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Biomedical subjects

L V Rizzo

Publications and source records attributed to L V Rizzo.

At least 19 recordsLinked to original sources
PubMed2006

The anti-IRBP IgG1 and IgG2a response does not correlate with susceptibility to experimental autoimmune uveitis.

Susceptibility to experimental autoimmune uveitis (EAU) in inbred mice has been associated with a dominant Th1 response. Elevated anti-inter-photoreceptor retinoid-binding protein (anti-IRBP) IgG2a/IgG1 antibody ratios have been implicated as candidate markers to predict disease severity. In the present study, both the anti-IRBP antibody isotype and severity of EAU phenotypes were examined in 4 non-isogenic genetically selected mouse lines to determine if they can be used as general markers of disease. Mice between 8 and 12 weeks old selected for high (H(III)) or low (L(III)) antibody response and for maximum (AIR(MAX)) or minimum (AIR(MIN)) acute inflammatory reaction (AIR) were immunized with IRBP. Each experiment was performed with at least 5 mice per group. EAU was evaluated by histopathology 21 days after immunization and the minimal criterion was inflammatory cell infiltration of the ciliary body, choroid and retina. Serum IgG1- and IgG2a-specific antibodies were determined by ELISA. EAU was graded by histological examination of the enucleated eyes. The incidence of EAU was lower in AIR(MIN) mice whereas in the other strains approximately 40% of the animals developed the disease. Low responder animals did not produce anti-IRBP IgG2a antibodies or interferon-gamma. No correlation was observed between susceptibility to EAU and anti-IRBP isotype profiles. Susceptibility to EAU is related to the intrinsic capacity to mount higher inflammatory reactions and increased production of anti-IRBP IgG2a isotype is not necessarily a marker of this immunologic profile.

Animals↗
PubMed2005

Protective immunity against Trypanosoma cruzi provided by oral immunization with Phytomonas serpens: role of nitric oxide.

We have previously demonstrated that Phytomonas serpens, a tomato parasite, shares antigens with Trypanosoma cruzi, the protozoa that causes Chagas' disease. These antigens are recognized by human sera and induce protective immunity in Balb/c mice. In the present study, inducible nitric oxide synthase (iNOS) knockout (KO) mice and C57BL/6 mice treated with the nitric oxide inhibitor, aminoguanidine (AG, 50 mg kg(-1)) infected with T. cruzi, were used to demonstrate the role of nitric oxide (NO) to host protection against T. cruzi infection achieved by oral immunization with live P. serpens. A reduction in parasitaemia and an increase in survival were observed in C57BL/6 infected mice and previously immunized with P. serpens, when compared to non-immunized mice. iNOS (KO) mice immunized and C57BL/6 immunized and treated with AG presented parasitaemia and mortality rates comparable to those of infected and non-immunized mice. By itself, immunization with P. serpens did not induce inflammation in the myocardium, but C57BL/6 mice so immunized showed fewer amastigotes nests in the heart following an acute T. cruzi infection than those in non-immunized mice. These results suggest that protective immunity against T. cruzi infection induced by immunization with P. serpens is dependent upon enhanced NO production during the acute phase of T. cruzi infection.

Administration, Oral↗
PubMed2004

Microchimerism does not correlate with survival of murine cardiac allografts.

The development of microchimerism was evaluated at different time points after infusion of a mixed population of bone marrow and spleen cells from (BALB/c x C57Bl/6)F1 mice in the presence or absence of a cardiac transplant. Microchimerism was observed in the spleen, bone marrow and thymus of transplanted BALB/c mice even after graft rejection. In the absence of transplantation, donor cells persisted especially in the thymus. The results show that despite augmentation of graft survival after donor cell infusion compared to nontreated controls, the development of microchimerism did not sustain cardiac semihistocompatible grafts. Moreover, the persistence of donor cells in the thymus in both situations suggests a role for this organ in the increased graft survival in our model.

Animals↗
PubMed2004

Ocular surface epithelium induces expression of human mucosal lymphocyte antigen (HML-1) on peripheral blood lymphocytes.

