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* Department of Medicine, Division of Infectious Diseases, and
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recently, we demonstrated prozone-like effects on Ab-mediated protection with an IgM mAb against the human pathogenic fungus Cryptococcus neoformans (5). For this mAb, the mechanism responsible for prozone-like phenomena is likely to be inference with oxidative killing by the deposition of large amounts of Ab on the fungal capsule (5). Our observations with IgM raised the question as to whether the prozone-like phenomenon would also occur for IgG, which interacts with Fc
Rs. The system used to study the prozone-like phenomena with IgG was the murine model of C. neoformans infection. C. neoformans is a major pathogen for individuals with impaired immunity, including those with AIDS (6). This organism is unusual in that it is a facultative intracellular pathogen that also has a polysaccharide capsule (7). In the absence of opsonins, the capsule interferes with phagocytosis. However, in the presence of opsonins, C. neoformans is readily phagocytosed and can replicate inside macrophages (7). Serum Ab to capsular polysaccharide has an important function in host defense against C. neoformans given that passive Ab administration is protective (reviewed in Ref. 8). Polysaccharide conjugate and peptide vaccines that elicit Abs to the capsule are protective in mice (9, 10). C. neoformans provides a good system for revisiting the problem of Ab efficacy and dose response because the pathogenesis of infection is relatively well understood, animal models exist, and well-characterized Ab reagents are available.
Despite the fact that protective and nonprotective Abs to the C. neoformans capsule have been described, the mechanisms of Ab action and efficacy in vivo are not well understood (9). Ab specificity and isotype are two properties that have been shown to be important for Ab efficacy (11, 12, 13). IgG3 mAbs were found be nonprotective or to enhance disease in various mouse models of cryptococcosis (12, 13, 14), although this IgG subclass is the predominant isotype produced to polysaccharide Ag, and is protective, against other encapsulated pathogens (15). Previously, we reported that a family of V region-identical, isotype-switched variants of IgG3, including IgG1, IgG2a, and IgG2b, differed in protective efficacy. The mechanism for isotype-related differences in Ab efficacy against C. neoformans is uncertain, because all subclasses are opsonic in vitro and clear polysaccharide Ag from serum. In this study, we investigated whether differences in isotype-related efficacy were a result of dose-response relationships for the various IgG subclasses. We demonstrate the occurrence of different prozone-like effects with IgG isotypes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Strain ATCC 24067 (serotype D; American Type Culture Collection, Manassas, VA) was used because it has been used extensively in prior studies of Ab-mediated protection (13, 14), and it is well characterized (16). C. neoformans cells were grown in Sabouraud dextrose broth at 30°C overnight with moderate shaking (150 rpm). Yeast cells were washed three times in PBS, suspended in PBS, and counted using a hemocytometer. Inoculum was confirmed by counting CFUs on Sabouraud dextrose agar (Difco, Detroit, MI).
Monoclonal Abs
The mAb 3E5 family consists of V region-identical isotype-switched variants of IgG3 and comprises mAbs of the four IgG subclasses (14). IgG mAbs were purified from ascites by protein A affinity chromatography (Pierce, Rockford, IL) as per the manufacturer’s instructions. The concentration of mAbs was determined by ELISA relative to isotype-matched standards of known concentration.
Mice and primary macrophages
Six- to 8-wk-old male A/JCr mice were obtained from the National Cancer Institute (Frederick, MD) and The Jackson Laboratory (Bar Harbor, ME). For peritoneal macrophage isolation, the abdominal cavity of euthanized mice was lavaged five times with sterile PBS using a Pasteur pipette. The lavage fluids were pooled, cells were collected by centrifugation, and erythrocytes were lysed by incubating the cell preparation in 0.17 M NH4Cl for 10 min in ice. A 10-fold excess of RPMI 1640 solution was then added to make the solution isotonic, and the cells were collected by centrifugation and suspended in DMEM (Life Technologies, Grand Island, NY), 10% NCTC-109 (Life Technologies), and 1% nonessential amino acids (Cellgro/Mediatech, Washington, DC).
