Immunosuppression in paracoccidioidomycosis: T cell hyporesponsiveness to two Paracoccidioides brasiliensis glycoproteins that elicit strong humoral immune response

To assess human cellular immune response to paracoccidioidomycosis (PCM), lymphocyte proliferative responses to purified antigens from Paracoccidioides brasiliensis were determined in healthy persons previously infected by the fungus (positive donors), in healthy noninfected persons (controls), and in PCM patients. Affinity-purified gp70 and gp43, the two major antigens in humoral immune responses, were used. Both induced lymphocyte proliferation (gp43 species-specific) in positive donors but not in controls; healthy persons previously infected by Histoplasma capsulatum reacted to gp70 and not to gp43. A similar cross-reactivity in antibody response to gp70 was previously reported; however, antibody response to gp43 has been considered specific. Lymphocytes from PCM patients, who, unlike positive donors, have high levels of anti-gp43 and anti-gp70 antibodies, proliferated poorly with gp70 and gp43 but better with other stimuli. This dichotomy between humoral and cellular antigen-specific responses suggests a Th2 immune response in PCM, which may be related to failure to control the infection.     

Aging and the immune response to tetanus toxoid: diminished frequency and level of cellular immune reactivity to antigenic stimulation

A dose-limiting component of a proton accelerator-based source of epithermal neutrons is the neutron production target. Possible targets are lithium, producing high yield but having low melting point and thermal conductivity, and beryllium, presenting less engineering problems but a much smaller neutron yield. We propose that a hybrid Be-Li target would provide the best of both worlds, with the upstream beryllium component producing neutrons and providing containment to the lithium, and the downstream liquid lithium in turn producing further neutrons as well as cooling the beryllium. The engineering considerations associated with such a target system are within the range of current technology. Calculations suggest a yield of such a practical target that is at least double that from pure beryllium.     

An in vitro model for infection with Leishmania major that mimics the immune response in mice

By using a primary in vitro response specific for Leishmania major, normal T cells from resistant CBA/CaH-T6J and susceptible BALB/c mice commit to a Th1 and a Th2 response, respectively. Since commitment occurred, we measured the production of gamma interferon (IFN-gamma), interleukin-1 (IL-1), IL-2, IL-4, IL-5, IL-10, and IL-12, prostaglandin E2 (PGE2), transforming growth factor beta (TGF-beta), and nitric oxide in the first 7 days of the response to identify factors that are critical for Th1 and Th2 development. While cells from resistant CBA mice produced more IFN-gamma, IL-10, and nitric oxide, cells from susceptible BALB/c mice produced more IL-1alpha, IL-5, PGE2, and TGF-beta. Although substantial amounts of IL-12 were detected, IL-12 did not associate with either Th1 or Th2 development. We did not anticipate that cells from resistant CBA mice would make more IL-10 in vitro. However, this also occurred in vivo since CBA mice produced substantial amounts of IL-10 following infection with L. major. Moreover, adding anti-IL-10 to primary in vitro responses enhanced production of IFN-gamma and nitric oxide by cells from CBA and BALB/c mice. Therefore, IL-10 cannot be regarded as a cytokine that associates with susceptibility to infection with L. major. Finally, the data presented here suggest that a collection of factors that can be produced by accessory cells influence Th commitment (e.g., IL-1, PGE2, and TGF-beta favor Th2 development).     

Dissection of antigenic and irritative effects of epicutaneously applied haptens in mice. Evidence that not the antigenic component but nonspecific proinflammatory effects of haptens determine the concentration-dependent elicitation of allergic contact dermatitis

