A 3-month course of ciprofloxacin does not prevent BK virus replication in heavily immunosuppressed kidney-transplant patients

BackgroundIn vitro and retrospective studies of kidney-transplant patients have shown that quinolones can efficiently prevent BK virus (BKV) replication. However, in a prospective study, a 3 month-course of levofloxacin did not decrease the rate of BK viruria in kidney-transplant patients treated with standard immunosuppression.ObjectivesThe aim of this study was to assess the effect of a 3-month course of ciprofloxacin prophylaxis on BKV replication in kidney-transplant patients that had received heavy immunosuppression (plasma exchange or immunoadsorption and rituximab) to achieve desensitization before undergoing HLA- and/or ABO-incompatible (ABOi) transplantation.Study designTwenty-nine patients were given ciprofloxacin (500 mg/d) for 3 months, starting immediately after transplantation. The results were compared with results from a previous study where patients had received a similar immunosuppression regimen without ciprofloxacin prophylaxis (n = 43). Around 60% of patients had undergone a retransplantation. After transplantation, all patients were given induction therapy, tacrolimus, mycophenolic acid and steroids. BK viruria and viremia were monitored at months 1, 3, 6 and 12 post-transplantation.ResultsThe rates of BK viruria, BK viremia, and BKV-associated nephropathy did not differ between patients who were given or not given ciprofloxacin prophylaxis. These rates were also identical when patients received quinolones at any time within the first year after transplantation compared to those that had not. The rate of bacterial infection was also similar in patients who had or had not received ciprofloxacin.ConclusionThe use of quinolones seemed to not have any beneficial effect in preventing BKV replication in kidney-transplant patients receiving heavy immunosuppression.     

The nature of immunosuppression in Trypanosoma brucei infections in mice: II. The role of the T and B lymphocytes

In an investigation of the immunosuppression associated with trypanosomiasis, the thymus-derived lymphocytes (T cells) and the thymus-independent lymphocytes (B cells) in mice with subacute Trypanosoma brucei infections were studied. It was shown that: (a) there was a massive plasma cell response in lymph nodes and spleen which replaced the thymus-dependent areas; (b) a failure of antibody production at the cellular level occurred as shown by the absence of IgM PFC responses to SRBC and lipopolysaccharide; (c) T cells appeared relatively normal as judged by their ability to proliferate following a primary stimulus with oxazolone unless measured during the terminal stages of the disease; (d) immune competence was rapidly restored after treatment with a trypanocidal drug.

It appeared that immunosuppression was closely associated with the presence of living trypanosomes, possibly mediated through a B-cell defect. The mechanism whereby this might occur is discussed.

     

A DTU-dependent blood parasitism and a DTU-independent tissue parasitism during mixed infection of Trypanosoma cruzi in immunosuppressed mice

Trypanosoma cruzi (Tc) diversity is determined by different biological, genetic, and biochemical markers and has been grouped into six discrete typing units (DTUs) or taxonomic groups (TcI–TcVI). This variability, coupled with natural reinfection or the hosts' immunosuppression, may play an important role in the pathogenesis of Chagas disease. Therefore, we evaluated the blood and tissue parasitism and genetic profile of mice coinfected with the TcII (JG) strain and TcI AQ1-7 (AQ) or MUTUM (MT) strains during the acute and chronic phases of the disease and during immunosuppression. T. cruzi blood populations in mixed infections were clearly associated with the TcII strain during acute and chronic phases or during immunosuppression. However, in tissues, the parasite populations were distributed according to the strain and the stage of infection. TcII populations overlapped TcI strains during the acute phase; in contrast, during chronic phase, both TcI strains were more prevalent than the TcII strain. The immunosuppression induced selective exacerbation of parasite populations, leading to reactivation of the TcII strain when associated with the AQ, but not with MT strain. Thus, a differential distribution of T. cruzi populations in blood and tissues with overlapping according to the stage of infection and strain used was observed. Blood parasitism was associated with the DTU TcII and tissue parasitism with a specific parasite strain and not with DTUs. Finally, to our knowledge, this is the first study to analyze subpatent blood parasitism and to simultaneously identify different T. cruzi populations in tissues and blood.     

