Learning from health care experiences in developing countries.
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Adult↗
Biomedical subjects
C E Taylor
Publications and source records attributed to C E Taylor.
Antigen specific suppressor T cells respond to cytokines released by T cells.
These studies were conducted to examine the cytokine requirement for clonal expansion of regulatory T cells. It was observed that the in vivo administration of recombinant IL2 (rIL2), rIL5 or interferon (IFN) gamma at the time of immunization with pneumococcal polysaccharide Type III (SSS-III) resulted in substantial suppression of the antibody response in each case. Using our well established cell transfer system we found that such suppression of the antibody response could be transferred using 10-100-fold fewer primed spleen cells providing these cells were treated in vitro with rIL2 before cell transfer; spleen cells from unimmunized mice or from mice primed with an unrelated antigen and then treated with rIL2 did not cause suppression of the antibody response to SSS-III, thereby eliminating the possibility of non-specific carry-over effects induced by rIL2. We also found that the in vivo administration of anti-IL2 receptor antibody inhibited the generation of Ts cells in vivo. Spleen cells from SSS-III primed animals treated with rIL4, rIL5 and IFN gamma--but not rIL6--likewise are able to transfer suppression of the antibody response with fewer cells than that required using primed cells not treated with cytokines. Thus, these studies indicate that Ts cell activity is greatly influenced by cytokines. The studies also suggest that these cytokines may be required during the activation and/or clonal expansion of Ts cells.
Animals↗
Bacterial polysaccharides, endotoxins, and immunomodulation.
These studies show that at least some--though certainly not all--of the adjuvant effects of LPS and its derivatives can be attributed to its ability to eliminate the inhibitory effects of Ts which are activated during the course of a normal immune response. The ability of nontoxic MPL to act in this fashion suggests that it can be used as a safe and acceptable alternative to Freund's complete adjuvant to increase the immunogenicity of poorly immunogenic antigens. More important, the ability of MPL to eliminate the expression of Ts activity, without adversely influencing other T cell functions (e.g., Th, Ta, and Tc activity) makes its use as an adjuvant even more promising since it can then permit those T cell functions to be expressed in a much more efficient manner. Obviously, this would have great significance for the development of tumor immunity.
Adjuvants, Immunologic↗
Immunosuppressive effects induced by the polysaccharide moiety of some bacterial lipopolysaccharides.
The immunomodulatory properties of several lipopolysaccharides (LPS) derived from clinical isolates of Pseudomonas aeruginosa, Branhamella catarrhalis, and Bordetella pertussis were evaluated for their capacity to influence the magnitude of the antibody response to type III pneumococcal polysaccharide (SSS-III), which is known to be regulated by suppressor and amplifier T cells (Ts and Ta, respectively). The administration of LPS, two days after immunization resulted in a significant increase in the antibody response. Such enhancement may be due mainly to the ability of the lipid A moiety of LPS to abolish the negative effects of activated Ts, thereby enabling Ta function to be more fully expressed; however, B cell mitogenicity of the LPS molecule also may be involved. By contrast, treatment with LPS at the time of immunization with SSS-III induces significant suppression of the SSS-III-specific antibody response; such suppression is not induced by LPS or lipid A derived from Escherichia coli and Salmonella minnesota, and is independent of the capacity of LPS to activate B cells polyclonally, an activity generally attributed to the lipid A fraction of LPS. Studies conducted with the LPS of P. aeruginosa indicated that the suppression induced is T cell dependent and mediated by the polysaccharide (PS) fraction of LPS; it appears to be due-at least in part-to the capacity of PS to expand or increase the size of the precursor pool of Ts, activated in response to SSS-III. The significance of these findings to the pathogenesis of certain gram-negative infections is discussed.
Animals↗
Effects of timing and dose of vitamin A on tissue retinol concentrations and antibody production in the previously vitamin A-depleted rats.
The effect of retinol repletion in previously vitamin A-depleted Lewis rats on antibody production to pneumococcal polysaccharide (SSS-III) was studied. When vitamin A-depleted rats were given either 0.35 mumol (0.1 mg) or 5.2 mumol (1.5 mg) retinol, plasma retinol became normal within 8 h. Liver and lymphoid-organ retinol concentrations were normalized by 1 d after repletion with 5.2 mumol but not 0.35 mumol retinol. Antibody production to SSS-III was compared after administering 5.2 mumol retinol either as a divided dose (half given 4 d before and half given on the day of immunization) or as a single dose concurrent with immunization. Vitamin A-depleted rats produced very little SSS-III-specific antibody. The divided dose of retinol consistently restored anti-SSS-III production whereas the single concurrent dose was less effective despite equal effects on tissue retinol concentrations. Interestingly, normalization of plasma retinol was not always a good predictor of the immune response to pneumococcal polysaccharide.