Allergic contact dermatitis differs from most other immune reactions by its strict dose dependence during the elicitation phase. Moreover, almost all known contact allergens can also induce dose-dependent irritative dermatitis and in general only elicit allergic contact dermatitis in sensitized individuals when applied within a narrow dose range. Therefore, we hypothesized that elicitation of contact hypersensitivity (CHS) may require two signals, antigen-specific effector cell activation and a non-antigen-specific proinflammatory signal, both of which are provided by application of a sufficient dose of hapten. To dissociate these putative two signals, oxazolone-sensitized mice were ear challenged with a dose of the specific hapten which was too low to elicit CHS. At the same time, an unrelated hapten was applied in a conventional concentration to the same skin site. Whereas neither treatment alone elicited a significant CHS response, application of both compounds together resulted in a strong CHS response that was indistinguishable from that elicited by the full dose of the specific hapten. Upon coadministration of the irrelevant hapten, allergic contact dermatitis could be elicited even when the dose of the specific hapten was further reduced by a factor of 10(3). In contrast, a dose reduction of the irrelevant hapten by a factor of two resulted in the loss of the CRS response. These data indicate that non-antigen-specific effects of epicutaneously applied haptens significantly contribute to the elicitation of CHS responses and that the capacity of the hapten to evoke this proinflammatory stimulus rather than its antigenicity is responsible for the strict concentration dependence.     

Dysregulation of the humoral immune response in old mice

The increase in autoantibodies with age of both experimental animals and humans has been thought to reflect a shift in the antibody repertoire from foreign to self antigens. In mice, before immunization, the age-associated increase in antibodies reactive with a prototypic autoantigen, bromelain-treated autologous erythrocytes (BrMRBC), reflected a 3-fold increase in serum IgM and the number of IgM-secreting spleen cells in old compared with young mice. However, the percentage of the IgM-secreting spleen cell repertoire reactive with BrMRBC in old mice was actually approximately 50% that in young mice. In contrast, after immunization with sheep erythrocytes (SRBC), old mice showed a 5-fold increase in the percentage of IgM-secreting cells reactive with BrMRBC while young mice showed no significant increase. The converse is true for the percentage of IgM-secreting spleen cells in old mice specific for SBRC, which is 10% the number generated by young mice. The increased autoantibody response of old mice is not, however, linked to their poor response to the nominal antigen. Thus, immunization with phosphorylcholine (PC) conjugated keyhole limpet hemocyanin, an antigen that induces a comparable anti-PC response in old and young mice, also induced more autoantibody forming cells in old than young mice. The increased autoantibody response of old mice after immunization can be accounted for by both an increased number of Ig-secreting spleen cells as well as an increased percentage of the expressed repertoire of IgM-secreting spleen cells that react with autoantigens.(ABSTRACT TRUNCATED AT 250 WORDS)     

Eosinophil-enriched inflammatory response to schistosomula in the skin of mice immune to Schistosoma mansoni

Exposure of the mouse skin to Schistosoma mansoni cercariae gives rise to acute, exudative inflammation in both normal and immune mice, but the immune response is anamnestically accelerated and is oesinophil-enriched, thereby enhancing opportunities for tegumental contact of schistosomula with host leukocytes, particularly with eosinophils. Many of the inflammatory changes occurring within the first 48 hours after exposure are due to cercarial products, e.g., "penetration tracts," but some remain demonstrable when schistosomula metamorphosed in vitro are injected intradermally and are therefore directed against the schistosomula themselves, such as the leukocyte "streaming patterns" seen in their pathways. In contrast to earlier observations in primates, cellular responses to schistosomula in the mouse lung 4 days after penetration are minimal in either normal or immune mice. Thus, immune cellular responses to schistosomula in mice are limited to an early time period after cercarial penetration and are morphologically suggestive of an antibody-mediated response rather than of delayed hypersensitivity. Our observations complement earlier evidence suggesting that antibody-mediated host leukocyte contact with schistosomula initiates the killing of challenge parasites in immune mice, with the eosinophil probably playing a crucial role.     

