Search PubMed⌕ Search

Biomedical subjects

L Romani

Publications and source records attributed to L Romani.

At least 55 records · Page 3Linked to original sources
PubMed1997

Interleukin-12 in infectious diseases.

Interleukin-12 (IL-12) is a potent immunoregulatory cytokine that is crucially involved in a wide range of infectious diseases. In several experimental models of bacterial, parasitic, viral, and fungal infection, endogenous IL-12 is required for early control of infection and for generation and perhaps maintenance of acquired protective immunity, directed by T helper type 1 (Th1) cells and mediated by phagocytes. Although the relative roles of IL-12 and gamma interferon in Th1-cell priming may be to a significant extent pathogen dependent, common to most infections is that IL-12 regulates the magnitude of the gamma interferon response at the initiation of infection, thus potentiating natural resistance, favoring Th1-cell development; and inhibiting Th2 responses. Treatment of animals with IL-12, either alone or as a vaccine adjuvant, has been shown to prevent disease by many of the same infectious agents, by stimulating innate resistance or promoting specific reactivity. Although IL-12 may enhance protective memory responses in vaccination or in combination with antimicrobial chemotherapy, it is yet unclear whether exogenous IL-12 can alter established responses in humans. Continued investigation into the possible application of IL-12 therapy to human infections is warranted by the role of the cytokine in inflammation, immunopathology, and autoimmunity.

Animals↗
PubMed1997

Th1 and Th2 cytokines in mice with invasive aspergillosis.

With a murine model of invasive aspergillosis we investigated cytokine production by CD4+ T helper cells and the effects of cytokine administration or neutralization on the course and outcome of infection. Patterns of susceptibility and resistance to infection were obtained with different strains of mice injected with different inocula of Aspergillus fumigatus conidia. Mice surviving the primary infection also resisted a subsequent lethal infection that was associated with production of gamma interferon by CD4+ T splenocytes. Impaired neutrophil antifungal activity, observed in susceptible mice, was concomitant with a predominant production of interleukin-4 (IL-4) by CD4+ splenocytes. In these mice, exogenous administration of IL-12 failed to induce resistance to infection; in contrast, treatment with soluble IL-4 receptor cured more than 70% of the mice from primary infection and resulted in the onset of acquired resistance to a subsequent lethal infection. These findings indicate that in murine invasive aspergillosis, production of IL-4 by CD4+ T cells may be one major factor discriminating susceptibility and resistance to infection.

Animals↗
PubMed1997

Initiation of T-helper cell immunity to Candida albicans by IL-12: the role of neutrophils.

The Th1/Th2 paradigm of acquired immunity is proving essential for a better understanding of immunoregulation in candidiasis and perhaps other fungal infections, conditions that may be life-threatening in humans and difficult to control by chemotherapy alone, especially in neutropenic and severely immunocompromised patients. In its basic conception applied to Candida infection in mice, this paradigm calls for: (i) an association between Th1 responses and the onset/maintenance of phagocyte-dependent immunity, critical for opposing infectivity of the commensal, focusing an infection, and clearing the yeast from infected tissue; (ii) the ability of the yeast to activate Th2 response as an evasive strategy; (iii) the reciprocal regulation of Th1 and Th2 responses, resulting in a dynamic balance between these two types of reactivity. This balance, in concert with a variety of environmental factors, may regulate the status of the yeast as a commensal or pathogen in the mucosal tissue of colonized humans, but may also determine the outcome of deep-seated systemic infections once hematogenous dissemination of the yeast has occurred. An important corollary of this hypothesis may be the possible combined effects on Th immunity of Candida carriage/infection and various disease states. While immune deficiency or dysregulation, resulting in an altered cytokine balance as may occur in AIDS, can reasonably be expected to increase local infectivity of the yeast, it is even more intriguing that antifungal chemotherapy will resolve some of the unusual skin (atopic dermatitis-like) disorders frequently observed in this clinical setting, patients with AIDS. Besides, an immunopathologic role for Candida has been suggested for atopic dermatitis, atopy, and other conditions, overtly associated or not with Candida. Thus, the Th cell dichotomy to Candida may have important implications not only for regulation of the balance between commensalism and infection, but may also contribute to the onset or dominance of Th2 responses in other disease states. A similar example, although with different effects, may be provided by the temporary improvement seen in atopic dermatitis patients in concomitance with acute severe infections, an effect that has been proposed to result from transient down-regulation of the predominant Th2 cell reactivity. With a view to either controlling Candida infections or opposing Candida-related immunopathology, the promotion of yeast-specific Th1 responses appears to be a promising immunotherapeutic approach. This, in principle, could be achieved by subtraction of Th2 cytokines or by administration of Th1-promoting cytokines. However, our initial studies with exogenous IL-12 were unsuccessful, suggesting that the recombinant cytokine: (i) is unable to oppose Th2 differentiation driven in vivo by IL-4/IL-10; (ii) may induce endogenous IL-10 production as a regulatory response, and (iii) may potentate local inflammatory responses in gastrointestinal infection or even trigger IFN-gamma-dependent mechanisms of fungal septic shock.. More recent studies seem to provide encouraging results, at least under specific conditions of testing. In acute candidemia, neutrophils appear to be a major source of the directive cytokines, IL-12 and IL-10, thus contributing to the selection of Th1 and Th2 cell responses to LVS or virulent infection, respectively. Neutrophils may also be an important source of IL-10 released in response to challenge with exogenous IL-12. As a result, the Th1-promoting role of IL-12 may be largely unopposed (by IL-10 induction) in neutropenic mice, which would otherwise succumb to LVS challenge. These animals are, in fact, cured by replacement therapy with IL-12 and acquire durable, Th1-associated anticandidal protection. These findings may be very important for immunotherapy of fungal infections in humans. Neutropenic patients are those at the highest risk for developing systemic candidal infections. (ABSTRACT TRUNCATED)