Animals↗
Surveillance for equity in primary health care: policy implications from international experience.
Experience around the world shows that health agencies can promote community-based surveillance for equity to focus low-cost interventions on priority needs. Social inequities which have seemed intractable can be resolved if care responds directly to demonstrated need. The concept of promoting equity as a basic principle of primary health care has an interesting psychological twist. The ethical imperative of equity can strengthen services when linked with the practical management tool of surveillance. Moral conviction in applying this social justice norm can facilitate action which is made efficient by the realism of statistically based methods of surveillance. If international agencies condition their aid on surveillance for equity their assistance will more likely go to those in greatest need. This is a more efficient and effective way of tracking their money than the previous tendency to set up vertical programmes which generally have poor sustainability. Surveillance helps mobilize political will and community participation by providing practical data for local, district and national decision-makers. The many field demonstrations of successful surveillance for equity tend to have been brushed off by development experts who say they are difficult to replicate nationally. The Model County Project in China shows how a systematic extension process can test procedures in experimental areas and adapt them for general implementation. Surveillance can help bureaucracies maintain capacity for flexible and prompt response as decentralization promotes decision-making by local units which are held responsible for meeting equity targets. Surveillance for equity provides a mechanism to ensure such accountability.
Adult↗
Structural features that influence the ability of lipid A and its analogs to abolish expression of suppressor T cell activity.
Lipid A preparations derived from the lipopolysaccharides of several gram-negative bacteria, as well as chemically defined synthetic lipid A's and their analogs (both glucosamine mono- and disaccharides), were used to establish the chemical structures required for (i) abolishing the expression of suppressor T cell (Ts) function and (ii) inducing polyclonal activation of B cells. Salmonella minnesota R595 lipid A (diphosphoryl lipid A) possesses both of these activities. Decreasing the number of phosphate groups in lipid A from two to one (monophosphoryl lipid A) as well as decreasing the fatty acyl content, primarily by removing the residue at the 3 position, resulted in a progressive reduction in toxicity; however, these structural modifications did not influence its ability to abolish the expression of Ts function. Reducing the fatty acyl content from five to four (lipid A precursor IVA or Ia) eliminated the capacity to influence Ts function but not to induce polyclonal activation of B cells. None of the monosaccharide analogs of lipid A examined influenced the expression of Ts activity, although some were able to activate B cells polyclonally. Thus, in order to be able to abolish the expression of Ts function, lipid A (i) must be a glucosamine disaccharide, (ii) may have either one or two phosphate groups, and (iii) must have at least five fatty acyl groups. Also, the chain length of the nonhydroxylated fatty acid, as well as the location of acyloxyacyl groups (2' versus 3' position), may play an important role. These findings indicate that the chemical structures responsible for the toxicity of lipid A differ from those that influence its capacity to abolish the expression of Ts function and to induce polyclonal activation of B cells.
Animals↗
Increase in severity of graft versus host disease by cytomegalovirus.
An allogeneic transplant recipient developed severe graft versus host disease (GvHD) 48 days after transplantation that was concomitant with a cytomegalovirus (CMV) viraemia, from which she subsequently died. CMV infection was detected in blood by the polymerase chain reaction and later in tissue by immunohistochemical techniques. CMV should be considered in patients in whom GvHD does not respond to appropriate treatment, and this case suggests that herpes viruses may increase the severity of GvHD by synergistically enhancing the graft versus host reaction.
Adult↗
Human herpes virus 6 and endogenous biotin in salivary glands.
AIMS: To detect the presence of human herpes virus 6 (HHV6) and endogenous biotin in paraffin wax embedded and frozen salivary glands. METHODS: Two stage indirect and streptavidin-biotin immunoperoxidase techniques were used to visualise the antigens. RESULTS: HHV6 could not be shown in any of the tissues. However, considerable endogenous biotin antigenicity was detected in the glandular elements of the paraffin wax embedded material. CONCLUSIONS: Results obtained with avidin-biotin detection systems should be interpreted with caution, especially when glandular epithelium is being stained. This may apply to both immunoperoxidase and in situ hybridisation techniques. The use of an anti-biotin antibody as a standard control should be considered.
Biotin↗
Vitamin A status and the immune response to pneumococcal polysaccharide: effects of age and early stages of retinol deficiency in rats.