Impaired macrophage function and enhanced T cell-dependent immune response in mice lacking CCR5, the mouse homologue of the major HIV-1 coreceptor

The CC-chemokine receptor CCR5 has been shown to be the major coreceptor for HIV-1 entry into cells, and humans with homozygous mutation in the ccr5 gene are highly resistant to HIV-1 infection, despite the existence of many other HIV-1 coreceptors. To investigate the physiologic function of CCR5 and to understand the cellular mechanisms of these clinical observations, we generated a CCR5-deficient mouse model (ccr5[-/-]) by targeted deletion of the ccr5 gene. We found that although developed normally in a pathogen-free environment, CCR5-deficient mice showed reduced efficiency in clearance of Listeria infection and exert a protective effect against LPS-induced endotoxemia, reflecting a partial defect in macrophage function. In addition, CCR5-deficient mice had an enhanced delayed-type hypersensitivity reaction and increased humoral responses to T cell-dependent antigenic challenge, indicating a novel role of CCR5 in down-modulating T cell-dependent immune response.     

In vitro amphotericin B effects on growth, viability and dimorphism of Paracoccidioides brasiliensis: reversal of the treatment

The reversed dermal graft has been employed in reconstructive plastic surgery for almost 80 years. It is recommended that the dermatologic surgeon use this graft technique whenever a case calls for the combined advantages of the split-thickness skin graft for poorly vascularized areas and the axial pedicle flap appropriate to areas subject to marked mechanical strain. We present cases in which defects on the scalp, sole, palm, and great toe have been covered by reversed dermal graft and split-thickness skin graft in a single operation with excellent results. Our modification of the technique has proved that simultaneous grafting with reversed dermis and split-thickness skin graft produces satisfactory results, reduces postoperative care by 2 weeks, and obviates repeated anesthesia.     

Immune response and lack of immune response to Plasmodium falciparum P126 antigen and its amino-terminal repeat in malaria-infected humans

A parasitophorous vacuole protein of Plasmodium falciparum, p126, is a potential candidate for a malaria vaccine. Its N-terminal region, composed of six repeats of eight amino acids, appears to be involved in the induction of protective immunity against P. falciparum challenge in monkeys. This study evaluated the immune response to p126 and to its N-terminal region (Nt47) in patients (n = 45) living in a malaria-endemic area of Brazil (Colina, Porto Velho, Rondonia). Cellular proliferative responses against Nt47 were low and infrequent. The study of the humoral immune response demonstrated that 95% of the patients had detectable anti-p126 antibodies and 77% had anti-Nt47 antibodies. Analysis of the antibody isotypes specific for Nt47 revealed that all four IgG subclasses were present and individuals with higher levels of anti-Nt47 cytophilic IgG antibody (IgG1 + IgG3/IgG2 + IgG4) had significantly lower parasitemia levels, suggesting that antibodies to the N-terminal region of the p126 protein may contribute to acquisition of immunity to P. falciparum malaria.     

Differential regulation of the interleukin-12 receptor during the innate immune response to Leishmania major

Previous studies have shown the central role of interleukin 12 (IL-12) in the development of resistance to Leishmania major infection in C3H mice. We now show that during the innate immune response the lymph node cells of L. major-infected C3H mice upregulate the IL-12 receptor on CD4(+), CD8(+), and B220(+) cells. An increase in the ability of the lymph node cells to bind IL-12 correlates with 9.3- and 4.6-fold increases in the mRNA expression levels of the IL-12Rbeta1 and -beta2 subunits, respectively. In contrast, BALB/c mice, which are susceptible to L. major infection, have no increase in the ability of the lymph node cells to bind IL-12 and correspondingly smaller increases in the mRNA expression levels of the IL-12Rbeta1 and -beta2 subunits of 2- and 1.5-fold, respectively. Neutralizing IL-4 and the administration of exogenous IL-12 upregulate IL-12R expression in BALB/c mice, while the neutralization of IL-12 in C3H mice blocks increased IL-12 receptor expression. These experiments reveal an important role for the regulation of the IL-12 receptor during the innate immune response after infection of mice with a pathogen.     

Prolactin, growth hormone and the immune system in humans

Prolactin (PRL) and growth hormone (GH) qualify as lymphoid growth and differentiation factors. Yet, long-standing hyper- or hyposecretion of PRL or GH does not induce any significant alteration of the immune system. Subclinical changes in laboratory parameters (such as chemotaxis or phagocytosis by granulocytes or macrophages or natural killer cell activity) have been reported in some of these conditions. The GH-insulin-like growth factor (IGF)-I axis is dysregulated in ageing, in catabolic states and in critical illness. Immune parameters, such as infection rate, are being monitored during clinical trials with GH or IGF-I. Hyperprolactinaemia may play an aggravating role in systemic lupus erythematosus, in autoimmune thyroiditis and in other autoimmune diseases. The patient may benefit from increased alertness about interactions between the endocrine and immune systems.     

