Analysis of immunological enhancement of immunosuppressed chickens by Chinese herbal extracts.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix astragali, Radix codonopis, Herba epimedii and Radix glycyrrizae are 4 plants commonly used in Chinese traditional medicine or veterinary medicine to improve immune functions against chronic diseases in humans and animals. AIM OF THE STUDY: We compared immunological enhancement by 4 herbal extracts in clinical healthy chickens or immunosuppressed chickens singly and in combination. MATERIALS AND METHODS: Water extracts of 4 herbs individually and in different combinations were supplemented in drinking water. Hemagglutination inhibition (HI) antibody titers against Newcastle disease virus (NDV) and H5 avian influenza virus (H5-AIV) after vaccination were measured as indicators to evaluate immunological stimulation across groups supplemented with different herbal extracts. The experiments were conducted in both clinically healthy chickens and chickens with immunosuppression induced by reticuloendotheliosis virus (REV) infection. RESULTS: In clinically healthy chickens HI antibody titers against NDV and H5-AIV after vaccination were not influenced by supplementation with the herbal extracts of Radix astragali, Radix codonopis, Herba epimedii and Radix glycyrrizae in drinking water. In chicks with REV-induced immunosuppression, however, supplementation of some herbal extracts significantly increased HI antibody titers to NDV and H5-AIV when compared to the immunosuppressed control group (P<0.01), but the titers were still lower than those in chicks not infected by REV. The 4 herbal mixtures produced the best enhancement among various combinations. The components of the herbal extract were water soluble and treatment by ether had no influence on immunological enhancement. The molecular weights of the active components of the herbal extracts were in the range of 10,000-100,000 Da. CONCLUSION: Our results show that the herbal extract supplementation in drinking water can induce an immune stimulation response in immunosuppressed chickens. It suggests that chickens with REV infection-induced immunosuppression could be used as an experiment model for determination of immunological enhancement effects of some herbal components.

PKCtheta is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice.

When used as therapy for hematopoietic malignancies, allogeneic BM transplantation (BMT) relies on the graft-versus-leukemia (GVL) effect to eradicate residual tumor cells through immunologic mechanisms. However, graft-versus-host disease (GVHD), which is initiated by alloreactive donor T cells that recognize mismatched major and/or minor histocompatibility antigens and cause severe damage to hematopoietic and epithelial tissues, is a potentially lethal complication of allogeneic BMT. To enhance the therapeutic potential of BMT, we sought to find therapeutic targets that could inhibit GVHD while preserving GVL and immune responses to infectious agents. We show here that T cell responses triggered in mice by either Listeria monocytogenes or administration of antigen and adjuvant were relatively well preserved in the absence of PKC isoform theta (PKCtheta), a key regulator of TCR signaling. In contrast, PKCtheta was required for alloreactivity and GVHD induction. Furthermore, absence of PKCtheta raised the threshold for T cell activation, which selectively affected alloresponses. Most importantly, PKCtheta-deficient T cells retained the ability to respond to virus infection and to induce GVL effect after BMT. These findings suggest PKCtheta is a potentially unique therapeutic target required for GVHD induction but not for GVL or protective responses to infectious agents.

Induction of long-term protective antiviral endogenous immune response by short neutralizing monoclonal antibody treatment.

Long-term immune control of viral replication still remains a major challenge in retroviral diseases. Several monoclonal antibodies (MAbs) have already shown antiviral activities in vivo, including in the clinic but their effects on the immune system of treated individuals are essentially unknown. Using the lethal neurodegeneration induced in mice upon infection of neonates by the FrCas(E) retrovirus as a model, we report here that transient treatment by a neutralizing MAb shortly after infection can, after an immediate antiviral effect, favor the development of a strong protective host immune response containing viral propagation long after the MAb has disappeared. In vitro virus neutralization- and complement-mediated cell lysis assays, as well as in vivo viral challenges and serum transfer experiments, indicate a clear and essential contribution of the humoral response to antiviral protection. Our observation may have important therapeutic consequences as it suggests that short antibody-based therapies early after infection should be considered, at least in the case of maternally infected infants, as adjunctive treatment strategies against human immunodeficiency virus, not only for a direct effect on the viral load but also for favoring the emergence of an endogenous antiviral immune response.

