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Starch microparticles as an adjuvant in immunisation: effect of route of administration on the immune response in mice.

This paper describes the effects on the development of an immune response by changing the route of administration of a new vaccine adjuvant, starch microparticles with human serum albumin (HSA) as a model antigen. The model vaccine was administered to mice by oral, subcutaneous and intramuscular routes in various combinations and both the local secretory immunoglobulin antibody (s-IgA) and systemic humoral and cellular (delayed-type hypersensitivity assay (DTH)) responses were followed. The only immunisation regimens inducing a significant s-IgA response were those incorporating oral booster doses. Oral and subcutaneous immunisations had similar effects on the Th1/Th2 balance, as indicated by the IgG subclass ratios and cytokine analyses. However, significant differences between oral and intramuscular immunisations were seen in the IgG subclass ratios. The Th2 influence was stronger after oral primary immunisation than after intramuscular primary immunisation, while oral boosters elicited a comparatively stronger Th1 response than intramuscular boosters. This result was also supported by the DTH analyses. Subcutaneous immunisation induced a stronger Th2 response than intramuscular immunisation, as indicated by subclass ratio and the IgE response. In conclusion, our results show that the profile of an immune response depends on the route of administration, which should be considered when developing new vaccines or new routes of administration.

Adjuvants, Immunologic↗

Suppression of murine allergic contact dermatitis by CTLA4Ig. Tolerance induction of Th2 responses requires additional blockade of CD40-ligand.

Blockade of costimulation through the B7-CD28 pathway by CTLA4Ig can lead to Ag-specific T cell tolerance. Most models studied to date involve a Th1-dependent response. To investigate whether the tolerizing effects of CTLA4Ig might vary depending upon the cytokine nature of the immune response, we studied its effects on contact hypersensitivity (CHS) in response to two allergens. In BALB/c mice, both 2,4-dinitrofluorobenzene (DNFB) and FITC induce CHS. However, the DNFB response is Th1-predominant, while the FITC response is Th2 predominant. CTLA4Ig treatment during primary sensitization induced long-lasting unresponsiveness to DNFB, with 88% and 76% inhibition of primary (first challenge) and secondary (re-sensitization and re-challenge) CHS, respectively. In contrast, CTLA4Ig inhibited primary CHS to FITC by over 82% but had little effect on secondary CHS. Consistent with its effects on CHS, the suppressive effect of CTLA4Ig on Th2 cells was short-lived in FITC-sensitized mice, while Th1-like cytokine-secreting cells remained reduced in DNFB-sensitized mice, even when the animals were rechallenged with DNFB. The addition of anti-CD40L Ab to CTLA4Ig was able to induce long-lasting unresponsiveness to FITC, indicating the ability of cells mounting this Th2 response to receive costimulatory signals through either pathway. In conclusion, CHS can be mediated by both Th1 and Th2 cells, and the ability of CTLA4Ig to lead to long-standing nonresponsiveness in this model depends on the nature (i.e., cytokine profile) of the immune response.

Abatacept↗

WI-1, a novel 120-kilodalton surface protein on Blastomyces dermatitidis yeast cells, is a target antigen of cell-mediated immunity in human blastomycosis.

