Immune modulation of acute kidney injury.
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Endobronchial instillation of Freund's complete adjuvant (FCA) induced epithelioid cell granulomas in the lungs of juvenile rabbits which had been kept free from contamination with the microbiol antigens. The granulomas were named "juvenile granulomas", because, unlike FCA granulomas in adult animals, prior immunization was unnecessary for their induction. The granulomas developed in several weeks with a peak at 14 weeks of age, after which the production decreased gradually. The rate of granuloma production seemed to vary with the acquisition of skin hypersensitivity to tuberculin (OT), suggesting that granuloma production, as well as skin hypersensitivity, is in the category of T-dependent immune reactions. In fact, T-generating lymphoid organs developed in parallel with the dermal and pulmonary reactions. Thus, juvenile rabbits at about 14 weeks of age are most susceptible to the microbial antigens. This susceptibility results in the unexpected production of immune granulomas in response to depot antigens at the site of instillation. The treatment of foetal or neonatal rabbits with FCA markedly suppressed granuloma production in juveniles but not in adults and did suppress but gradually enhanced the tuberculin skin reaction. It is suggested that generation of suppressor T cells is the cause of suppression of juvenile granuloma production.
Lactic acid bacteria in food can transiently colonize the intestine and exert beneficial effects (probiotic). Survival during intestinal transit or adhesion to epithelium or both seem to be important for modifying the host's immune reactivity. Because Lactobacillus acidophilus strain La1 is adherent to enterocytes in vitro, we hypothesize that contact with immune cells may occur in vivo. However, Bifidobacterium bifidum strain Bb12, which shows high fecal colonization, is another potential immunomodulator. Twenty-eight volunteers were divided into two groups and given a fermented product containing one of the two strains. Lymphocyte subsets and leukocyte phagocytic activity were studied in blood. No modifications were detected in lymphocyte subsets. In contrast, phagocytosis of Escherichia coli ssp. was enhanced in both groups (P < 0.001 for both). Bacterial adhesion to enterocytes, fecal colonization, or both seem to be valuable selection criteria for immunomodulation. Antiinfective mechanisms of defense can be enhanced after ingestion of specific lactic acid bacteria strains.
Natural killer cell cytotoxicity (NKC) is a nonspecific, primary immunodefense system active against a variety of pathogens, including herpes simplex virus (HSV). Evidence suggests that during pregnancy, NKC is attenuated. The regulatory mechanisms for this immune attenuation have yet to be defined. We examined two cytokines (interleukin-2 [IL-2] and alpha interferon [IFN]) for their ability to alter NKC responsiveness during pregnancy, utilizing an HSV-infected target cell model. Peripheral mononuclear effector cells were isolated from 19 pregnant and 19 nonpregnant subjects by Ficoll-Paque separation. These cells were incubated with IFN, IL-2, or media alone, and analyzed for %NKC by an 18 h chromium release assay. The percentage of NKC was lower using the effector cells from the pregnant subjects as compared to nonpregnant controls. Incubation with either IFN or IL-2 resulted in a significant augmentation of NKC in both the pregnant and nonpregnant derived cells. There were no differences in IL-2 dose requirements or levels of cytotoxicity achieved (43.1 +/- 6.8% vs. 44.4 +/- 6.8%, respectively) between pregnant and nonpregnant derived cells. The IFN-mediated augmentation of NKC was somewhat blunted in pregnancy both in terms of absolute levels of cytotoxicity achieved (26.1 +/- 3.9% vs. 37.2 +/- 4.9%, respectively) and dose response curves generated. These results demonstrate that NKC against HSV infected cells is attenuated during pregnancy and can be immunoregulated with the use of either IFN and IL-2. The restoration of NKC responsiveness with IFN, however, remains incomplete during pregnancy, suggesting that this cytokine's mechanism of action differs from that of IL-2.
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The agents responsible for the therapeutic effects of many botanical supplements have not been established in spite of their popularity. Here we show that melanin is a previously unrecognized immunostimulatory compound that is a major component of botanicals traditionally used to enhance immune function. While melanin is present in commonly consumed vegetables, its specific activity is several orders of magnitude less than melanin extracted from these botanicals. The major reason that this agent has eluded detection is its solvent-specific requirement for extraction/solubility. Melanin activates NF-kappa B in monocytes in vitro through a toll-like receptor 2-dependent process. Ingestion of melanin by mice for four days increases production ex vivo of interferon-gamma by spleen cells and IgA and interleukin-6 by Peyer's patch cells. The identification of this new class of mucosal immune stimulants will allow further characterization of botanical products and advances our understanding of the basis for their traditional use.