When to switch and what to switch to: strategic use of antiretroviral therapy.

Clinical cohort studies suggest that as many as 60% of patients experience virologic failure of a first-line antiretroviral regimen. Second-line and rescue (or salvage) regimens have a poorer success record: Most studies presented to date show a short-term virologic response rate of only approximately 30% in treatment-experienced individuals. That rate will improve with better understanding of what causes initial virologic failure, continued development of new antiretroviral agents (including drugs with new mechanisms of action) and new treatment strategies (including dual-protease inhibitor regimens), and more widespread use of resistance testing. Further clinical research is needed to improve salvage options, and physicians should consider enrolling treatment-experienced patients in clinical trials.

Prevention of immune dysfunction and vitamin E loss by dehydroepiandrosterone and melatonin supplementation during murine retrovirus infection.

Female C57BL/6 mice infected with the LP-BM5 leukaemia retrovirus developed murine acquired immune-deficiency syndrome (AIDS). Dehydroepiandrosterone (DHEA) and melatonin (MLT) modify immune dysfunction and prevent lipid peroxidation. We investigated whether DHEA and MLT could prevent immune dysfunction, excessive lipid peroxidation, and tissue vitamin E loss induced by retrovirus infection. Retrovirus infection inhibited the release of T helper 1 (Th1) cytokines, stimulated secretion of Th2 cytokines, increased hepatic lipid peroxidation, and induced vitamin E deficiency. Treatment with DHEA or MLT alone, as well as together, largely prevented the reduction of B- and T-cell proliferation as well as of Th1 cytokine secretion caused by retrovirus infection. Supplementation also suppressed the elevated production of Th2 cytokines stimulated by retrovirus infection. DHEA and MLT simultaneously reduced hepatic lipid peroxidation and prevented vitamin E loss. The use of DHEA plus MLT was more effective in preventing retrovirus-induced immune dysfunction than either DHEA or MLT alone. These results suggest that supplementation with DHEA and MLT may prevent cytokine dysregulation, lipid oxidation and tissue vitamin E loss induced by retrovirus infection. Similarly, hormone supplementation also modified immune function and increased tissue vitamin E levels in uninfected mice.

Neuroimmunopathogenesis of ts1 MoMuLV viral infection.

Newborn mice infected with ts1, a mutant of the Moloney murine leukemia virus, develop neuroimmunodegeneration with death and damage of thymocytes, astrocytes, and motor neurons by 24-38 days. T cells, B cells, and astrocytes, but not neurons, are infected by the virus. Primary splenocytes and thymocytes isolated from age-matched infected or control mice, when incubated in serum-deficient media containing phytohemagglutinin-L, either homotypically aggregate and survive or swell, expose their inner membrane phospholipids, and then shrink as they fragment their nuclei and excrete DNA-containing hypoploid minicells. In our present studies, the rates of these apoptotic changes were greatly increased in the infected cells. This thymocyte death was ameliorated in vitro by addition of Th2 cytokines, but not by Th1 cytokines, or by redox agents. In contrast, death of splenocytes, which were already mitogenically activated in vivo by the virus, was prevented by Th1 and Th2 cytokines plus redox support. In vivo, this ts1-induced neuroimmunodegenerative syndrome could be completely prevented by the immunomodulator polyinosine-cytosine and partially prevented by cytokines or redox modifiers. Viral titer primarily in the brain was also diminished by polyinosine-cytosine therapy. These observations indicate that the cell death in T cells and neurons in these ts1-infected neonatal mice can be prevented in vitro and in vivo by appropriate upregulation of the immune system.

Alcohol stimulation of lipid peroxidation and esophageal tumor growth in mice immunocompromised by retrovirus infection.

Tumor appearance can be accelerated in the immunodeficient and immunosuppressed animal. The role of lipid peroxidation and immune dysfunction induced by retrovirus and ethanol treatments on cancer promotion were investigated. Following the initiation of esophageal cancer by methylbenzylnitrosamine, ethanol consumption and retrovirus infection individually and concomitantly increased growth of esophageal tumors. Dietary supplementation with vitamin E reduced the size and frequency of the developed tumors. Tumor growth modifications in the vitamin E supplemented animals may be due to changes in T-cell numbers and functions stimulated by vitamin E. In addition, increased production of free radicals following ethanol treatment and retrovirus infection, and the suppression of these formations lipid peroxide by vitamin E is accompanied by lower incidence and size of tumors. Thus, the mechanisms of tumor enhancement observed in immunocompromised animals may include a combination of immunomodulation and modification of oxidant production by ethanol consumption and retrovirus infection.