A large body of experimental data has demonstrated the central role of T cells in acquired resistance to the dimorphic fungus Blastomyces dermatitidis. We examined the human T-cell response to WI-1, a 120-kDa B. dermatitidis yeast cell surface protein recently shown to be an immunodominant antigen of the B-cell response in infected humans. Peripheral blood lymphocytes from 10 blastomycosis patients studied proliferated in response to WI-1 (mean, 19,431 cpm) and to the standard, crude cell wall antigen, Blastomyces alkali- and water-soluble antigen (B-ASWS) (mean, 19,131 cpm); lymphocytes from 10 histoplasmosis patients and 10 normal control subjects did not respond to WI-1. WI-1 stimulation of patient lymphocytes and rechallenge with WI-1 or B-ASWS showed that the antigens share immunodominant epitopes. Of 100 WI-1-responsive T-cell clones derived from peripheral blood, 10 were studied in detail to assess the phenotype, function, and ligands recognized. The clones exhibit the CD3+ CD4+ phenotype of helper T cells; 2 of 10 clones (and 21% of antigen-stimulated peripheral blood lymphocytes) use the V beta 8 T-cell receptor gene element to respond to WI-1. All the clones proliferate in response to both WI-1 and B-ASWS but not other fungal antigens, and some mediate potent cytolytic effects on WI-1- and B-ASWS-labeled targets. WI-1 recognition requires antigen processing and presentation of epitopes in association with HLA-DR (to noncytolytic clones) and HLA-DP (to cytolytic clones). From these findings, we conclude that CD4+ T cells with regulatory and cytolytic properties are involved in the development of acquired resistance of B. dermatitidis, that the cells are directed against WI-1, and that the manner of display of WI-1 peptide epitopes in conjunction with major histocompatibility complex class II may influence the profile of the immune response.

Antigens, Fungal↗

Evaluation of cytokine gene expression in porcine spleen cells, peripheral blood mononuclear cells, and alveolar macrophages by competitive RT-PCR.

Cytokines act as an important regulator of immune responses. Since cytokine expression levels are generally very low, more accurate and reliable methods of measuring their expression are needed. In this study, a modified competitive reverse transcription-polymerase chain reaction assay was developed to determine the expression levels and patterns of porcine IFN-gamma, IL-2, IL-4, IL-10, IL-12 p 35, and IL-12 p40 in spleen cells, peripheral blood mononuclear cells (PBMC), and alveolar macrophages that were stimulated for 4 h by lipopolysaccharide or phytohemagglutinin. Of these cytokines, the expression level of IFN-gamma was the highest in all examined cells. Constitutive expression of IL-2 and IL-4 was demonstrated in spleen cells and PBMC stimulated with phytohemagglutinin. However, their expression extent was not determinable or extremely low in the lipopolysaccharide-stimulated spleen cells and alveolar macrophages. Moderately high IL-10 expression was observed in all examined cells. IL-12 p 35 expression in alveolar macrophages was always higher than in spleen cells and PBMC. IL-12 p40 expression in alveolar macrophages was higher than in PBMC, but was lower than in spleen cells. In spleen cells, the expression of IL-12 p40 was higher than that of IL-12 p 35. In alveolar macrophages and PBMC, however, IL-12 p 35 showed a higher expression than IL-12 p40. These results indicate that each cytokine has its own characteristic expression profile in different immune cells.

Animals↗

Circulating cytokines and chemokines in acute symptomatic parvovirus B19 infection: negative association between levels of pro-inflammatory cytokines and development of B19-associated arthritis.

The aim of the study was to characterise the profile and clinical correlates (arthritis, rash, and fatigue) of cytokines, chemokines, and other mediators in symptomatic acute parvovirus B19 infection. Serum was examined from cases of acute B19 infection (as defined by serum anti-B19 IgM positivity) (n = 84), and in normal persons (n = 43) for B19 markers (serum B19 antibodies and DNA), rheumatoid factor (RF), and antinuclear antibody (ANA). A panel of cytokines/chemokines was measured in duplicate using the Bioplex Protein Array system (BioRad Hemel Hempstead, UK). These included interleukin-1 beta (IL-1 beta), IL-4, IL-5, IL-6, IL-8, IL-13, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), macrophage chemoattractant protein-1 (MCP-1), granulocyte-monocyte colony stimulating factor (GM-CSF), transforming growth factor-beta1 (TGF-beta 1), endothelin-1 (ET-1), and neopterin. Acute symptomatic infection was characterised by specific IgG positivity (83%), serum B19 DNA positivity (96%), and raised levels of IL-4, IL-6, IL-8, TNF-alpha, IFN-gamma, MCP-1, GM-CSF, TGF-beta 1, and ET-1. Patients with acute B19-associated arthritis were found to have lower levels of IL-6, TNF-alpha, and GM-CSF than patients without arthritis, while those with rash had lower levels of TGF-beta 1. It is concluded that cytokine levels following acute symptomatic infection with parvovirus B19 indicate a state of immune activation. The profile of circulating mediators may provide insights into the possible pathogenesis of particular clinical manifestations of this infection.

