antigens on their cell surface. These antigens have been identified and can be categorized into three groups. 

A limited study in animals also presents evidence for increased susceptibility to Streptococcus zooepidomicus (Aran d et al. 1986). Immune system effects observed in mice exposed orally to trichloroethylene included inhibition of cell-mediated immunity, delayed type hypersensitivity, and inhibition of antibody-mediated immunity (Sanders et al. 1982). Female mice appeared to be more sensitive than male mice. A study in which a susceptible strain of mice was treated with intraperitoneal injections of trichloroethylene suggests that trichloroethylene can accelerate the autoimmune response (Khan et al. 1995). The immune system may be a sensitive end point for toxic effects from low-level exposure to trichloroethylene however, no firm conclusions can be drawn from the available information. Additional human and animal studies are needed to better characterize this end point and determine the potential for immunological effects for people exposed to trichloroethylene at hazardous waste sites. 

PCP is commonly used as a wood preservative having both antifungal and insecticide properties. It has also been used in a range of areas for antifungal, antibacterial, general herbicide, and slime prevention in both industrial and consumer applications. Chronic exposure to PCP has effects on the liver, kidneys, and immune system. PCP also has the potential to cause reproductive problems and has been listed as a probable carcinogen. 

Iwamura and Ueda [386] described compound (611) as a CB2 selective inverse agonist in a patent application. The potential therapeutic roles of CB2 antagonists are not clearly defined at the moment, although roles in regulation of the immune system and inflammation have been widely proposed. This patent application describes that activity of compound (611) in a mouse model of asthma, in which the compound suppressed immediate and late-phase asthmatic response and airway hyper-responsiveness. 

The skin is the largest organ of the human body. One of its most important functions is to assist the immune system by serving as a barrier that protects underlying structures from trauma, infection, and exposure to harmful environmental elements. The skin also holds in place essential organs and fluids necessary for life. Any significant injury to this outer protective layer may potentially compromise an individual s overall health. 

One of the more difficult to manage aspects of compound reactivity is the potential for idiosyncratic immunological reactions to covalent protein-compound complexes. Normally the immune system does not respond to xenobiotics of molecular weight less than 1000 Daltons. When, however, a drag is covalently linked to a... 

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