Survival and organ fungal burden
For survival analysis, mice were infected i.p. with 105, 106, 107, and 108 yeast cells in PBS. IgG1, IgG2a, IgG2b, and IgG3 mAbs were administered 30 min i.p. before infection. This results in rapid diffusion to the serum compartment (17). Mice were monitored daily for mortality and morbidity. On day 160, surviving mice were sacrificed. For CFU experiments, A/JCr mice were infected as described above. At days 7 and 14 postinfection, organ CFUs were determined by homogenizing the lung, brain, and spleen (right and left, alternatively) and plating on Sabouraud’s agar as described (18). The number of CFUs was corrected by the grams of tissue used in the homogenization.
Cytokine analysis
A/JCr mice were given either 1.0, 0.5, or 0.1 mg of IgG3 or IgG2a mAbs 30 min before i.p. infection with 105 yeast. Sham-infected groups were given two i.p. infections of PBS separated by 30 min. Experimental groups were given purified mAb or PBS before infection with yeast cells. In addition, another group of mice was treated with 1 mg of IgG2a and infected with 107 yeast. Mice were sacrificed at days 7 and 14, and lung, brain, and spleen (right and left, alternatively) were homogenized in 2 ml of PBS in the presence of protease inhibitors (Complete Mini; Boehringer Mannheim, Indianapolis, IN). The homogenates were centrifuged, and the supernatants were frozen at -80°C until tested. The supernatants were assayed for concentrations of IL-2, IL-4, IL-6, IL-10, IL-12p40, TNF-
, IFN-, and monocyte chemoattractant protein-1 (MCP-1)4 using ELISA kits (BD PharMingen, San Diego, CA). The detection limits of these assays were as follows: 3.1 pg/ml for IL-2; 7.8 pg/ml for IL-4; 31.25 pg/ml for IL-10 and IFN-; 15.6 pg/ml for IL-6, TNF- and MCP-1; and 62.5 pg/ml for IL-12p40, as determined by the manufacturer.
Endotoxin precautions
Disposable pyrogen-free plastic ware and endotoxin-free water or PBS were used for all experiments. Ascites and purified mAb were passaged through Detoxi-Gel columns (Pierce) to remove any endotoxin contamination. Additionally, J774.16 or peritoneal macrophages were incubated with 100 U/ml polymyxin B (Sigma-Aldrich, St. Louis, MO) as an additional precaution against endotoxin contamination.
Phagocytosis assay
Peritoneal and macrophage-like cell line J774.16 was used in phagocytosis and oxidative burst experiments. The J774.16 cell line is derived from a reticulum cell sarcoma (19) and has been extensively used to study C. neoformans-macrophage interactions (20). Peritoneal macrophages (prepared as described in Mice and primary macrophages) and J774.16 macrophage cells were cultured in DMEM supplemented with 10% FCS, 10% NCTC-109, and 1% nonessential amino acids. Phagocytosis assays were done as described in our prior studies with minor modifications (5, 20, 21). Briefly, macrophages were plated at a density of 105 cells/well in a 96-well culture plate and stimulated with 100 U/ml recombinant murine IFN- overnight. The medium were replaced with fresh medium that contained 100 U/ml IFN- and 1 µg/ml LPS for 1 h before phagocytosis assay. IFN- and LPS stimulation was used because it increases the efficacy of phagocytosis and reduces interexperimental variation by activating the cells in a standard fashion. Phagocytosis was measured in medium without FCS in the presence and absence of glucuronoxylomannan-binding mAbs. In some experiments, mouse serum from BALB/c mice (National Cancer Institute, Frederick, MD) was added (10%) as a complement source. C. neoformans cells were added at an E:T ratio of 1:5, and the suspension was incubated at 37°C for various time intervals. The macrophage monolayer was then washed several times with sterile PBS, fixed with cold absolute methanol, and stained with 1:20 solution of Giemsa. To quantify the phagocytosis, 200 macrophages were counted per well in at least five different fields using a magnification of x600. The phagocytic index is expressed as the number of ingested yeast cells per every 100 macrophages counted. All conditions were tested in triplicate.