Adolescent↗

Cytokine production after influenza vaccination in a healthy elderly population.

Influenza vaccination is less efficacious in the elderly than in the young. To characterize this age-related decrease in immune response to influenza vaccination, antibody and cell-mediated responses to influenza vaccine were assessed before immunization and 4 weeks after vaccination of a population of 270 healthy elderly individuals (mean age: 80.2 years) living in eight local continuing care retirement communities (CCRCs) and 30 young individuals (mean age: 27.8 years). The antibody titres produced against all three influenza strains increased significantly after vaccination in both the young and elderly (p < 0.0005); however, the young demonstrated significantly higher titres to all three strains than did the elderly (p < 0.03). Peripheral blood mononuclear cells (PBMC) cultured with influenza vaccine demonstrated significantly increased proliferation (elderly: p < 0.00005; young: p < 0.001) after vaccination, with proliferative responses in the young significantly higher than the elderly both before (p < 0.04) and after (p < 0.0005) vaccination. Similarly, IFN gamma production in these PBMC cultures increased significantly pre- to postvaccination in both young and elderly (young: p < 0.006; elderly: p < 0.00005), but the young produced more than the elderly both pre- and postvaccination (p < 0.0001). Following vaccination, PBMC production of IL-10 was higher in the young than in the elderly (p < 0.0015), while IL-6 production was comparable in both young and elderly individuals. Greater than 13% of the elderly population did not produce detectable IL-6, IL-10, or IFN gamma either before or after vaccination. The data show that the decreased cell-mediated and humoral responses to influenza vaccination of this healthy elderly population are accompanied by the production of lower levels of cytokines. A unique finding in this population of 270 healthy elderly was the association between a TH0 cytokine profile and intact immune responses to influenza vaccine. A similar relationship was not seen in the young.

Adult↗

Immunization against East Coast fever: the use of selected stocks of Theileria parva for immunization of cattle exposed to field challenge.

Two antigenically different stocks of Theileria parva parva (Kilifi and Marikebuni), previously characterized as belonging to groups A and C respectively on monoclonal antibody (MAb) profiles, were selected for immunization of different breeds of cattle against East Coast fever (ECF) by the infection and treatment method. A total of 52 immunized cattle and 33 susceptible controls of different group sizes were exposed to field challenge by ticks for periods of 42-90 days at three field sites where ECF is endemic on the Kenyan coast. All immunized cattle survived ECF challenge, but 87% of the controls died of the disease. The cattle exposed at one site had been immunized 1 year earlier and maintained tick-free in the intervening period. The level of immunity in these cattle was similar to that of cattle which had been immunized 1 or 2 months prior to exposure. Thus, immunity had not waned over the 1-year period. A study at another site showed that acaricidal treatment of immunized cattle could be safely extended from twice a week to once every three weeks, whereas in susceptible cattle even twice weekly spraying did not control ECF. The isolates made from infected controls during the trials indicated the presence of three T. p. parva stocks as defined by MAb profiles. Of the two stocks used for immunization, T. p. parva Marikebuni induced broader protection. In view of the apparent limited antigenic diversity of T. p. parva strains within the Coast Province it is suggested that the Marikebuni stock might represent a key stock for vaccination in this area.

Animals↗

Th1 and Th2 in human diseases.