Animals↗
PubMed1996

Impaired neutrophil response and CD4+ T helper cell 1 development in interleukin 6-deficient mice infected with Candida albicans.

To define the role of interleukin (IL)6 in Candida albicans infection, IL-6 deficient mice were assessed for susceptibility to systemic or gastrointestinal infection, as well as for parameters of elicited T helper cell (Th) immunity. IL-6-deficient mice were more susceptible than wild-type mice to either type of infection caused by virulent C. albicans. In response to systemic challenge with a live vaccine strain of yeast, IL-6-deficient mice failed to mount Th1-associated protective immunity, but the resulting Th2-biased response could be redirected to the Th1 phenotype by IL-10 neutralization. Severe impairment of the macrophage and neutrophil response to infection was observed in IL-6-deficient mice, but administration of IL-6 would increase both neutrophil response and resistance to infection. IL-6 seems to oppose the Th2-promoting role of IL-10 in candidiasis, its early regulatory activity involving effects on neutrophil function.

Animals↗
PubMed1996

CD4+ T-helper-cell responses in mice with low-level Candida albicans infection.

Resistance and susceptibility to Candida albicans infection have been shown to be dependent upon the activation of CD4+ T helper (Th) type 1 or Th2 cells, respectively. To study the type, kinetics, and cytokine dependency of CD4+ Th-cell responses in low-level C. albicans infection, susceptible mice were infected with sublethal doses of C. albicans and assessed for parameters of CD4+ Th-dependent immunity. Interleukin (IL)-12 and gamma interferon were always produced early in infection regardless of the pathogen load. In contrast, production of IL-4, and hence Th2-cell reactivity, was strictly dose dependent, being induced at the higher dose of the fungus. Production of IL-12 correlated with a successful control of infection in mice exposed to the lower doses of C. albicans but not with the development of acquired immunity. An antigenic stimulus appeared to be required for IL-12 to induce a protective anticandidal response. Cytokine depletion in vivo revealed that neutralization of IL-4 was protective early but not late in infection, suggesting a different role for IL-4 in the induction versus maintenance of an ongoing anticandidal Th response. Late in infection, an exacerbative effect was also observed upon IL-12 neutralization. These results indicate that the fungal burden and timing of cytokine appearance greatly influence CD4+ Th induction and effector functions in mice with candidiasis.

Animals↗
PubMed1995

TGF-beta is important in determining the in vivo patterns of susceptibility or resistance in mice infected with Candida albicans.