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OBJECTIVE: Despite the rapid spread of human immunodeficiency virus (HIV) in the developing countries of Africa, Asia and Latin America, accessible and affordable antiretroviral therapies have not been developed. Dinitrochlorobenzene (DNCB) is an inexpensive contact sensitizing agent that stimulates cell-mediated immunity when applied to the skin. We have examined the clinical and immunologic effects of topical DNCB therapy in a cohort of indigent patients with HIV disease from Brazil. DESIGN AND METHODS: Thirty-five HIV-infected subjects were divided into a control group that refused DNCB therapy (6 patients) and a treatment group that applied topical DNCB on a weekly basis throughout the study (29 patients). Subjects were monitored for adverse clinical events, progression to AIDS and changes in body weight. CD4 and CD8 T-cell counts were also monitored in both groups. RESULTS: Control and treated patients were evenly matched in terms of age, initial clinical status and prior adverse clinical events. The mean follow-up was 19.7 months for the control group and 17.8 months for the DNCB group. Control patients had significantly more adverse clinical events and progression to AIDS during the study than the treatment group (p = 0.002 and p = 0.013, respectively). There were no deaths in either group. Control patient weights decreased over the study period while DNCB patient weights increased (p < 0.001). CD4 and CD8 T-cell counts decreased significantly in the control group and increased in the DNCB group (p < 0.001 and p = 0.031, respectively). DNCB therapy was well tolerated. CONCLUSIONS: Topical DNCB therapy affords a rational, effective and inexpensive treatment approach for HIV disease. DNCB should benefit patients in developing nations with limited access to health care.
Measles still causes high mortality in children younger than 1 year of age. Administration of high titre measles vaccines before 7 months of age led to increased overall mortality, raising questions as to the immunological effects of measles vaccine in young infants. We investigated the immune response to standard titre vaccines given to children in Bangladesh in a single dose at age 9 months, or two doses at 6 and 9 months. Of the children vaccinated at age 9 months, 95% serocoverted, compared with 70% at age 6 months. Delayed-type-hypersensitivity reactions to candida antigen were significantly reduced in both vaccine groups at 6 weeks post-vaccination, but responses to other recall antigens studied were not significantly different from controls. In both vaccine groups, peripheral blood lymphocytes isolated at 6 and 24 weeks after vaccination showed significantly higher expression of activation markers upon in vitro stimulation, and a sustained increase in IL-2 production. These findings suggest prolonged immune activation after measles vaccination at the same time as some reduction in delayed hypersensitivity responses. Further study of the clinical effects of these changes is warranted.
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Previously, we reported that mouse tumors contain a low molecular weight factor which is capable of affecting in vitro properties of macrophages. We now describe the purification to homogeneity of the only factor with macrophage modulating activity from one of these tumors Lewis lung carcinoma. The purified tumor factor appears to be a carboxylic acid and it retains all of the macrophage modulating properties which are characteristic of the unfractionated crude tumor extracts. This factor therefore reverses the spreading of macrophages, enhances the migration of macrophages out of capillary tubes and inhibits their chemotactic and tumoricidal activities. The purified tumor factor also inhibits immune responses of spleen cells. Specifically, proliferation of normal lymphocytes in response to mitogens and to alloantigens, as well as the generation of cytotoxic T lymphocytes in a mixed leukocyte culture, are suppressed when these cells are cultured in the presence of the purified tumor factor. The mixed leukocyte reaction of lymphoid cells obtained from mice which had been treated with the tumor factor is reduced compared to the response of lymphocytes obtained from normal mice. It is possible that there is a relation between production of this factor by tumor cells and survival of the tumor in a host.
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BACKGROUND: Polyclonal B-cell activation induced by periodontopathic bacteria has been cited as being important for elevated numbers of B cells, but the role of bacteria in the pathogenesis of periodontal disease remains unknown. In this study, we used an in vitro model to investigate the activation of immune cells by the periodontopathic bacterium Porphyromonas gingivalis in healthy subjects. METHODS: Peripheral blood mononuclear cells (PBMC) or purified subsets of lymphocytes were stimulated with sonicated extracts of P. gingivalis for 24 hours. Cells were harvested and monitored for expression of CD69 by flow cytometry. Cytokine production (IL-10, IL-12, and IL-15) in P. gingivalis-stimulated PBMC cultures was measured by ELISA. To identify IL-10 producer cells, a cell depletion experiment was used and confirmed by the ability of the purified cell population to produce IL-10. To evaluate the effect of P. gingivalis and IL-10, the proliferative response of purified B cells was assessed by [3H] thymidine uptake. RESULTS: PBMC cultured with P. gingivalis led to a large number of activated B and natural killer (NK) cells as monitored by CD69 expression. When positively sorted cells were used, the bacterium itself could directly activate only B cells but not NK cells, alphabeta, and gammadelta T cells. Measurement of B-cell regulatory cytokine production in P. gingivalis-stimulated PBMC cultures revealed a large amount of IL-10 but no detectable IL-12 or IL-15; the major producing cells were monocytes, not B cells or alphabeta T cells. When IL-10 was added to B cells in the presence of bacteria, significantly increased B-cell proliferative responses were observed. CONCLUSIONS: These results suggest that P. gingivalis, both directly and indirectly via macrophage IL-10, may play an important role in polyclonal B-cell activation associated with periodontal disease.