Adenovirus-mediated gene transfer of viral interleukin-10 inhibits the immune response to both alloantigen and adenoviral antigen

Although adenoviral vectors are attractive for gene transfer, their effectiveness is limited by host antiviral immune responses. In this study, we determined if host antiallograft and antiviral immunity could be diminished with an adenoviral vector encoding the immunosuppressive cytokine viral interleukin-10 (vIL-10). AdSV40vIL-10, a vIL-10-expressing adenoviral vector with an SV40 promoter, induced significant prolongation of murine cardiac allograft survival to 32.2 +/- 1.7 days compared to 14.2 +/- 1.0 days for controls (p < 0.01). This effect was specific for vIL-10 encoding vector and could be inhibited by anti-vIL-10 monoclonal antibody (mAb). In vivo administration of adenovirus facilitated the generation of adenovirus-specific cytotoxic T lymphocytes (CTL), whereas treatment with AdSV40vIL-10 prevented CTL priming and generation of virus-specific immunity. AdSV40vIL-10 also induced extended expression of a beta-galactosidase reporter from a co-injected LacZ-encoding adenoviral vector. These results demonstrate that adenovirus-mediated gene transfer and expression of vIL-10 prolong allograft survival and inhibit the immune response to adenoviral antigens, thereby improving the persistence of the vector and extending transgene expression. The efficacy of adenoviral vectors can be improved by incorporating immunosuppressive genes into the vector.     

Expression of mouse CD43 in the B cell lineage of transgenic mice causes impaired immune responses to T-independent antigens

CD43 (leukosialin), a sialylated glycoprotein expressed on the surface of most hematopoietic cells, has been implicated in cell adhesion and signaling. However, its precise physiological function remains unclear. We used mouse CD43 (mCD43)-immunoglobulin enhancer-transgenic (TG) mice to study the role of mCD43 in vivo. Previous work revealed that mCD43 expression on mature B cells in these mice resulted in immunodeficiency to T-dependent (TD) antigens (Ag), possibly by impairing B-T cell interactions. In the present study we have immunized the TG mice with the T-independent (TI) Ag fluorescein-(Fl) lipopolysaccharide (LPS) (TI type 1 Ag) and Fl-Ficoll (TI type 2 Ag). Surprisingly, the mCD43-Ig enhancer expressing mice were impaired in their ability to mount humoral responses to both Fl-LPS and Fl-Ficoll, and had decreased numbers of cells responding to Ag in vivo. Flow cytometric analysis was performed on peritoneal B-1 cells, a population which often plays a major role in humoral responses to TI Ag such as bacterial Ag. This analysis revealed similar B220, IgM and CD5 expression patterns for the TG and nontransgenic (NTG) B-1 cells. In addition, purified peritoneal B-1 cells from TG and NTG mice were able to respond to LPS. Stimulation of splenic B cells in vitro with Fl-LPS and Fl-Ficoll revealed that, in contrast to NTG B cell responses, TG B cell responses could not be enhanced by co-culture with T cells. However, soluble T cell factor enhancement of the TG B cell responses was normal. These data suggest that the mCD43 expression on B cells may inhibit cell interactions that are important for enhanced TI Ag responses. The anti-adhesive forces of mucins in general may thus be critical in regulating both TD and TI humoral responses.     