Resistance and susceptibility of mice to systemic infection with the fungus Candida albicans are associated with the preferential expansion of Th1 and Th2 cells, respectively. In this study, endogenous production of TGF-beta was found to be increased soon after infection of healer mice with a live vaccine strain of the fungus, but down-regulated in nonhealer mice with virulent yeast challenge. Although not affecting the outcome of primary challenge, serologic ablation of TGF-beta in the former animals abrogated development of acquired resistance and resulted in impaired production of IL-12/IFN-gamma and higher expression of IL-4/IL-10 at the time of reinfection with virulent yeast. A CD4+ population expressing the memory phenotype, CD44highMEL-14low, which appeared to be expanded by yeast infection of nonhealer mice, was similarly increased in the healer mice by anti-TGF-beta treatment. In vitro rTGF-beta impaired the candidacidal function of IFN-gamma-activated macrophages. Yet in nonhealer mice infected with virulent C. albicans, administration of rTGF-beta delayed progression of the disease, which was concomitant with the detection of lower levels of IL-4. In addition to previous evidence for an obligatory role of IFN-gamma and IL-12 in Candida-driven Th1 cell differentiation in vivo, the present data establish TGF-beta as a third cytokine, the presence of which may be required for optimal Th1 development leading to long-lived anticandidal resistance.

Animals↗
PubMed1995

Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice.

C/EBP beta is considered a key element of interleukin-6 (IL-6) signalling as well as an important transcriptional regulator of the IL-6 gene itself. We describe here how mice lacking C/EBP beta develop a pathology similar to mice overexpressing IL-6 and nearly identical to multicentric Castleman's disease in human patients, with marked splenomegaly, peripheral lymphadenopathy and enhanced haemopoiesis. Humoral, innate and cellular immunity are also profoundly distorted, as shown by the defective activation of splenic macrophages, the strong impairement of IL-12 production, the increased susceptibility to Candida albicans infection and the altered T-helper function. Our data show that C/EBP beta is crucial for the correct functional regulation and homeostatic control of haemopoietic and lymphoid compartments.

Animals↗
PubMed1995

Interleukin-4 and -10 exacerbate candidiasis in mice.

Neutralization of endogenous interleukin (IL)-4 or IL-10 in mice with Candida albicans infection initiates or accelerates development of a T helper (Th)1-associated protective response. Here, we report the effect of IL-4 and IL-10 administration on the course of systemic or gastrointestinal (GI) candidiasis and on the development of Th immunity using yeast/host combinations that result either in Th1-associated self-limiting infection (healer mice) or in Th2-associated progressive disease (nonhealer mice). Treatment with IL-4 or IL-10 greatly exacerbated the course of systemic infection in nonhealer mice and rendered healer mice, inoculated with attenuated yeast cells, susceptible to infection. Under the latter conditions of yeast challenge and IL-4/IL-10 administration, the development of a fatal disease was associated with inhibition of IL-12 production and detection of progressive Th2 cell dominance. In contrast, in healer mice allowed to resolve their infections and to develop long-lived anti-candidal resistance, the expression of this acquired resistance was not impaired by IL-4 and/or IL-10, as shown by the outcome of reinfection with virulent yeast cells. In the GI model of infection, both IL-4 and IL-10 were found to exacerbate the course of infection and to induce the appearance of CD4+ T cells producing high levels of IL-4 and IL-10 in Peyer's patches. These findings demonstrate that exogenous IL-4 and IL-10 may greatly affect the development of Th responses to C. albicans in vivo, but do not modify the expression of established and predominant Th1 cell reactivity.

Animals↗
PubMed1995

T helper cell dichotomy to Candida albicans: implications for pathology, therapy, and vaccine design.

Acquired immunity to Candida albicans is believed to prevent mucosal colonization of adult immunocompetent individuals from progressing to symptomatic infection. Resistance to disease appears to correlate with the detection of delayed-type hypersensitivity responses in vivo and a T helper type 1 (Th1) cytokine secretion profile in vitro. Cellular immunodeficiency, particularly HIV infection, greatly increases the risk of mucosal infection, confirming that CD(4+)-cell-directed immunity is effective locally in controlling infectivity of the yeast. While Th1-type CD4+ cell activation resulting in phagocyte-dependent immunity clearly represents an important mechanism of anticandidal resistance, clinical observations suggest that Th2-type CD4+ cell reactivity may be triggered by Candida antigens in several disease states, including symptomatic infections and immunopathology. This may imply that a Th1-type pattern of reactivity characterizes the saprophytic yeast carriage and resistance to disease by healthy humans, whereas Th2-type responses would be mostly associated with pathology. Moreover, Candida-specific T helper responses, namely humoral and cell-mediated immunity, appear to be reciprocally regulated, as typically occurs in experimental models of parasitic and retroviral infection, where the Th1/Th2 paradigm of acquired immunity has been best characterized. Recent studies, besides providing direct evidence for the occurrence of cross-regulatory Th1 and Th2 responses in mice with candidiasis, emphasize the potential of cytokine/anticytokine therapy for recruiting Candida-specific responses toward protective, Th1-type CD4+ cell reactivity. At the same time, these studies call attention to the possible consequences of C. albicans infection for immunopathology, allergy, and coinfection.