A large body of evidence suggests the existence of functionally polarized human T cell responses based on their profile of cytokine secretion in both the CD4+ T helper (Th) and the CD8+ T cytotoxic (Tc) cell subset. Human Th1 and Th2 cells not only produce a different set of cytokines but also exhibit distinct functional properties and the preferential expression of some activation markers, such as LAG-3 and CD30, respectively. Several factors may influence Th cell differentiation into the polarized Th1 or Th2 pathway. They include the cytokine profile of "natural immunity" evoked by different offending agents, the nature of the peptide ligand, as well as the activity of some costimulatory molecules and microenvironmentally secreted hormones, in the context of different host genetic backgrounds. Strongly polarized human Th1-type and Th2-type responses not only play different roles in protection, Th1 being effective in the defense against intracellular pathogens and Th2 against intestinal nematodes, but are also responsible for different types of immunopathological reactions. Th1-dominated responses may be involved in the pathogenesis of organ-specific autoimmune disorders, acute allograft rejection, unexplained recurrent abortions, contact dermatitis, and some chronic inflammatory disorders of unknown etiology. In contrast, Th2-type responses are responsible for Omenn's syndrome, reduced protection against some intracellular pathogens, transplantation tolerance, chronic GVDH, atopic disorders, and some systemic autoimmune diseases.

Humans↗

Biology of human TH1 and TH2 cells.

Evidence is accumulating to suggest the existence of polarized human T-cell responses, reminiscent of TH1 and TH2 subsets described for mouse T cells. Human TH1 cells preferentially develop during infections by intracellular bacteria and trigger phagocyte-mediated host defense, whereas TH2 cells, which predominate during helminthic infestations and in response to common environmental allergens, are responsible for phagocyte-independent host response. Human TH1 and TH2 cells exhibit not only different functional properties but probably also distinct surface markers; TH2, but not TH1, clones express membrane CD30 and release the soluble form of CD30, a member of the TNF receptor superfamily. The cytokine profile of "natural immunity" evoked by different offending agents in the context of different host genetic backgrounds appears to be the most critical factor in determining the phenotype of the subsequent specific response. IL-12 and IFN-alpha and gamma produced by macrophages and NK cells favor the development of TH1 cells, whereas the early production of IL-4 by a still-unidentified cell type favors the development of TH2 cells. Clearly, polarized human TH1 and TH2 responses not only play different roles in protection, they can also promote different immunopathological reactions. Strong and persistent TH1 responses seen to be involved in organ-specific autoimmunity, contact dermatitis, and some chronic inflammatory disorders of unknown etiology. In contrast, polarized TH2 responses favor a reduced protection against the majority of infectious agents (including HIV) and, in genetically predisposed hosts, are responsible for triggering of allergic atopic disorders.

Humans↗

Nitric oxide and polyamine pathway-dependent modulation of neutrophil free amino- and alpha-keto acid profiles or host defense capability.

We have examined the effects of N(omega)-nitro-L-arginine-methylester-hydrochloride [L-NAME; inhibitor of nitric oxide synthase], S-nitroso-N-acetyl-penicillamine [SNAP; nitric oxide donor], alpha-difluoro-methyl-ornithine [DFMO; inhibitor of ornithine decarboxylase] arginine or ornithine as well as the combination of arginine or ornithine with L-NAME, SNAP or DFMO on intracellular free amino- and alpha-keto acid profiles and the immune function markers superoxide anion and hydrogen peroxide generation as well as released myeloperoxidase activity in neutrophils (PMN). Although the underlying mechanisms still remain unclear, we believe from our results that nitric oxide as well as polyamine-dependent pathways are involved in the signal transmission of free radical molecule, beneficial nutritional therapy or maleficient pharmacological stress-induced alterations in PMN nutrient composition. Relevant changes in intragranulocyte free amino- and alpha-keto acid homeostasis and metabolism, especially, may be one of the determinants in PMN nutrition that positively or negatively influences and modulate neutrophil host defence capability and immunocompetence.

Adult↗

Characterization of the effects of direct alkylators on in vitro immune responses.