Vitamin E protection against nitrosamine-induced esophageal tumor incidence in mice immunocompromised by retroviral infection.

Retrovirally induced immunosuppression may elevate the incidence of chemically induced cancers. A proposed hypothesis to explain this relationship is the increased free radical activity observed during retroviral infection and carcinogen activation. We previously found that vitamin E retarded growth of esophageal tumors accompanied by reductions of free radical products. This study investigated the contribution that retroviral immunosuppression has on esophageal cancer induced by the carcinogen N-nitrosomethylbenzylamine (NMBzA), and the response that increased levels of dietary vitamin E has on this induced carcinogenesis. Female C57BL/6 mice received NMBzA or vehicle (corn oil) i.p. weekly for 3 weeks. Then some of the mice were infected with LP-BM5 murine retrovirus and fed diets containing 30 IU vitamin E or 172 IU vitamin E/kg of diet. As an assessment of free radical activity, exhaled ethane was measured prior to killing the animals at 26 weeks. Esophagi from the various mice groups were assessed for size and frequency of tumors. Livers homogenates were analyzed for vitamins A and E, lipid fluorescence, conjugated dienes and malondialdehyde. Hepatic levels of vitamin A and E were decreased (P < 0.05) and indices of lipid peroxidation were greater (P < 0.05) in NMBzA-treated mice relative to controls. Lipid peroxidation and serum transaminases (ALT and AST) were greatest in mice given NMBzA and infected with the retroviruses. Incidence of esophageal tumors were also greatest in the NMBzA-treated, immunocompromised animals. Mice fed vitamin E-supplemented diets showed increased (P < 0.05) hepatic concentrations of vitamin E and vitamin A, decreased activities of serum transaminases, decreased indices of lipid peroxidation, and decreased size and frequency of esophageal tumors in both the immunocompromised and non-immunocompromised mice. These results suggest that vitamin E plays an antioxidant function that retards the incidence of esophageal cancers in immunocompromised and non-immunocompromised animals.

The role of passive immunity in bovine respiratory syncytial virus-infected calves.

The role of passive immunity in bovine respiratory syncytial virus (BRSV) infections in neonatal calves was evaluated. Calves were divided into groups as follows: colostrum-deprived, sham-inoculated; colostrum-deprived, BRSV-inoculated; and colostrum-fed, BRSV-inoculated. Calves were inoculated with a low-passage field isolate of BRSV for 4 consecutive days by a combined respiratory tract route and were euthanized 6 days after receiving the last inoculation. Arterial oxygen tension (Pao2) decreased significantly over time in colostrum-deprived, BRSV-inoculated calves (P less than .01) and was significantly different among treatment groups (P less than .05). A significant decrease in arterial oxygen saturation was observed in this same group over time (P less than .01). Mean percentage of pneumonic lung volume (determined by computer data digitalization) was significantly greater in infected, colostrum-deprived calves compared with the other groups (P less than .01), and BRSV antigen was detected in these calves by avidin-biotin immunoperoxidase staining. Thus, passive immunity derived from colostrum feeding decreased the severity of BRSV infections in calves.

The effect of colostrum-derived antibody on neo-natal transmission of caprine arthritis-encephalitis virus infection.

Two groups of 6 newborn goat kids were artificially fed colostrum containing antibody to caprine arthritis-encephalitis (CAE) virus, obtained from clinically affected does. Kids in group A were fed the colostrum from birth until 7 days of age, while kids in group B were fed colostrum from 1 to 3 days after birth for 7 days. Kids were fed cow's milk at all other times. Serum antibody resulting from the consumption of colostrum, detected by agar gel immunodiffusion (AGID) tests, lasted for up to 8 weeks in group A, but none was detected in group B. Four kids from each group became infected with CAE virus as demonstrated by the emergence of active immunity and by virus isolation procedures. It appeared that uptake of colostral antibody by group A did not prevent viral transmission, interfere with development of active immunity, or modify the outcome of the CAE virus infection.