Effects of taste aversion conditioning on the primary antibody response to sheep red blood cells and Brucella abortus in the albino rat

It has been shown that use of the saccharin/cyclophosphamide taste aversion paradigm produced conditioned immunosuppression as well as saccharin avoidance after two post-conditioning exposures to the aversive stimulus [3,18]. In the present study the effects of saccharin/cyclophosphamide conditioning on the primary humoral antibody response to two antigens: sheep red blood cells (SRBC), a T-cell dependent antigen and Brucella abortus (B. abortus), a T-cell independent antigen, were examined. In addition the effects of a third exposure to the aversive stimulus, saccharin, on conditioned immunosuppression were examined. The results indicate that the target cell of taste aversion conditioning, in relation to immune dysfunction, could be the T-lymphocyte and that conditioned immunosuppression is dependent on the presence of the behavioral response. These results constitute a replication of previous studies [3,18] and provide evidence which indicates that behaviorally conditioned immunosuppression is a consequence of the parameters of taste aversion conditioning.     

The immunosuppressive effect of mycoplasma infection: I. Effect on the humoral and cellular response

Mycoplasma-induced immunosuppression in rats was demonstrated with Mycoplasma arthritidis strain PN. Immunosuppression involving the humoral antibody response was complete or partial when mycoplasma was injected concurrently with the antigen. Mycoplasma did not interfere with the antibody response when injected after primary immunization.

Inhibition of blast transformation was shown to occur in lymphocytes derived from rats infected with the above mycoplasma. The inhibition was partial or complete depending on the interval between the infection and the time when the lymphocytes were taken from the animal, and blast transformation reverted to normal when the infection was over.

Although the question of mechanism remains open, it was concluded that immunosuppression might be the result of the effect of M. arthritidis on a particular population of cells.

     

Functional and Phenotypic Changes in Circulating Lymphocytes from Hospitalized Zambian Children with Measles

Measles is associated with immunosuppression and increased susceptibility to secondary infections and is a particular problem in developing countries. Lymphocyte changes accompanying immune activation and regulation of the immune response may contribute to immunosuppression. To evaluate lymphocyte changes during measles, children (n = 274) hospitalized with measles in Lusaka, Zambia, were evaluated at entry, discharge, and 1-month follow-up and compared to healthy Zambian children (n = 98). Lymphopenia was present on hospital admission and reflected decreased CD4 and CD8 T cells but resolved quickly. Lymphopenia was most marked in girls, in those with temperatures of >38.5°C, and in malnourished children. CD4/CD8 ratios were decreased at all time points and were lower in boys than in girls at discharge and follow-up. Spontaneous death occurred in cultured lymphocytes, and the proportions of freshly isolated cells undergoing apoptosis, based on annexin V and propidium iodide staining, were increased. Surface Fas was increased on both CD4 and CD8 T cells compared to controls, and expression was greater on CD4 T cells and was inversely correlated with lymphocyte viability in culture at study entry. Mitogen stimulation of lymphocytes improved viability, but inhibitors of Fas, tumor necrosis factor (TNF)-related apoptosis-inducing ligand, and TNF did not. Plasma levels of β₂ microglobulin and soluble Fas, Fas ligand, CD8, CD4, and TNF receptor were increased, and soluble CD8 was higher in boys than in girls. The multiple effects of measles on lymphocytes from Zambian children include decreased numbers in circulation, increased activation, and increased susceptibility to cell death, with substantive differences in the magnitude of these changes between boys and girls.     