Animals↗
PubMed1995

Mechanisms of resistance to fungal infections.

In the past year, significant advances have been made in our understanding of immune defenses to fungal infections, which may be instrumental in the development of rational approaches to immunodiagnosis and therapy of these infections. The highlights have been the result of the direct application of advances in molecular biology and basic immunology, particularly cytokine research, leading to improved definition of fungal antigens and increased understanding of the roles of functionally distinct T-cell subsets, the activity of which may be either host-protective or disease-promoting.

Animals↗
PubMed1995

A TH1-TH2-like switch in candidiasis: new perspectives for therapy.

An imbalance in TH1-type and TH2-type responses may allow Candida albicans to modify the host response to favor its own persistence. This hypothesis has important consequences for allergy, autoimmunity and co-infection, and also highlights a potential role for cytokine and anti-cytokine therapy in Candida-related pathology.

Animals↗
PubMed1995

T helper cell type 1 (Th1)- and Th2-like responses are present in mice with gastric candidiasis but protective immunity is associated with Th1 development.

The relative contributions of local T helper cell type 1 (Th1)- and Th2-like responses to the course of primary and secondary gastrointestinal (GI) candidiasis were examined in adult immunocompetent BALB/c mice. Both Th1 cytokines, such as interferon-gamma (IFN-gamma), and the Th2 cytokines, interleukin (IL)-4 and IL-5, were produced by CD4+ cells from Peyer's patches (PP) and mesenteric lymph nodes at a time when the fungus was cleared from the stomach and intestine. Augmentation of antigen-specific Th2-like responses by treatment with cholera toxin did not modify the course of disease. In contrast, treatment with soluble IL-4 receptor, which increased Th1 cells, was associated with enhanced yeast clearance. In addition, IFN-gamma but not IL-4 mRNA was present in PP and spleen CD4+ cells in mice resistant to subsequent GI inoculation. Activation of Th1- but not Th2-like responses may be responsible locally for controlling GI candidiasis and generating protective immunity.

Animals↗
PubMed1994

IL-12 is both required and prognostic in vivo for T helper type 1 differentiation in murine candidiasis.

In murine models of systemic candidiasis, healing and nonhealing patterns of disease are associated with preferential expansion of Th1 and Th2 cells, respectively. As previous studies have shown IL-12 to be expressed transcriptionally in healer mice and to be required for Th1 development in vitro, this cytokine might play a role in Candida-driven Th1 cell differentiation in vivo. In the present study, IL-12-neutralizing Abs or recombinant IL-12 were administered to mice with healing or progressive candidiasis, respectively, and the animals were monitored for mortality, resistance to reinfection, serum levels of specific Abs, and IFN-gamma, IL-4, and IL-10 message/protein expression by CD4+ cells. In self-limiting infection by a yeast vaccine strain, neutralization of IL-12 ablated development of acquired anticandidal resistance and led to appearance of Candida-specific IgE and IL-4-producing cells. In mice with progressive systemic disease as well as in a mucosal infection model, administration of IL-12 did not result in therapeutic activity under conditions of yeast infection that would instead be resolved by serologic ablation of IL-4 or IL-10. Yet, in systemically infected mice cured by anti-IL-4 or anti-IL-10 therapy, the emergence of a Th1 response correlated with the detection of high levels of circulating IL-12 and splenic IL-12 transcripts. Although exogenous IL-12 may not be sufficient for Th conversion in the presence of an overwhelming IL-4/IL-10 response, endogenous production of IL-12 may be both required and prognostic for Th1 differentiation in vivo.

Animals↗
PubMed1994

Neutralization of IL-10 up-regulates nitric oxide production and protects susceptible mice from challenge with Candida albicans.