BCG-activated NK cells regulate the antibody response to SRBC and restore immune reactivity to PPD in BCG-infected mice

C57B1/6 mice show a significant increase in the number of natural killer (NK) cells in the peritoneal cavity, four days after intraperitoneal infection with Mycobacterium bovis strain BCG. Cell transfer experiments demonstrated that BCG-induced NK cells are able to depress the induction of antibody response to an unrelated antigen (i.e., sheep red blood cells) in recipient mice. The involvement of macrophages, B and T cells in the phenomenon was ruled out by using different purification steps. In addition, BCG-induced NK cells were shown to be able of partially restoring the DTH response to PPD in recipient mice that were anergic to the latter antigen as a consequence of intravenous infection with large doses of BCG.     

The differences between the structural repertoires of VH germ-line gene segments of mice and humans: implication for the molecular mechanism of the immune response

Although human and murine antibodies are similar when considering their diversification strategies, they differ in the proportion by which kappa and lambda type chains are present in their receptive V, repertoires. It has been shown that this difference implies a divergence in the structural repertoire of the kappa and lambda genes of these species. Nonetheless, the differences in VH have not been systematically studied. In this paper a systematic characterization of the VH structural repertoire of mice is made, so that a comparison with the VH structural repertoire of humans, described in detail elsewhere, could be properly accomplished. Our study shows the structural repertoire of mice to be dominated by canonical structure class 1-2 (approximately 60%), while in humans the dominant one is class 1-3 (approximately 40%). Analysis of the evolutionary relationships between human and mice suggest that this divergence may have a functional meaning. The implications of such findings are discussed.     

Complement, opsonins, and the immune response to bacterial infection in burned patients

Studies were performed to evaluate complement, opsonins, and the immune response to bacterial infection in burned patients. Concentrations and functional acitivities of components of the classical and alternative complement pathways were measured in the sera of four septic, two bacteremic, and four nonseptic burned patients. In addition, heat-labile and heat-stable opsonic activity and agglutinin titers directed against the infecting bacterial strains were measured in the sera of the four septic patients and in an additional group of 11 septic burned patients with abnormal complement profiles. Functional activity of the alternative complement pathway and the concentration of properdin were shown to be persistently decreased during eight weeks postburn in the septic, bacteremic, and nonseptic burned patients; reduced classical pathway activity was demonstrated during the initial postburn period only in the septic patients. Two of the 15 septic patients had decreased heat-labile serum opsonic activity for their infecting bacterial strains, which occurred only during the initial postburn period. Heat-stable opsonins and agglutinin titers in the patients' sera directed against the infecting bacterial strains were equivalent to those in normal human sera, except for the agglutinin titers to Streptococcus faecalis which were increased in the patients' sera in comparison to the normal sera. These results indicate that the multiple complement abnormalities which occur in septic burned patients do not predispose these patients to bacterial infection by decreasing serum opsonic activity. Moreover, heat-stable immune IgG antibodies are not produced during septicemia which facilitate opsonization of the infecting bacterial strains in the absence of an intact complement system.     

The normalization of the immune response in old stressed mice by apomorphine

A case of Rochalimaea henselae infection in an AIDS patient is reported. The R. henselae infection was revealed by febrile pancytopenia associated with liver and spleen enlargement. The diagnosis was made on the finding at histology of hepatic peliosis lesions. Within these lesions Warthin Starry staining displayed bacilli that were identified as R. henselae. This case shows that all HIV-infected patients with these symptoms might be infected with this organism.     

Halothane-associated enhancement of the secondary immune response to sheep erythrocytes in mice: cell transfer studies

The effect of halothane anesthesia on the humoral immune response to sheep red blood cells was studied in mice immunized twice, with a 15-day interval. On both occasions, mice were exposed to 1.5% halothane for 40 min immediately after sensitization. Halothane reexposure resulted in increased numbers of IgG-secreting cells (IgG-SC) as well as circulating 7S-serum agglutinins. To examine further whether this effect could be obtained in syngeneic recipients, adoptive transfer experiments employing spleen cells were performed. While mice receiving cells from unimmunized and anesthetized donors displayed significantly higher levels of IgG-SC, recipients of cells from normal, immunized and immunized-anesthetized donors showed a depressed response when compared to control counterparts. Besides the possibility of an enhancing effect of halothane reexposure on the humoral response, this procedure may counteract normal physiological immunoregulatory processes during the generation of the immune response.