Mycoplasma-Associated Immunosuppression: Effect on Hemagglutinin Response to Common Antigens in Rabbits

A Mycoplasma-associated immunosuppression of the primary and secondary hemagglutinin response to a common gram-negative antigen of Escherichia coli (014) was demonstrated in the rabbit when preincubated mixtures of common gram-negative antigen and Mycoplasma arthritidis membranes were injected intravenously. A similar immunosuppression was demonstrated only for the secondary hemagglutinin response to a common gram-positive antigen of Staphylococcus aureus when preincubated mixtures of common gram-positive antigen and M. arthritidis membranes were employed as immunizing materials. The immunosuppressive effect occurred with small quantities of M. arthritidis membranes and appeared not to be limited to the host in which arthritogenic properties of the organism were manifested.     

Immune response and immunodepression inHymenolepis diminuta infection in rats

Maximum size range ofHymenolepis diminuta was found in rats 22 days postinfection (p.i.) with single or several (3–6) tapeworms. Immunologic reactions of the host were connected with the growth and development of parasites. Positive results of macrophage migration inhibition test (MMI) were recorded from 7 until 22 days p.i. in infection with a single and to 16 days p.i. in those with 3–6H. diminuta. The negative results of the MMI test observed at later postinfection times are considered as a manifestation of immunosuppression caused by the presence ofH. diminuta. The expulsion of tapeworm by anthelmintic treatment with Yomesan ® restored for a short time cell-mediated immunity, as demonstrated by MMI test. The level of antibodies, as determined by passive hemagglutination test (HA), varied during the infection; it was highest at 22 days p.i. The removal of tapeworms as a results of drug treatment caused a rise in titers.     

The induction of immunological tolerance to the parasitic nematode Trichuris muris in cortisone-treated mice

Tolerance to the parasitic nematode Trichuris muris was induced in mice by treatment with cortisone acetate given during the second week of a primary infection, the time at which the host is known to be beginning to respond to the antigens of the parasite. Continuation of the antigenic stimulus provided by infection beyond the period of immunosuppression was an essential requirement for tolerance; if the infection was terminated immediately after treatment the mice remained susceptible to subsequent infection, but then made a primary self-cure response. It is suggested that tolerance involves a long-lasting change in immunological reactivity of the host rather than a paralysis due to an excess of antigen, as tolerance was induced by small infections and persisted for at least 7 weeks in the absence of infection.     

Acquired resistance to ticks: IV. Skin reactivity and in vitro lymphocyte responsiveness to salivary gland antigen

Guinea-pigs developed resistance to the ixodid tick, Dermacentor andersoni, after one infestation. Resistance was characterized by guinea-pigs allowing significantly fewer larvae (10–20%) to engorge during a second infestation than during an initial infestation (90–99%). Data reported here further confirm the immunological nature of guinea-pig resistance to D. andersoni larvae and indicate the presence of a cell-mediated immune component to the resistance. An antigen isolated from the salivary glands of adult female D. andersoni was shown to stimulate in vivo delayed skin reactivity when administered intradermally to tick-resistant guinea-pigs. Salivary gland antigen (SGA) initiated in vitro lymphocyte blastogenesis when added to cultures of lymph node cells from tick-resistant hosts. Antigen-specific responsiveness of lymphocytes to SGA occurred over a period of from 2 to 4 days after the termination of an initial infestation with tick larvae until the termination of a second infestation. Basophils first appeared at tick attachment sites at the time when antigen-specific lymphocyte responsiveness was first significant. Peak responsiveness occurred 24 h after the initiation of a second laval infestation at a time when large numbers of basophils were attracted to the tick attachment site. Evidence is also presented to suggest that tick infestation might induce a degree of immunosuppression in the host.     

Immunosuppression in murine malaria. II. The effect on reticulo-endothelial and germinal centre function

The mechanism of the immune suppression of mice infected with the rodent malaria parasite Plasmodium berghei yoelii has been investigated.

The clearance from the peripheral blood of carbon and ⁵¹Cr-labelled sheep erythrocytes was enhanced during the period of maximal parasitaemia and maximal immunosuppression, but the uptake of sheep erythrocytes by the spleens of infected mice did not differ significantly from the uptake by the spleens of healthy mice.