BACKGROUND/AIMS: Peripheral blood CD8+ lymphocytes that home to mucosal surfaces express the human mucosal lymphocyte antigen (HML-1). At mucosal surfaces, including the ocular surface, only intraepithelial CD8+ lymphocytes express HML-1. These lymphocytes are retained in the intraepithelial compartment by virtue of the interaction between HML-1 and its natural ligand, E-cadherin, which is expressed on epithelial cells. The purpose of this study was to determine whether ocular surface epithelial cells (ocular mucosa) could induce the expression of human mucosal lymphocyte antigen on peripheral blood lymphocytes. METHODS: Human corneal and conjunctival epithelial cells were co-cultured with peripheral blood lymphocytes. Both non-activated and activated lymphocytes were used in the experiments. After 7 days of incubation, lymphocytes were recovered and analysed for the antigens CD8/HML-1, CD4/HML-1, CD3/CD8, CD3/CD4, CD3/CD25, CD8/CD25, and CD4/CD25 by flowcytometry. RESULTS: Significant statistical differences were observed in the CD8/HML-1 expression when conjunctival epithelial cells were co-cultured with non-activated and activated lymphocytes (p = 0.04 for each) and when corneal epithelial cells were co-cultured with non-activated lymphocytes (p = 0.03). Significant statistical difference in CD4/HML-1 expression was observed only when conjunctival epithelial cells were co-cultured with activated lymphocytes (p = 0.02). CONCLUSION: Ocular surface epithelial cells can induce the expression of human mucosal lymphocyte antigen on CD8+ (and to some extent on CD4+) lymphocytes. This may allow the retention of CD8+ and CD4+ lymphocytes within the epithelial compartment of the conjunctiva and play a part in mucosal homing of lymphocytes.

Antigens, CD↗
PubMed2003

Development of CD4+ T cell lines that suppress an antigen-specific immune response in vivo.

It has been suggested for many years that the regulation of the immune system for the maintenance of peripheral tolerance may involve regulatory/suppressor T cells. In the past few years, several investigators have demonstrated that these cells can be generated in vitro. It has also been shown that they can inhibit the progression of various autoimmune disease models when infused into susceptible mice. We have generated two murine T cell lines in the presence of KLH-specific T cell clones from BALB/c or DBA2 mice. The lines are characterized by a low proliferative response to mitogens, the capacity to secrete high amounts of IL-10 and TGF-beta, and small amounts of IFN-gamma. Interestingly, these cells are unable to produce IL-2, IL-4 or IL-5. The study of the surface phenotype of both lines revealed CD4+, CD25high, CD44low and CTLA-4- cells. When injected intravenously in (CBy.D2) F1 mice, these cells were able to inhibit 50-100% of the TNP-specific antibody production, when the hapten was coupled to KLH. In the present study we offer another evidence for the existence of regulatory T cells in the T lymphocyte repertoire, suggesting that they can also regulate immune responses to foreign antigens. Furthermore, we demonstrate an alternative pathway to generate these cells different from approaches used thus far.

Adjuvants, Immunologic↗
PubMed2002

Ocular toxoplasmosis: more than just what meets the eye.

Toxoplasma gondii is an intracellular parasite whose life cycle may include the man as an intermediate host. Close to a billion people are infected with this parasite worldwide. Ocular lesions may occur in up to 25% of those individuals infected. The infection may occur intra-uterus, through the placenta when the mother is infected during pregnancy. The parasite may also infect adults after the ingestion of contaminated food products, most notably meats or water. We have shown that although congenital and post-natal (acquired) infection results in similar ocular lesions, the immunological mechanisms behind the development of disease are different. On the other hand, contrary to published data obtained in mice, we were unable to find evidence that the T. gondii express superantigen activity for human lymphocytes. Our findings are important because they suggest that superantigen activity is not important as a pathological mechanism in human disease. Our data also suggest that, whereas the ocular lesion caused by infection after birth is the result of an excessive or dysfunctional immune response, the lesions caused by congenital infection may be due to a lack of an appropriate response to the parasite.

Animals↗
PubMed2001

Chronic Chagas' disease cardiomyopathy patients display an increased IFN-gamma response to Trypanosoma cruzi infection.

One-third of all Trypanosoma cruzi -infected patients eventually develop chronic Chagas' disease cardiomyopathy (CCC), a particularly lethal inflammatory dilated cardiomyopathy, where parasites are scarce and heart-infiltrating mononuclear cells seem to be the effectors of tissue damage. Since T. cruzi is a major inducer of interleukin-12 production, the role of inflammatory cytokines in the pathogenesis of CCC was investigated. We assayed cytokine production by peripheral blood mononuclear cells (PBMC) from CCC and asymptomatic T. cruzi -infected (ASY) individuals, as well as by T cell lines from endomyocardial biopsies from CCC patients. PBMC from CCC and ASY patients produced higher IFN-gamma levels than normal (N) individuals in response to B13 protein and phytohaemagglutinin PHA; IFN-gamma high responders (> or =1 ng/ml) were 2-3 fold more frequent among CCC patients than ASY individuals. Conversely, IL-4 production in response to the same stimuli was suppressed among T. cruzi -infected patients. The frequency of PHA-induced IFN gammaproducing cells on PBMC was significantly higher among CCC than ASY and N individuals. IFN-gamma and TNF-alpha were produced by ten out of ten PHAstimulated T cell lines from CCC patients; IL-2 and IL-10 were produced by four out of ten and one out of ten lines, respectively; IL-4, IL-1alpha, IL-1beta, IL-6 and IL-12 were undetectable. Our results suggest that CCC and ASY patients may respond differentially to the IFN-gamma-inducing stimulus provided by T. cruzi infection. Given the T(1)-type cytokine profile of heart-infiltrating T cell lines from CCC patients, the ability to mount a vigorous IFN-gamma response may play a role on the differential susceptibility to CCC development.