Production of antibodies to pneumococcal polysaccharide from Streptococcus pneumoniae, type III was determined in young rats at different ages and stages of vitamin A deficiency. At 30, 35 and 45 d of age, serum retinol concentrations of vitamin A-depleted rats were 46, 35 and 9%, respectively, of the serum retinol concentrations of pair-fed controls. Specific antibody production was low at 30 d of age for both vitamin A-depleted rats and control rats. Between 30 and 45 d of age, antibody production increased considerably in normal rats; however, the response of vitamin A-depleted rats was only 22% (P less than or equal to 0.001) that of controls at 35 d of age and 8% that of controls (P less than or equal to 0.001) for 45-d-old rats. Lymphocyte populations were examined by flow cytometry. The numbers of immunoglobulin M- and immunoglobulin D-positive cells changed with age, but not as a result of dietary treatment. The numbers of total T cells or helper and suppressor T cell subsets did not differ with age or with vitamin A status. These studies showed that the normal antibody response to pneumococcal polysaccharide develops rapidly after 30 d of age in the rat, that this antibody response is impaired even during the early stages of vitamin A deficiency, and that impaired antibody production does not seem to be accompanied by quantitative differences in splenic lymphocyte populations.
Aging↗
Immunological memory to tetanus toxoid is established and maintained in the vitamin A-depleted rat.
We have previously shown that vitamin A deficiency severely impairs the young rat's ability to produce specific antibodies after primary immunization with tetanus toxoid (TT). In the present studies, we asked whether immunologic memory to TT is established even in the vitamin A-depleted animal, and if so, whether such memory can be elicited after subsequent repletion with retinol. Vitamin A-depleted rats produced very low concentrations of TT-specific IgM and IgG antibodies in both the primary and secondary responses; however, the ratios of secondary to primary IgM anti-TT and of IgG anti-TT were normal. When rats were repleted with retinol 1 day after immunization, IgM and IgG anti-TT concentrations in both the primary and secondary responses were at least as great as those of control rats. For rats repleted with retinol 2 days before the booster immunization, secondary IgM and IgG anti-TT concentrations were equal in magnitude to those of vitamin A-sufficient controls. For all groups, the kinetics of the antibody response were similar. We conclude that immunological memory is intact in the vitamin A-depleted animal, as shown by 1) the normal ratio of its secondary to primary antibody responses, 2) the restoration of a quantitatively normal secondary antibody response in previously vitamin A-depleted animals repleted with retinol just before boosting with TT, and 3) a normal class switch from IgM to IgG. Retinol deficiency is also characterized by an abnormal elevation of total plasma IgG, despite the inability of the vitamin A-depleted animal to produce normal quantities of specific antibodies after challenge with antigen.
Animals↗
Antigen-specific suppressor T cells respond to recombinant interleukin-2 and other lymphokines.
Previous studies have shown that transfer of whole spleen cell populations obtained from primed donors or transfer of purified T cells enriched for suppressor activity (Ts) to recipient mice decreased the antibody response to pneumococcal polysaccharide type III (SSS-III) when the animals were simultaneously immunized with SSS-III. In the present studies, such suppression of the antibody response was transferred with 10- to 100-fold fewer primed spleen cells when the cells were treated in vitro with recombinant interleukin-2 (rIL-2) before transfer; spleen cells from naive mice or mice primed with an unrelated antigen (dextran) and then treated with rIL-2 did not cause suppression of the antibody response to SSS-III, thereby eliminating the possibility of nonspecific carryover effects induced by rIL-2. In vivo administration of rIL-2 at the time of immunization with an optimally immunogenic dose of SSS-III resulted in significant (P less than 0.05) suppression of the antibody response relative to that of control animals, suggesting that IL-2 augments the clonal expansion of Ts cells in vivo. Further, the ability of passively administered anti-IL-2 receptor antibody to inhibit generation of Ts cells in vivo is consistent with such a view. Spleen cells from primed animals treated with rIL-4, rIL-5, or gamma interferon--but not those from primed animals treated with rIL-6--likewise were able to transfer suppression of the antibody response with fewer cells than those required when primed cells not treated with lymphokines were used. Thus, these studies indicate that Ts cell activity is greatly influenced by lymphokines produced by helper T cells. The studies also suggest that these lymphokines are required during activation and/or clonal expansion of Ts cells.
Animals↗
Differential effects of monophosphoryl lipid A on expression of suppressor T cell activity in lipopolysaccharide-responsive and lipopolysaccharide-defective strains of C3H mice.
Lipopolysaccharide (LPS)-responsive and LPS-defective strains of C3H mice did not differ in the capacity to make an antibody response to type III pneumococcal polysaccharide or in the degree of thymus-derived suppressor cell (Ts) activity generated following exposure to type III pneumococcal polysaccharide. However, treatment with monophosphoryl lipid A (MPL) abolished the expression of Ts function in LPS-responsive but not LPS-defective mice. Since this effect was elicited by different preparations of MPL, it appears to be a general property of MPL mediated by direct action of MPL on activated Ts.