Nitrite production
NO production was assessed by measuring nitrite in both peritoneal macrophages and macrophage-like J774.16 cells as described (22). Cells were stimulated with 100 U/ml IFN- (Roche, Indianapolis, IN) for 16 h. Ab-coated C. neoformans cells (5 x 106) were added to macrophages and incubated for 4–5 days. Yeast cells were incubated with mAb and then washed to remove free Ab to avoid cross-linking of FcR by soluble IgG aggregates or Ag-Ab complexes which can trigger NO release (22). Supernatants were collected and nitrite was measured using the Greiss reagent (1% sulfanilamide, 0.1% N-1-naphthylethylenediamine, and 2.5% phosphoric acid). The amount of NO produced directly correlates with the amount of nitrite measured (23). The concentration of nitrite was calculated from the absorbance at 540 nm measured in a using a Labsystem multiscan reader (Labsystem, Helsinki, Finland) and a standard linear curve (0–250 µM).
Oxidative burst assay
Oxidative burst production by primary peritoneal macrophages and J774.16 macrophage-like cells was measured through oxidation of the cyclic hydrazide 5-amino-2,3-dihydro-1,4-phthalazinedione (luminol) by reactive oxygen species (Fig. 5). Luminol-dependent chemiluminescence provides a convenient assay for phagocytic function as well as opsonization efficiency (24, 25, 26). For this experiment, yeast were opsonized as described above in the nitrate production experiments and chemiluminescence was measured for 10-min intervals for a total of 240 min. Experiments were performed as described with modifications (27). The J774.16 cells or peritoneal macrophages were prepared for assaying by incubating cells with 0.5 mM EDTA/PBS for 30 min at 37°C. The detached cells were then collected by centrifugation and suspended at a density of 106 cells/ml in HBSS containing 50 µM luminol (sodium salt; Sigma-Aldrich). C. neoformans (5 x 106 cells) and mAb (10 µg/ml) were incubated for 1 h at room temperature. Cuvettes (12 x 75 mm; BD PharMingen) containing 1 ml of macrophage suspension were prewarmed at 37°C for 5 min, mixed with 100 µl of mAb-coated C. neoformans at an E:T ratio of 1:5, and placed immediately in a luminometer (moonlight 2010; Analytical Luminescence Laboratory, San Diego, CA). Chemiluminescence was measured for 2 h at 10-min intervals.
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Organ cytokine data was analyzed by the Student t test and/or the Kruskal-Wallis statistic (Primer; McGraw-Hill, New York, NY). Survival experiments were compared by log rank analysis (SigmaStat; SPSS, Chicago, IL).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To analyze the relationship between Ab dose, infective inoculum and protection, different amounts of IgG1, IgG2a, IgG2b, and IgG3 mAbs were administered before i.p. infection with different inocula of C. neoformans. Mice given 1.0, 0.5, and 0.1 mg of each mAb subclass and infected with 108 yeast lived longer (p < 0.05) than mice given no Ab (data not shown). Prolongation of survival was observed in mice given IgG3 (p < 0.05), an isotype associated with either no protection or enhancement of disease in prior studies (12, 13). The relative efficacy of the four subclasses was as follows: IgG2a > IgG1 > IgG2b > IgG3 (data not shown). Similar results were obtained when the inoculum was reduced to 107 yeast, except that IgG3 administration no longer prolonged survival, such that the 0.5- and 0.1-mg doses were neither protective nor disease-enhancing and the 1-mg dose was disease-enhancing (Fig. 1A). For all IgG subclasses except IgG2a, the dose of 1 mg was less protective than a dose of 0.5 or 0.1 mg. Similar results were obtained with the group of mice infected with 106 C. neoformans (data not shown). When the infecting inoculum was reduced to 105 yeast, we noted that all the isotypes were disease-enhancing at all the doses evaluated, such that mice that received mAb died before controls (Fig. 1B). Mice infected with 105 yeast and treated with mAbs IgG2a and IgG1, the two isotypes most effective at prolonging survival in mice infected with higher inocula, had shorter survival compared with mice treated with IgG2b and IgG3 (Fig. 1B). Hence, relative efficacy of IgG subclasses differed in protection against high and low C. neoformans inocula, and IgG subclasses that were protective for one inoculum mediated no protection, or enhanced disease, with smaller inocula.