There was no uptake of aggregated human γ-globulin into germinal centre areas of the spleens of infected mice during the period of maximal immune suppression, but the ability to localize human γ-globulin returned at a time when the mice recovered immune competence.

It seems probable that acute malaria infections of mice induce a quantitative or qualitative defect in the cells responsible for transporting immune complexes into germinal centres. This defect may play a part in the immunosuppression induced by the malaria parasite.

     

Ivermectin-induced immunopotentiation in onchocerciasis: recognition of selected antigens following a single dose of ivermectin

Onchocerciasis is associated with blindness and gross skin changes, believed to be a consequence of the immune response to antigens released from the offspring of the female worm of Onchocerca volvulus, the microfilariae (mf). An effective microfilaricidal drug is now available which quickly reduces the mf burden without affecting the adult worm. There exist foci in onchocerciasis endemic areas where some of the patients have many mf in their skin but relatively few clinical symptoms. This state of hyposensitivity is believed to be due to immunosuppression. The aim of this study was to address the question of the basis of, and the effect of ivermectin treatment on this immunosuppression. Female adult worms of O. volvulus were used as whole or fractionated antigens to stimulate peripheral blood mononuclear cells. Microfilariae are found in the reproduction tract of the female worms, and thus an antigen preparation of the female adult O. volvulus contains both exclusive adult antigens as well as antigens from microfilariae. Cells were obtained from onchocerciasis patients, individuals of similar socio-economic status living in the same Ghanaian village, but who showed no parasitological or clinical evidence of onchocerciasis (exposed endemic controls), healthy Ghanaians living in areas where transmission of onchocerciasis does not seem to occur (non-exposed endemic controls) and unexposed healthy Swedish donors. As a group, cells from onchocerciasis patients proliferated to a lesser degree than cells from the exposed endemic control and the non-exposed endemic control groups to the whole worm antigen, whereas the phytohaemagglutinin (PHA) response was strongest in the patients. Proliferative responses of above 1000 ct/min to fractions of the worm extract were only evident in the cells from a few individuals in each of the various groups. However, 28 days following ivermectin treatment, cells from all onchocerciasis patients were able to mount significantly enhanced proliferation to a fraction of approximately 96 kD (fraction 3), while only four of nine of this group showed an increased response to the whole worm antigen. The proportional increase in the response to the whole organism in these individuals was of a much lower magnitude than the increased response to fraction 3. The O. volvulus antigen-specific immunosuppression observed in these onchocerciasis patients appears to be due to suppressive antigens which have the capacity to mask the potential response to selected antigens of O. volvulus, and ivermectin treatment possibly modulates the immune response, allowing for stepwise recognition of such antigens. Since ivermectin treatment kills only the microfilariae and not the adult worm, the putative suppressive antigens would be expected to be from the microfilariae.     

A new kind of immunosuppression associated with erythropoiesis

A new type of immunosuppression associated with erythropoiesis in genetic low responder mice is reported. C57B1/6J mice do not produce antibodies after a single dose of Escherichia coli β-D-galactosidase but become primed and mount memory. These two immunological functions are confined to the spleen and are abrogated by erythropoiesis occurring in this organ at the time of first antigen contact. This finding reveals new aspects of the relationship between hematopoiesis and the immune response, particularly their regulatory interactions when they occur close to each other.     

The effect of amphotericin B treatment on Candida albicans-induced immunosuppression in mice

The data presented shows that C. albicans-infected mice had a reduced capacity to mount a delayed-type hypersensitivity response to sheep red blood cell antigens. During treatment of these mice with amphotericin AmB, the drug caused a further significant reduction of the immune response. However, when AmB treatment was stopped, the immunosuppression caused by C. albicans and also AmB was alleviated. Nevertheless, it seems, from these findings, that the host may experience a combined immunosuppression which may be a problem relevant to cancer patients, since fungal infections are common in such patients.     