Adult↗
PubMed2001

Lack of evidence for superantigen activity of Toxoplasma gondii towards human T cells.

Toxoplasma gondii is an obligatory intracellular parasite whose life cycle may include man as an intermediate host. More than 500 million people are infected with this parasite worldwide. It has been previously reported that T. gondii contains a superantigen activity. The purpose of the present study was to determine if the putative superantigen activity of T. gondii would manifest towards human T cells. Peripheral blood mononuclear cells (PBMC) from individuals with no previous contact with the parasite were evaluated for proliferation as well as specific Vbeta expansion after exposure to Toxoplasma antigens. Likewise, PBMC from individuals with the congenital infection were evaluated for putative Vbeta family deletions in their T cell repertoire. We also evaluated, over a period of one year, the PBMC proliferation pattern in response to Toxoplasma antigens in patients with recently acquired infection. Some degree of proliferation in response to T. gondii was observed in the PBMC from individuals never exposed to the parasite, accompanied by specific Vbeta expansion, suggesting a superantigen effect. However, we found no specific deletion of Vbeta (or Valpha) families in the blood of congenitally infected individuals. Furthermore, PBMC from recently infected individuals followed up over a period of one year did not present a reduction of the Vbeta families that were originally expanded in response to the parasite antigens. Taken together, our data suggest that T. gondii does not have a strong superantigen activity on human T cells.

Adult↗
PubMed2000

Discrimination between patients with acquired toxoplasmosis and congenital toxoplasmosis on the basis of the immune response to parasite antigens.

Many persons infected with Toxoplasma gondii develop ocular lesions. Immunologic parameters in the response to T. gondii were evaluated in infected persons with and without ocular lesions and in noninfected controls. Subjects were divided into groups on the basis of presence of serum antibodies to T. gondii, presence of ocular lesions, and clinical history. Production of interleukin-2 and interferon-gamma by peripheral blood mononuclear cells from patients with probable congenital toxoplasmosis was decreased, compared with that in persons with presumed acquired infection. Cell proliferation and delayed-type skin reaction induced by soluble toxoplasma tachyzoite antigen followed the same pattern. Asymptomatic persons showed high levels of interleukin-12 and interferon-gamma, whereas persons with ocular lesions had high interleukin-1 and tumor necrosis factor-alpha responses toward soluble toxoplasma tachyzoite antigen. These data suggest that patients with ocular disease due to congenital infection show tolerance toward the parasite. Furthermore, susceptibility to ocular lesions after acquired toxoplasmosis is associated with high levels of interleukin-1 and tumor necrosis factor-alpha, whereas resistance is associated with high levels of interleukin-12 and interferon-gamma.

Adolescent↗
PubMed2000

The role of IL-12 in the induction of late-phase cellular infiltration in a murine model of allergic conjunctivitis.

BACKGROUND: The applied murine model of allergic conjunctivitis mimics human disease, and an immediate hypersensitivity reaction (IHR) and a late-phase cellular reaction typically develop in sensitized mice after topical challenge with the allergen. OBJECTIVE: We investigated the role of IL-4, IFN-gamma, and IL-12 in the early and late phases of ocular allergy with use of cytokine knockout (KO) mice and neutralizing antibodies. METHODS: Ragweed-sensitized wild-type or IL-4KO, IL-12KO, IFN-gamma KO, anti-IL-12 mAb-treated, recombinant murine IL-12-treated, and anti-IFN-gamma mAb-treated mice were challenged with the allergen 10 days after the immunization. IHR, cellular infiltration, lymphoproliferative response, and cytokine production from draining lymph nodes were recorded and compared among groups. RESULTS: We show that IL-12KO mice and anti-IL-12 antibody-treated wild-type animals failed to have a cellular infiltration into the conjunctiva. Treatment with recombinant murine IL-12 also reduced the number of infiltrating PMNs but increased the percentage of mononuclear cells in the conjunctiva compared with controls. IFN-gamma KO mice had a significantly stronger IHR and prolonged infiltration into the conjunctiva after challenge with ragweed than controls. CONCLUSION: Our data suggest that the presence of IL-12, although better known as a T(H)1-inducing cytokine, is important for the development and the regulation of the late-phase pathologic features in ocular allergy. Furthermore, IFN-gamma is a limiting factor in the late phase of allergy and thus may be important in preventing chronic allergic disease.