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To explore the mechanisms for the Ab-mediated effects on survival, organ CFUs were determined at 7 and 14 days after infection. IgG2a and IgG3 were studied because these subclasses exhibited the greatest extremes in the protection study. Compared with mice given no Ab, mice that received 1 mg of IgG2a followed by 107 yeast, had a significant reduction of lung and spleen CFUs (Fig. 2). Dissemination to the brain, lung, and spleen was observed in both groups at 7 and 14 days after infection. Mice that received PBS followed by yeast appeared sick and started to die by day 14 of infection, whereas mice in the IgG2a group did not manifest any disease symptoms. Mice that were infected with the smaller inoculum of 105 yeast after receiving IgG2a or IgG3 (1, 0.5, and 0.1 mg) had a different pattern of dissemination (Fig. 3). The group of mice that received 1 mg of IgG2a had dissemination to the brain, lung, and spleen, whereas mice given 0.5 or 0.1 mg had dissemination to the lung and spleen, but not to the brain either 7 or 14 days after infection (Fig. 3). On day 7 after infection, IgG2a-treated mice had higher spleen CFUs compared with those of mice given PBS. On days 7 and 14 after infection, mice given IgG3 had evidence of dissemination in all three organs. Hence, Ab doses that prolonged survival were associated with lower CFUs in certain organs. Conversely, Ab doses that did not prolong survival or hastened death were associated with comparable or higher organ CFUs.
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Prior studies have established that Ab-mediated protection is dependent on cellular immunity (28) and NO expression (29), and associated with changes in cytokine expression (29, 30). Consequently, organ cytokine levels were measured in mice infected with C. neoformans and treated with PBS or with Ab, and in sham-infected mice. First, we studied mice given 1 mg of IgG2a that were infected with 107 yeast cells, a condition where Ab was protective. On day 7 after infection, lungs from mice that received IgG2a had higher levels of IL-2, compared with the mice that received PBS and lower levels of IL-6, IL-12, IFN-, TNF
, and MCP-1. In the spleen, only IFN- was reduced in the IgG2a-treated, compared with the PBS control, group (Tables I and II). On day 14 after infection, most cytokine differences were found in the lungs of IgG2a-treated mice, and included significantly higher levels of IL-4, IL-6, IL-12, and TNF-, and reduced levels of MCP-1. The IL-12 level in the brain and spleen of IgG2a-treated mice was significantly different from in non-Ab-treated mice, but the effects were discordant, being lower in brain and higher in spleen of the Ab-treated group. In contrast, MCP-1 was reduced in lung, brain, and spleen tissue of IgG2a-treated mice.
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in brain compared with mice that did not receive Ab. On day 7 after infection, mice that received IgG3 had higher levels of IL-4, IL-6, IFN-, and TNF- in lung tissue, IFN- and TNF- in brain tissue, and IL-4, IL-10, IFN-, and TNF- in spleen tissue compared with mice that did not receive Ab. On day 14 of infection, there was a significant decrease in lung IL-6 and IFN- in IgG2a-treated mice, and in lung IL-2, IL-6, IL-10, IL-12, and TNF- in IgG3-treated mice, compared with PBS-treated mice. However, brain tissue revealed significantly higher levels of IL-10 and IL-12 in IgG2a-treated mice and reduced amounts of IFN- in IgG3-treated mice, compared with PBS-treated mice. In the spleen, mice receiving IgG2a had higher levels of IL-10 than PBS-treated mice.
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We compared the opsonic efficacy of IgG1, IgG2a, IgG2b, and IgG3 to that of complement as a function of time using both J774.16 (Fig. 4) and peritoneal macrophages (data not shown). All IgG subclasses promoted phagocytosis of C. neoformans. The relative order of phagocytic efficacy in this system was as follows: IgG1 > IgG2a = IgG2b > IgG3; however, the differences were not statistically significant. Complement alone was a relatively inefficient opsonin compared with IgG. In the absence of Ab or complement, there was little or no phagocytosis even after 6 h. Similar results were obtained with peritoneal cells (data not shown).