There is a growing amount of evidence suggesting that cannabinoids may be neuroprotective in CNS inflammatory conditions. Advances in the understanding of the physiology and pharmacology of the cannabinoid system have increased the interest of cannabinoids as potential therapeutic targets. Cannabinoid receptors and their endogenous ligands, the endocannabinoids, have been detected in cells of the immune system, as well as in brain glial cells. In the present review it is summarized the effects of cannabinoids on immune reactivity and on the regulation of neuroinflammatory processes associated with brain disorders with special attention to chronic inflammatory demyelinating diseases such as multiple sclerosis.
The availability of nucleoside analogues has broadened treatment options for chronic hepatitis B virus (HBV ) infection. Registered treatment for chronic hepatitis B currently consists of (pegylated) interferon, lamivudine and adefovir, while entecavir is expected to be licensed in the short term. Treatment is generally recommended for patients with high serum HBV DNA and elevated ALAT, indicating the host's immune response against HBV. Induction of an HBV -specific immune response seems crucial for persistent control of HBV infection. Currently available treatment strategies can be differentiated into those that provide sustained off-treatment response and those that provide therapy maintained response. A finite treatment course with immunomodulatory agents (interferon-based therapy) results in sustained response in about one third of patients, while nucleoside analogue treatment generally requires indefinite therapy without a clear stopping point. Since nucleoside analogues are well tolerated, prolonged therapy is feasible, but a major drawback is the considerable risk of developing antiviral resistance, which occurs most frequently in lamivudine treated patients and to a lesser extent during adefovir or entecavir therapy. In our opinion, treatment with peginterferon should therefore be considered first-line therapy in eligible patients with a high likelihood of response based on serum HBV DNA, ALAT and HBV genotype. Patients not responding to PEG-IF N therapy or not eligible for peginterferon therapy should be treated with nucleos(t)ide analogues.
Although it is common knowledge that some dietary lectins can adversely affect the growth and health of young animals and that, therefore, lectins are implicated in nutritional disorders of the digestive system, it has not been rigorously established that findings with animals are also directly applicable to humans. However, because the glycosylation state of the human gut is basically similar to that of higher animals, it may be confidently predicted that the effects of dietary lectins will have similarities in both humans and animals. The more recent but not generally appreciated realization that lectins also have many beneficial effects on the gut and metabolism of animals makes the exploration of these for possible use in medical-clinical practice even more attractive. Most lectins in our diet are resistant to breakdown during gut passage and are bound and endocytosed by epithelial cells. These lectins are powerful exogenous growth factors for the small intestine, can induce dramatic shifts in its bacterial flora and interfere with its hormone secretion. In addition, lectins which are transported across the gut wall into the systemic circulation can modulate the body's hormone balance, metabolism and health. Although these physiological effects are mediated or reinforced by immune responses, they are primarily the result of the specific chemical reactivity of lectins with cell surface receptors of the gut. Clearly, as the interactions between lectins and the gut are predictable and may be manipulated to our advantage, the exciting scientific challenge is now to explore the possible transfer of the existing knowledge gained from animal experimentation to medical-clinical practice.
The limitations of currently available treatment for severe respiratory infection are demonstrated by the relatively fixed mortality associated with these infections despite advances in nutrition, vaccines, antibiotics, and critical care. This might be due in part to the changing spectrum of pathogens and development of drug resistance. Cytokines are potent molecules that function as growth factors and orchestrate both innate and adaptive immune responses. Several of these factors have entered the clinical arena to support or augment the immune response. Moreover, the use of cytokines has recently been expanded to patients without an overtly defective immune system but who have either significant infection or infection with drug resistant organisms. The use of cytokines as adjuvants in the treatment of respiratory infections is reviewed.
Acute exacerbations (AEs) of chronic hepatitis B (CH-B) are accompanied by increased T cell responses to hepatitis B core and e antigens (HBcAg/HBeAg). Why patients are immunotolerant (IT) to the virus and why AEs occur spontaneously on the immunoactive phase remain unclear. The role of HBcAg-specific CD4(+)CD25(+) regulatory T (T(reg)) cells in AE and IT phases was investigated in this study. The SYFPEITHI scoring system was employed to predict MHC class II-restricted epitope peptides on HBcAg overlapping with HBeAg that were used for T(reg)-cell cloning and for the construction of MHC class II tetramers to measure T(reg) cell frequencies (T(reg) f). The results showed that HBcAg-specific T(reg) f declined during AE accompanied by increased HBcAg peptide-specific cytotoxic T lymphocyte frequencies. Predominant Foxp3-expressing T(reg) cell clones were generated from patients on the immune tolerance phase, while the majority of Th1 clones were obtained from patients on the immunoactive phase. T(reg) cells from liver and peripheral blood of CH-B patients express CD152 and PD1 antigens that exhibit suppression on PBMCs proliferation to HBcAg. These data suggest that HBcAg peptide-specific T(reg) cells modulate the IT phase, and that their decline may account for the spontaneous AEs on the natural history of chronic hepatitis B virus infection.