Although their mechanism of degradation may differ, both the SN1 alkylators, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-nitroso-N-methylurea (MNU), and the SN2 alkylators, dimethyl sulfate (DMS) and methyl methanesulfonate (MMS), spontaneously decompose under aqueous conditions to the methyldiazonium ion or a direct methylating intermediate, respectively. Thus, these agents serve as useful probes to investigate the immunosuppressive potential of the putative primary reactive intermediate of dimethylnitrosamine (DMN) metabolism, the methyldiazonium ion. The effects of these direct alkylating agents on the in vitro immune response were characterized. Direct addition of both the SN1 and SN2 alkylators to naive B6C3F1 murine splenocytes produced a dose-dependent suppression of the in vitro antibody-forming cell (AFC) response to the T-dependent antigen, sheep erythrocytes (sRBC), T-independent antigen, dinitrophenyl (DNP)-Ficoll, and the polyclonal activator, lipopolysaccharide (LPS). The T-dependent and T-independent responses proved to be more sensitive than the polyclonal response to the effects of these compounds, except for MNNG in which all 3 antibody responses were equally affected. The suppression of the AFC response for all antigens was unaffected by the addition of 2-ME, and was observed at concentrations below those affecting viability, although at the highest concentrations an effect on viability was often observed. The addition of MNNG to the T-dependent AFC response at any time within the first 96 h produced a marked suppression, while the addition of DMS to cultures was only effective in suppressing the AFC response if added within the first 24 h. MNNG and DMS suppressed the proliferative responses to both B-cell (LPS) and T-cell (Concanavalin A; Con A) mitogens, as well as in the mixed lymphocyte response (MLR). In addition, a positive correlation between immunosuppression and DNA damage, as measured by single-strand breaks, was observed. Although these compounds produced suppression of in vitro immune responses, their profile of activity on immunocompetence and DNA damage was different from that associated with DMN and thus, the direct alkylators may not prove to be useful models to elucidate the mechanism of the DMN-induced immunosuppression.

Alkylating Agents↗

Elevated membrane IgA+ and CD4+ (T helper) populations in murine Peyer's patch and splenic lymphocytes during dietary administration of the trichothecene vomitoxin (deoxynivalenol).

Recent investigations indicate that dietary exposure to the trichothecene vomitoxin increases total and antigen-specific serum immunoglobulin A (IgA) and glomerular IgA accumulation in mice. In this study, the effects of 25 ppm dietary vomitoxin on the histological and lymphocytic profile of component immune organs in the mucosal lymphocyte migratory pathway were evaluated in the B6C3F1 mouse. Vomitoxin administration resulted in marked stimulation of the size and frequency of germinal centres in Peyer's patches, mesenteric lymph nodes and the spleen. A slight increase in the percentage of B cells in the Peyer's patch was observed, although vomitoxin treatment had no effect on the percentage of B cells in the spleen. The percentage of IgA+ cells in Peyer's patches and spleen were approximately twice that of controls at 4, 8 and 12 wk of vomitoxin exposure whereas the percentage of IgG+ cells decreased in these two organs. Exposure to vomitoxin increased the percentage of T cells in Peyer's patches and the spleen. The percentage of CD4+ cells (T helper subset) increased slightly in Peyer's patches and more markedly (30-50%) in the spleen following vomitoxin treatment. Contrastingly, there was only a slight increase in the percentage of CD8+ cells (T cytotoxic/suppressor subset) in the spleens of vomitoxin-treated mice in comparison with controls, and no effect in Peyer's patches. The relative effects of vomitoxin on these two T cells populations was also reflected in increased CD4+: CD8+ ratios in Peyer's patches and spleen. These results are consistent with the hypothesis that dietary vomitoxin modulates normal regulation of the IgA response at the Peyer's patch level and that this is manifested in an altered lymphocyte distribution pattern in both the mucosal and systemic compartment. Notably increased levels of IgA+ and CD4+ cells are indicative of IgA-producing progenitors and T helper subsets, respectively, that in tandem could favour IgA hyperproduction and elevated IgA in serum.