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Because macrophage oxidative burst and NO production are important mediators of cellular microbicidal function, we evaluated the relative ability of IgG subclasses to mediate these effects. Cells incubated with C. neoformans and Abs IgG1, IgG2a, IgG2b, and IgG3 induced three to four times more nitrite than cells incubated with C. neoformans and PBS or irrelevant mAb. No statistical differences were observed between IgG subclasses (result not shown). Similar results were obtained with J774.16 and peritoneal macrophages cells (data not shown). All IgG subclasses triggered an oxidative burst, but IgG2a was most effective (Fig. 5). Similar results were obtained with peritoneal macrophages (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our results echo early 20th century studies that demonstrated Ab protection at only certain proportions of Ab and S. pneumoniae inocula in the mouse protection test used to standardize horse antisera for the treatment of pneumococcal pneumonia (29). The amount of serum below which no protection was observed against a certain inoculum was called the limiting titer zone, and the upper infective dose against which protection could be achieved with a defined amount of immune serum was known as the Schewellenwert (2). When no protection was observed in mice that received large amounts of serum, the phenomenon was called a zone effect or prozone effect. At the time, the absence of protection at low doses of immune sera could be understood on the basis of an insufficient amount of Ab, but the absence of protection when large amounts of immune serum were administered was perplexing and posed significant practical and theoretical problems (2, 3, 4). An explanation based on the possibility of toxic substances in heterologous horse sera was unsatisfactory, because the prozone effect disappeared if sera were administered after infection, when pneumococcal replication in vivo effectively increased the bacterial load relative to the Ab amount. As serum therapy was abandoned in the 1940s, this phenomenon was largely forgotten despite its clear implications for Ab function.
Prozone-like effects were recently described in protection experiments using human polyvalent Ig in neutropenic BALB/c mice infected with S. pneumoniae (31). Doses of 50 and 100 µg/mouse were protective, but doses of 250 and 500 µg/mouse were not (31) in a study in which the infective inoculum and the Ab dose were given in different compartments. Together with our recent findings with IgM (5), these observations and the IgG data reported in this study confirm the existence of a paradoxical loss of efficacy for Ab at high dose using homologous and defined Ab reagents. Given that the phenomenon of prozone-like effects in Ab protection has now been demonstrated for two pathogens in vivo, namely S. pneumoniae and C. neoformans, it is likely to be applicable to other microbes. Prozone effects have been described in Ab neutralization assays in vitro for human immunodeficiency, varicella zoster, and rubella viruses (32, 33, 34). Recently, a vaccine against herpesvirus failed to confer to protection despite eliciting high titers of neutralizing Abs (35), a finding that raises the possibility of a prozone-like effect. For bacteria, similar results have been described for Ab neutralization assays of Chlamydia trachomatis and bactericidal assays of Pseudomonas aeruginosa in vitro (36, 37). The existence of prozone-like effects is not limited to microbial Ab neutralization assays because a prozone was described for a bispecific cytotoxic Ab in an assay against leukemic cells (38).
Our data show that mice given high Ab doses and infected with low inocula died before mice treated with saline. A toxic effect of the Ab on the host can be excluded, because the same Ab dose mediated protection against higher inocula. The finding that some IgG2a-treated mice had higher brain CFUs provides a potential explanation for their earlier demise when infected with low inocula. In light of evidence that Ab-mediated phagocytosis results in internalization of C. neoformans by macrophages without killing (7, 39) and that excess Ab in the yeast capsule can interfere with oxidative killing (5), excess of Ab on the C. neoformans capsule may interfere with killing of yeast cells in the various organs resulting in increased organ fungal burden.