The decreased number and function of lymphocytes is associated with Penicillium marneffei infection in HIV-negative patients

Background/purposePenicillium marneffei (P. marneffei) infection, which has been traditionally considered as an indicator of immunosuppression, is one of the most common systemic opportunistic infections in patients with AIDS. Recently, more and more P. marneffei infections have been documented in HIV-negative patients without underlying diseases, which challenges the traditional view that P. marneffei infection is an indicator of immunosuppression. We aimed to evaluate the number and function of lymphocytes in HIV-negative patients with P. marneffei infection.Methods15 HIV-negative P. marneffei-infected patients and 18 healthy controls were recruited and investigated. The number and function of lymphocytes were analyzed by flow cytometry.ResultsMost laboratory tests were within the reference ranges, except for a significant increase in total IgE in P. marneffei-infected patients. Lymphocyte subset analysis showed that the number of CD4⁺ T cells and NK cells was significantly decreased in HIV-negative marneffei-infected patients compared with healthy controls. However, almost half of the marneffei-infected patients still had normal levels of lymphocytes. A further analysis of cell function showed that the activation and proliferation of CD4⁺ T cells, the cytotoxicity of CD8⁺ T cells and NK cells, and the cytokine secretion potential of CD4⁺ T cells and NK cells were all impaired, in comparison with healthy controls.ConclusionsP. marneffei infection has to be regarded as an indicator of immunosuppression. A further investigation of cell function is required in patients with opportunistic infection, as the cell function may be impaired in this condition.     

Rothia aeria as a Cause of Sepsis in a Native Joint

Rothia aeria is a recently described Gram-positive rod from the family Micrococcaceae. An elderly woman with rheumatoid arthritis and dental abscesses who was undergoing immunosuppression had R. aeria isolated from synovial fluid. This report characterizes this rare organism and contributes to the literature on its pathogenicity and likely oral source.     

The nanomaterial-dependent modulation of dendritic cells and its potential influence on therapeutic immunosuppression in lupus

Targeting dendritic cells with nanoparticles is an attractive modality for instigating immunity or inducing immunosuppression. An important aspect of successful delivery of antigen and immune modulators to these cells is the efficacy of nanoparticle internalization, which can dictate the strength and robustness of immune responses; optimizing particulate uptake is thus key. We compared the internalization of two nanoparticulate platforms: a vesicular “nanogel” platform with a lipid exterior, and the widely-used solid biodegradable poly(lactic-co-glycolic acid) (PLGA) system. We found that nanogels were more effectively internalized by dendritic cells in vitro, as demonstrated by fluorescent tracer measurements. Additionally, the magnitude of dendritic cell immunosuppression achieved by nanogels loaded with mycophenolic acid, an immunosuppressant, was greater than similarly drug-loaded PLGA. Although both types of particles could mitigate the production of inflammatory cytokines and the up-regulation of stimulatory surface markers, nanogels yielded greater reductions. These in vitro measurements correlated with in vivo efficacy, where immunosuppressive therapy with nanogels extended the survival of lupus-prone NZB/W F1 mice whereas PLGA particles did not. Our results highlight the importance of material on nanoparticle uptake by dendritic cells, which impacts the quality of therapeutic immunosuppression.     

Effects of SK&F 105685, a novel anti-arthritic agent,on immune function in the dog

SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2-propanamine dihydrochloride) is a novel azaspirane with beneficial activity in animal models of autoimmune disease such as adjuvant-induced arthritis and experimental encephalomyelitis in the Lewis rat and lupus-like disease in the MRL mouse. The activity of SK&F 105685 in these models is associated with the induction of non-specific suppressor cell (SC) activity as defined by the ability of cells from drug-treated animals to inhibit the proliferative response of lymphocytes from control animals to concanavalin A. To evaluate the immunotoxicologic potential of SK&F 105685, the effect on immune function of one month of dosing with 1 mg/kg/day of SK&F 105685 was examined in the dog. Differential blood cell counts and ex vivo immune function assays were performed using blood collected before dosing on days 1 (baseline), 15 and 29, of the study. Immune function assays were performed on spleen cells on day 30. Under the conditions of the study, SK&F 105685 displayed pharmacological activity as demonstrated by the induction of splenic SC activity. The drug did not affect the total number or relative percentages of the various white blood cell types present in peripheral blood and did not cause generalized immunosuppression. The ability of peripheral blood lymphocytes or spleen cells to produce IL-2 or proliferate in response to mitogenic stimulation was not affected by drug treatment. SK&F 105685 also failed to affect the candidacidal activity of polymorphonuclear leucocytes and spleen cells indicating that it is unlikely to compromise nonspecific resistance to infection. SK&F 105685 however, was able to inhibit the generation of a specific in vitro antibody response to sheep red blood cells (SRBC) by splenocytes from treated animals. Inhibition of the anti-SRBC antibody response was also observed upon addition of the drug to normal spleen cells. Addition of the drug at different time points during the culture period indicated that SK&F 105685 was interfering with an event(s) occurring during the first 72 h of culture. Taken together, these results suggest that, in a therapeutic setting, SK&F 105685 in unlikely to compromise the immune status of the host as it can down-regulate a specific immune response without causing generalized immunosuppression.     

Concurrent Infection of the Urinary Tract with Encephalitozoon cuniculi and Enterocytozoon bieneusi in a Renal Transplant Recipient

A urinary tract coinfection, caused by Encephalitozoon cuniculi genotype II and Enterocytozoon bieneusi genotype D, was identified in an HIV-seronegative renal transplant recipient kept under lifelong immunosuppression. To our knowledge, this is the first report describing concurrent infection with these two microsporidia species in organ transplant recipients.     

Nitric oxide mediates immunosuppression induced byListeria monocytogenesinfection: quantitative studies

Our laboratory has shown that immunization of mice with an attenuated strain ofSalmonella typhimuriuminduces profound suppression in the capacity of splenocytes to mount anin vitroantibody plaque-forming cell (PFC) response to sheep red blood cells (SRBC) and to proliferate in response to mitogens.In vitroaddition of N^G-monomethyl-L-arginine (NMMA), an inhibitor of nitric oxide (NO) synthase, to cell cultures fromSalmonella-immunized mice completely blocked suppression of the PFC responses, implicating that NO is the suppressor factor. The present study quantified the role of nitric oxide in immunosuppression induced byListeria monocytogenes, a gram positive intracellular pathogen of macrophages.Listeriainfection resulted in suppression of the PFC assay at inoculating doses of greater than 6.5×10³colony forming units, with no suppression observed at lower doses. Suppression correlated with increased nitrite production. Addition of NMMA to spleen cell cultures taken fromListeria-infected mice completely blocked suppression of the PFC response, and returned nitrite production to baseline levels. In regard toListeria-induced suppression of responses to the mitogen, Concanavalin A (Con A), the parameters were different from those observed for the PFC response. There was a direct correlation between the log₁₀of the inoculating dose ofListeriaand degree of immunosuppression, with suppression observed at doses as low as 1×10³cells. Addition of NMMA to the Con A-stimulated cultures resulted in reduced nitrite levels, but only partial restoration of the proliferative responses. Co-culture of splenocytes fromListeriainoculated mice with normal splenocytes in media with NMMA and reduced levels of L-arginine resulted in complete reversal of suppressed responses to Con A. Similar differences in ease of reversing suppression of the PFC response, as compared with responses to Con A, were previously noted using cells taken fromSalmonella-infected mice. The present results show that a gram positive intracellular pathogen of macrophages,L. monocytogenes, induces immunosuppression in mouse spleen cells by a nitric oxide mediated mechanism that closely parallels that induced by the gram negative pathogen,S. typhimurium.