Animals↗
Lipopolysaccharidelike immunological properties of cell wall glycoproteins isolated from Cytophaga johnsonae.
Glycoproteins (GP) previously shown to be involved in the gliding motility of Cytophaga johnsonae were examined for biological activities characteristic of lipopolysaccharide (LPS). These integral membrane proteins activated 70Z/3 pre-B cells to synthesize immunoglobulin M, induced B cells to synthesize non-antigen-specific polyclonal immunoglobulin, induced macrophages to produce tumor necrosis factor, and modulated the antibody response to type III pneumococcal polysaccharide in the absence of thymus-derived (T) lymphocytes. Except for the GP activity in the 70Z/3 assay, all activities of the GP were comparable to or greater than those of LPS. No LPS was detected in the preparations of GP used or in the phenol-water extracts of C. johnsonae. The mechanism by which these GP exerted their biological activities was distinct from that of LPS, since LPS-resistant C3H/HeJ mice responded to GP. Furthermore, biologically inactive diphosphoryl lipid A obtained from nontoxic LPS of Rhodopseudomonas sphaeroides (an analog of toxic lipid A), which is an antagonist of LPS, did not block the induction of tumor necrosis factor by GP in macrophages. These results showed that the cell surface GP from C. johnsonae are potent LPS-like activators of B cells and macrophages. We suggest that these GP might be good candidates for use in developing an effective adjuvant system.
Animals↗
Differential sensitivity of CD8+ suppressor and cytotoxic T lymphocyte activity to bacterial monophosphoryl lipid A.
Treatment with a preparation of monophosphoryl lipid A, known to be capable of abolishing the expression of CD8+ suppressor T cell activity generated during the antibody response to type III pneumococcal polysaccharide (SSS-III), was found to have no adverse effect upon either induction or expression of CD8+ cytotoxic T lymphocyte activity specific for influenza A virus antigens. This suggests that suppressor T cells and cytotoxic T lymphocytes represent functionally distinct subsets of CD8+ T cells which can be differentiated on the basis of their sensitivities to inactivation by monophosphoryl lipid A.
Animals↗
Hepatitis A virus antibody in East Anglian blood donors.
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Adolescent↗
Local antibody production and respiratory syncytial virus infection in children with leukaemia.
Children undergoing therapy for acute lymphoblastic leukaemia (ALL) are at increased risk of severe viral respiratory infection, and some find it difficult to terminate virus secretion. This increased severity may result from a defect in the mucosal immune response. To test this hypothesis, nasal immunoglobulin secretion and specific antiviral antibody responses to infection with respiratory syncytial (RS) virus in children with ALL have been compared with those in a normal age-matched comparison group. Children with leukaemia secreted normal levels of IgA and slightly raised IgM levels. IgG levels were depressed. Following RS virus infection, the majority of children with leukaemia secreted normal amounts of IgA and IgG nasal antibody and successfully cleared the virus. However, three of the 13 children studied made poor or undetectable nasal antibody responses, which correlated with their inability to clear the virus.
Antibodies, Viral↗
Vitamin A deficiency decreases natural killer cell activity and interferon production in rats.
We examined the effect of vitamin A deficiency on natural killer (NK) cell activity and interferon (IFN) production. Rats were weaned at 16 or 21 d of age onto semisynthetic diets containing either 0 or 4 micrograms retinol/g diet. At the time of study, retinol-depleted rats had serum vitamin A concentrations less than 7% of those of pair-fed controls. In two studies, rats exhibited no external signs of retinol deficiency, but with further depletion some symptoms were observed. Splenic NK cell activity against chromium-51-labeled YAC-1 cells was significantly decreased in vitamin A-depleted rats (22-80% of values for control rats, depending on the degree of retinol deficiency), regardless of the ratio of effector to target cells used. When vitamin A-depleted rats were repleted orally with retinol, NK cell activity was consistently normalized. To understand the possible mechanisms involved in decreasing NK cell activity, we investigated IFN production by concanavalin A-stimulated spleen cells from vitamin A-depleted, from repleted and from control animals. IFN titers were significantly decreased (22-33% of values for control rats) in supernatants of spleen cell cultures of the vitamin A-depleted rats. Repletion with vitamin A resulted in IFN activities ranging from 80 to 130% of controls. Adding alpha/beta IFN in vitro to the spleen cells of vitamin A-depleted animals increased their NK cell activity. The number of spleen cells reacting with a monoclonal antibody specific for rat NK cells was slightly lower in retinol-depleted rats, but not enough to account for the differences in NK cell and IFN activities. These data suggest that vitamin A deficiency affect the nonspecific arm of the immune system, possibly by altering the functional capacity of cells to produce lymphokines needed for the generation of an appropriate cytolytic response.
Animals↗