There is general consensus that cellular immunity is essential for host defense against C. neoformans infection (40, 41) and that granulomatous (42, 43), Th1-polarized responses (44) are protective. Given that Ab-mediated effects against C. neoformans are dependent on cellular immunity (28) and that Ab administration can result in modified cytokine expression (29, 30), we measured cytokine levels in three organs of mice treated with IgG2a in conditions where protection and nonprotection were observed. The cytokine profile of mice given 1 mg of IgG2a or PBS and 107 yeast, a condition that resulted in Ab protection, revealed that IgG2a-treated mice had higher IL-12 in lungs, lower IL-6, IL-12, IFN-, and TNF- in brain, and lower IFN- and MCP-1 in spleen than non-Ab-treated mice on day 7 after infection. In contrast, for mice given 1 mg of IgG2a and 105 cells, a condition that results in no protection, there was an increase in TNF- in brain. Therefore, the major difference between low and high inocula for mice treated with a high dose of IgG2a was a down-regulation of proinflammatory cytokines in brain tissue and an increase in IL-12 in lung tissue in the conditions associated with Ab-mediated protection. At day 14, in the condition where protection was observed (e.g., 1 mg of IgG2a and infection with 107 yeast), there were increased levels of IL-4, IL-6, IL-12, TNF- and reduced MCP-1 in lung, and reduced IL-12 and MCP-1 in brain relative to the non-Ab-treated mice. In contrast, in the condition where no protection was observed, IgG2a-treated mice had reduced levels of IL-6 and IFN- in lung and higher levels of IL-10 and IL-12 in brain tissue relative to the non-Ab-treated mice. The prolongation of survival observed in the group receiving IgG2a and 107 yeast may have reflected a more robust inflammatory response in the periphery with reduced inflammation in the brain.
Comparison of cytokine levels in IgG2a- and IgG3-treated mice infected with 105 yeast, a condition where neither Ab is protective or disease-enhancing, revealed statistically significant differences in organ cytokine profile depending on IgG subclass. Overall, IgG3 had a greater effect on organ cytokine profiles than IgG2a. Although the mechanisms responsible for different cytokine responses in different tissues are uncertain, this phenomenon may reflect differences in resident immune cells, timing of fungal dissemination to the various organs and organ-related differences in FcR expression.
The ability of IgG subclasses to promote phagocytosis and trigger oxidative burst and nitrate production was examined in vitro in an effort to understand mechanisms responsible for their relative protective efficacy. IgG1 and IgG2a were the most effective isotypes in promoting C. neoformans phagocytosis by J774.16 cells. This result is similar to prior reports using different Abs to C. neoformans (21, 45). Although we found no significant differences among IgG isotypes in promoting nitrate synthesis, IgG2a was most effective in triggering an oxidative burst. Both nitrogen- and oxygen-related oxidants have been implicated in antifungal activity by host effector cells (46, 47, 48, 49). The high phagocytosis observed with IgG2a, combined with its ability to trigger a strong oxidative burst, suggest these mechanisms may contribute to the greater efficacy of this isotype in prolonging survival in conditions where protection occurs. The in vitro studies provide a potential explanation for the superiority of IgG2a relative to the other IgG subclasses, but did not explain the relative inefficacy of IgG3 or the mechanisms for prozone-like effects.
In summary, our results confirm that prozone-like effects can accompany the administration of Ab in passive protection experiments, such that Ab-mediated protection can be lost at high doses of Ab for certain inocula. The mechanisms by which Ab fails to mediate protection in conditions where a large amount of Ab is administered relative to a microbial inoculum may involve interference with host microbicidal mechanisms. Ab administration was accompanied by large changes in cytokine expression that were influenced by Ab dose, IgG subclass, inoculum, and the tissue examined. The contribution of the differences in cytokine expression to prozone-like effects, if any, is difficult to assess, because the presence of specific Ab may have had pleiotropic effects on the host immune response that affected disease outcome. Nonetheless, the ability of Ab to affect cytokine levels in various organs attests to the powerful immunomodulatory properties of passive Ab. Our finding of prozone-like effects, and the complex variables that influence this phenomenon, illustrate the importance of varying the dose of Ab and inoculum size in passive immunization experiments. Specifically, investigators undertaking passive immunization experiments with large inocula should consider the possibility of prozone-like effects affecting the experimental outcome, namely, that high doses of Ab may not be protective or may be detrimental.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Microbiology, University of Sao Paulo, Avenue Professor Lineu Prestes, 1374, Sao Paulo, SP-Brazil.