Animals↗

Breast cancer metastasis alters acetylcholinesterase activity and the composition of enzyme forms in axillary lymph nodes.

Because of the probable involvement of cholinesterases (ChEs) in tumorigenesis, this research was addressed to ascertaining whether breast cancer metastasis alters the content of acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE) in axillary lymph nodes (LN). ChE activity was assayed in nine normal (NLN) and seven metastasis-bearing nodes (MLN) from women. AChE and BuChE forms were characterised by sedimentation analyses, hydrophobic chromatography and western blotting. The origin of ChEs in LN was studied by lectin interaction. AChE activity dropped from 21.6 mU/mg (nmol of the substrate hydrolysed per minute and per milligram protein) in NLN to 3.8 mU/mg in MLN (p < 0.001), while BuChE activity (3.6 mU/mg) was little affected. NLN contained globular amphiphilic AChE dimers (G2A, 35%), monomers (G1A, 30%), hydrophilic tetramers (G4H, 8%), and asymmetric species (A4, 23%, and A8, 4%); MLN displayed only G2A (65%) and G1A (35%) AChE forms. NLN and MLN contained G4H (79%), G4A (7%), and G1H (14%) BuChE components. Neither the binding of ChE forms with lectins and antibodies nor the subunit size were altered by metastasis. The higher level of AChE in NLN than in brain and the specific pattern of AChE forms in NLN support its role in immunity. The different profile of AChE forms in NLN and MLN may be useful for diagnosis.

Acetylcholinesterase↗

Composition and surface charge of DNA-loaded microparticles determine maturation and cytokine secretion in human dendritic cells.

PURPOSE: Biodegradable microparticles prepared from poly(lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) have been shown to be promising carrier systems for vaccine delivery. Here, we have investigated the capacity of different PLA and PLGA microparticle formulations to induce stimulation of human blood monocyte-derived dendritic cells (DCs). METHODS: Stimulation of human derived dendritic cells by plain microparticles were compared with microparticles loaded with plasmid DNA or double-stranded salmon DNA either by encapsulation or adsorption to the surface of cationic microparticles. Stimulation of DCs was monitored by the up-regulation of surface maturation markers CD83 and CD86 and the secretion of IL-12 and TNF-alpha. RESULTS: Slowly degrading PLA microparticles did not induce any detectable stimulation or activation of DCs. In contrast, fast degrading PLGA microparticles were able to influence DC maturation and cytokine secretion dependent on their surface charge. Anionic PLGA microparticles induced an up-regulation of CD83 and high TNF-alpha secretion, which was further enhanced up to the level of the potent stimulator lipopolysaccharide (LPS) when plasmid DNA was encapsulated. Moreover, the secretion of significant amounts of IL-12 was observed. Cationic PLGA microparticles induced an up-regulation of CD86 and moderate TNF-alpha secretion, but no IL-12 secretion, with no additional effects in the presence of plasmid DNA. CONCLUSIONS: The data suggest that the composition and charge of biodegradable DNA-loaded microparticles profoundly influences maturation and cytokine secretion in DCs. Thus, the individual formulation of microparticles used as a vaccine carrier system might considerably influence the profile of the immune response.

Biodegradation, Environmental↗

Adjuvant effect of Ubenimex on a DNA vaccine for HIV-1.