In contrast to several inbred strains of mice that develop Th1-associated anticandidal protection, DBA/2 mice are highly susceptible to systemic infection with Candida albicans cells of the attenuated variant PCA-2, and fatal outcome is observed in concurrence with sustained CD4+ cell production in vitro of IL-4 and IL-10. These Th2 cytokines were previously shown to inhibit nitric oxide (NO) production and yeast killing by activated macrophage cultures. We now show that macrophages from DBA/2 mice, either intact or infected with PCA-2, have lower capacity than resistant strains to synthesize NO in response to IFN-gamma. However, when treated with anti-IL-10 Abs at the time of infection, DBA/2 mice survived challenge and displayed increased production of NO in vitro after IFN-gamma activation. Cure was associated with the onset of footpad responses and durable protection, and higher frequencies of IFN-gamma-secreting cells were found in splenic CD4+ lymphocytes that expressed lower levels of IL-4 and IL-10 mRNA. Therefore, in DBA/2 mice, IL-10 contributes significantly to the selection of a Th2 response and lethality after PCA-2 challenge. An IL-10-induced defect in the activation and/or expansion of IFN-gamma-producing Th1 cells, IL-10 suppression of yeast killing, and the relative inability of DBA/2 macrophages to produce adequate levels of candidacidal NO may all contribute to the abnormal susceptibility of these mice to candidiasis.

Animals↗
PubMed1994

Interleukin-12 but not interferon-gamma production correlates with induction of T helper type-1 phenotype in murine candidiasis.

By means of polymerase chain reaction-assisted mRNA amplification, we have monitored message levels of interleukin (IL)-12 in splenic macrophages and of interferon-gamma (IFN-gamma), IL-4, and IL-10 in CD4+ and CD8+ T cells using Candida albicans/host combinations that result either in a T helper type-1 (Th1)-associated self-limiting infection ("healer mice") or in a Th2-associated progressive disease ("nonhealer mice"). The timing and pattern of message detection did not differ qualitatively by the expression of IFN-gamma or IL-10 mRNA in CD4+ and CD8+ cells from healer (i.e. PCA-2 into CD2F1) vs. nonhealer (i.e. CA-6 into CD2F1 or PCA-2 into DBA/2) mice. In contrast, IL-4 mRNA was uniquely expressed by CD4+ cells from nonhealer animals. IL-12p40 was readily detected in macrophages from healer mice but was detected only early in infection in mice with progressive disease. Cytokine levels were measured in sera, and antigen-driven cytokine production by CD4+ and CD8+ cells was assessed in vitro, while IFN-gamma-producing cells were enumerated in CD4- CD8- cell fractions. Overall, our results showed that (i) antigen-specific secretion of IFN-gamma protein in vitro by CD4+ cells occurred only in healing infection; (ii) IL-4- and IL-10-producing CD4+ cells would expand in nonhealer mice in the face of high levels of circulating IFN-gamma, likely released by CD4- CD8- lymphocytes; (iii) a finely regulated IFN-gamma production correlated in the healer mice with IL-12 mRNA detection, and IL-12 was required in vitro for yeast-induced development of IFN-gamma-producing CD4+ cells. Although the mutually exclusive production of IL-4/IL-10 and IFN-gamma by early CD4+ cells may be the major discriminative factor of cure and noncure responses in candidiasis, IL-12 rather than IFN-gamma production may be an indicator of Th1 differentiation.

Animals↗
PubMed1994

Untreated or drug-treated tumor cells are differentially recognized by allogeneic lymphocytes.

Murine tumor cells treated with triazene compounds (TZC), in vivo or in vitro, are capable of eliciting specific transplantation resistance in syngeneic hosts, and T-cell-mediated proliferative and cytotoxic responses, directed against novel drug-induced antigen(s). Since this phenomenon, referred to as chemical xenogenization (CX) could open up new perspectives in the immunochemotherapy of human neoplasias, it was of interest to investigate whether CX could also occur in human tumors. However, established human tumor cell lines along with fully immunocompetent autologous lymphocytes, are seldom available. Therefore studies were carried out to test whether parental or TZC-treated tumor cells could be differentially recognized by allogeneic lymphocytes. Experiments were performed in both human and murine models, using a lung adenocarcinoma line treated in vitro with TZC, or an established xenogenized mouse lymphoma, respectively. The results indicate that allogeneic cytotoxic T-lymphocytes (CTL) recognize specifically murine TZC-treated tumor cells. This was supported by the finding that antisera directed against the drug-treated cells abrogated the generation and the cytolytic activity of allogeneic CTL reactive against the TZC-treated tumor. In addition it was found that changes of the antigenic pattern of cell membrane recognizable by cloned allogeneic CTL occur in the TZC-treated human carcinoma cell line.

Animals↗