3 Address correspondence and reprint requests to Dr. Arturo Casadevall, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail address: casadeva{at}aecom.yu.edu
4 Abbreviation used in this paper: MCP-1, monocyte chemoattractant protein-1.
Received for publication October 31, 2002. Accepted for publication January 31, 2003.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-stimulated murine macrophage-like J774.16 cells. J. Leukocyte Biol. 57:657.[Abstract]
(IFN-)-dependent protection and synthesis of chemoattractants for mononuclear leucocytes caused by IL-12 in the lungs of mice infected with Cryptococcus neoformans. Clin. Exp. Immunol. 117:113.[Medline]
-interferon-induced nitric oxide in pulmonary clearance of Cryptococcus neoformans. Am. J. Respir. Cell Mol. Biol. 13:116.[Abstract]
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J. Rivera, O. Zaragoza, and A. Casadevall Antibody-Mediated Protection against Cryptococcus neoformans Pulmonary Infection Is Dependent on B Cells Infect. Immun., February 1, 2005; 73(2): 1141 - 1150. [Abstract] [Full Text] [PDF]
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 B. C. Fries, E. Cook, X. Wang, and A. Casadevall Effects of Antifungal Interventions on the Outcome of Experimental Infections with Phenotypic Switch Variants of Cryptococcus neoformans Antimicrob. Agents Chemother., January 1, 2005; 49(1): 350 - 357. [Abstract] [Full Text] [PDF]
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T. T. Brandhorst, M. Wuthrich, B. Finkel-Jimenez, T. Warner, and B. S. Klein Exploiting Type 3 Complement Receptor for TNF-{alpha} Suppression, Immune Evasion, and Progressive Pulmonary Fungal Infection J. Immunol., December 15, 2004; 173(12): 7444 - 7453. [Abstract] [Full Text] [PDF]
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R. W. Maitta, K. Datta, Q. Chang, R. X. Luo, B. Witover, K. Subramaniam, and L.-a. Pirofski Protective and Nonprotective Human Immunoglobulin M Monoclonal Antibodies to Cryptococcus neoformans Glucuronoxylomannan Manifest Different Specificities and Gene Use Profiles Infect. Immun., August 1, 2004; 72(8): 4810 - 4818. [Abstract] [Full Text] [PDF]
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O. Zaragoza and A. Casadevall Antibodies Produced in Response to Cryptococcus neoformans Pulmonary Infection in Mice Have Characteristics of Nonprotective Antibodies Infect. Immun., July 1, 2004; 72(7): 4271 - 4274. [Abstract] [Full Text] [PDF]
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R. W. Maitta, K. Datta, A. Lees, S. S. Belouski, and L.-a. Pirofski Immunogenicity and Efficacy of Cryptococcus neoformans Capsular Polysaccharide Glucuronoxylomannan Peptide Mimotope-Protein Conjugates in Human Immunoglobulin Transgenic Mice Infect. Immun., January 1, 2004; 72(1): 196 - 208. [Abstract] [Full Text] [PDF]
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T. R. Kozel, R. S. MacGill, A. Percival, and Q. Zhou Biological Activities of Naturally Occurring Antibodies Reactive with Candida albicans Mannan Infect. Immun., January 1, 2004; 72(1): 209 - 218. [Abstract] [Full Text] [PDF]
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T. Burns, Z. Zhong, M. Steinitz, and L.-a. Pirofski Modulation of Polymorphonuclear Cell Interleukin-8 Secretion by Human Monoclonal Antibodies to Type 8 Pneumococcal Capsular Polysaccharide Infect. Immun., December 1, 2003; 71(12): 6775 - 6783. [Abstract] [Full Text] [PDF]
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A. Casadevall Antibody-Mediated Immunity against Intracellular Pathogens: Two-Dimensional Thinking Comes Full Circle Infect. Immun., August 1, 2003; 71(8): 4225 - 4228. [Full Text] [PDF]
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