Enhancement of DNA vaccine immunogenicity is a current topic of high priority in the field of applied immunology, especially as a means of controlling HIV infection. The adjuvant effect of Ubenimex (UBX), an anti-cancer immunomodulator, on a DNA AIDS vaccine which we developed was examined in a murine model. UBX was formulated into a preparation containing DNA plasmids encoding env and rev genes of HIV-1 strain III(B), and was inoculated intramuscularly into BALB/c mice. The sera obtained with this mixture had 2(3)-2(5) times higher specific IgG titres than those obtained without the use of the adjuvant. UBX also elicited both a stronger HIV-1-specific DTH reaction, as measured by the footpad swelling test, and stronger cytotoxic T lymphocyte activity, as assayed by the 51Cr-release method, compared with responses using DNA alone. The cytokine secretion profile of restimulated immune lymphoid cells showed that UBX raised IL-2 and interferon-gamma levels and decreased IL-4 production. HIV-1-specific immunoglobulin subtype analysis demonstrated that UBX stimulated IgG2a production but suppressed synthesis of IgG1 and IgE. These results indicate that activation of the T-helper type 1 subset was induced by UBX, suggesting a mechanism of immunomodulation mediated by this agent. We conclude that UBX acts as an immunologic adjuvant for DNA vaccination against HIV-1. UBX may be a suitable adjuvant for clinical use because of its lack of antigenicity and low toxicity.

AIDS Vaccines↗

Clonal dominance: loss and restoration in adoptive transfer.

An adoptive transfer system was used to study the mechanism responsible for clonal dominance of the anti-phosphorylcholine response in BALB/c mice. The adult spleen contains phosphorylcholine-specific precursor cells that are capable of developing into antibody-producing cells after transfer into lethally irradiated animals. The neonatal liver of the BALB/c mouse lacks precursor cells specific for phosphorylcholine but contains immature cells that differentiate into specific precursors during the normal course of ontogeny. The transfer of fetal or neonatal liver cells into lethally irradiated recipients prevents the appearance of the dominant H8 clone which constitutes the majority of the clones responding to phosphorylcholine in adult BALB/c mice. However, if these cells are transferred into neonatally suppressed recipients that lack the H8 idiotype, dominance of the H8 clone can develop. The conversion of the committed immature progenitor cell into a responsive B lymphocyte precursor is a regulated event. Regulation at the level of progenitor cells determines the eventual clonal profile of the immune response to phosphorylcholine. It is suggested that selection of the dominant clone occurs at this level.

Animals↗

Structural changes in rat Pneumocystis carinii surface antigens after terbinafine administration in experimental P. carinii pneumonia.

Terbinafine is a synthetic antifungal agent which has recently been found to be highly effective against Pneumocystis carinii. This study evaluated the efficacy of terbinafine on rat P. carinii antigenic profile and the immune response by Western blot analysis, in comparison with atovaquone and co-trimoxazole in rats with pneumocystosis. Terbinafine was shown to target two specific major antigens, particularly those of 116 and 35-40 kDa. Antibodies reactive against these moieties were found in all rats treated with atovaquone and co-trimoxazole, but not in those treated with terbinafine. These surface antigen modifications could be related to disease severity and could provide additional information for monitoring the efficacy of this treatment.

Animals↗

A new acute inflammatory syndrome related to the introduction of mycophenolate mofetil in patients with Wegener's granulomatosis.

Mycophenolate mofetil (MMF) is increasingly used for prevention of allograft rejection and to treat immune disorders. We report the development of an acute inflammatory syndrome in two patients with Wegener's granulomatosis after MMF was introduced, because of persistent renal and systemic disease activity despite cyclophosphamide treatment. Within 1 week both patients developed an acute inflammatory syndrome, characterized by fever, arthralgias and muscle pain. No infection could be detected and no indications for increased Wegener's activity were present. MMF was stopped resulting in a rapid and complete resolution of the syndrome. A rechallenge with 2 g of MMF in the second patient resulted in a relapse of the syndrome within 4 days. There was an association between symptoms and increased levels of mycophenolic acid (MPA) acyl glucuronide and serum interleukin-6, suggesting the induction of inflammatory cytokines by MPA acyl glucuronide as the cause of the syndrome. Therefore, special attention should be given to side effects such as fever, arthralgias and muscle pain when treating patients with Wegener's granulomatosis during the active phase. Because this side effect of MMF may also occur after solid organ transplantation and in other immune disorders, pharmacokinetic profiling of MPA and MPA acyl glucuronide is needed in future studies with MMF.

Acute Disease↗