Animals↗
PubMed1999

IL-4 and IL-10 are both required for the induction of oral tolerance.

Protection from the development of experimental autoimmune uveitis (EAU) can be induced by feeding mice interphotoreceptor retinoid binding protein before uveitogenic challenge with the same protein. Two different regimens are equally effective in inducing protective tolerance, although they seem to do so through different mechanisms: one involving regulatory cytokines (IL-4, IL-10, and TGF-beta), and the other with minimal involvement of cytokines. Here we studied the importance of IL-4 and IL-10 for the development of oral tolerance using mice genetically engineered to lack either one or both of these cytokines. In these animals we were able to protect against EAU only through the regimen inducing cytokine-independent tolerance. When these animals were fed a regimen that in the wild-type animal is thought to predominantly induce regulatory cells and is associated with cytokine secretion, they were not protected from EAU. Interestingly, both regimens were associated with reduced IL-2 production and proliferation in response to interphotoreceptor retinoid binding protein. These findings indicate that both IL-4 and IL-10 are required for induction of protective oral tolerance dependent on regulatory cytokines, and that one cytokine cannot substitute for the other in this process. These data also underscore the fact that oral tolerance, manifested as suppression of proliferation and IL-2 production, is not synonymous with protection from disease.

Animals↗
PubMed1999

Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon gamma, nitric oxide, and apoptosis.

Pathogenic effector T cells in experimental autoimmune uveitis (EAU) are T helper type 1-like, and interleukin (IL)-12 is required for their generation and function. Therefore, we expected that IL-12 administration would have disease-enhancing effects. Mice were immunized with a uveitogenic regimen of the retinal antigen interphotoreceptor retinoid-binding protein, treated with IL-12 (100 ng/d for 5 d), and EAU was assessed by histopathology. Unexpectedly, IL-12 treatment failed to enhance EAU in resistant strains and downregulated disease in susceptible strains. Only treatment during the first, but not during the second, week after immunization was consistently protective. High levels of interferon gamma (IFN-gamma) were present in the serum during IL-12 treatment, but subsequent antigen-specific IFN-gamma production in protected mice was diminished, as were IL-5 production, lymph node cell proliferation, and serum antibody levels. Treated mice had fewer cells and evidence of enhanced apoptosis in the draining lymph nodes. Unlike wild-type mice, IFN-gamma-deficient, inducible nitric oxide synthase (iNOS)-deficient, and Bcl-2(lck) transgenic mice were poorly protected by IL-12, whereas IL-10-deficient mice were protected. We conclude that administration of IL-12 aborts disease by curtailing development of uveitogenic effector T cells. The data are compatible with the interpretation that IL-12 induces systemic hyperinduction of IFN-gamma, causing activation of iNOS and production of NO, which mediates protection at least in part by triggering Bcl-2 regulated apoptotic deletion of the antigen-specific T cells as they are being primed.

Animals↗
PubMed1999

Protective effect of the type IV phosphodiesterase inhibitor rolipram in EAU: protection is independent of IL-10-inducing activity.

PURPOSE: Experimental autoimmune uveoretinitis (EAU) is a cell-mediated model of retinal autoimmunity that is negatively regulated by interleukin (IL)-10. The antidepressant drug rolipram, a type IV phosphodiesterase inhibitor, enhances IL-10 production by monocyte/macrophages. The effect of rolipram on induction of EAU and its associated immunologic responses was investigated. METHODS: Mice were challenged for EAU induction by immunization with the retinal antigen interphotoreceptor retinoid-binding protein (IRBP) or by adoptive transfer of uveitogenic T cells and were treated with rolipram. EAU severity and immunologic responses to IRBP were analyzed. In addition, the effect of rolipram added to the culture on antigen-driven responses of primed lymph node cells was tested. RESULTS: Rolipram treatment from days -1 to 7 after immunization (afferent phase) was not protective, but severity of EAU was reduced to 50% by treatment from days 8 to 16 after immunization or when EAU was induced by adoptive transfer (efferent phase). Antigen-specific proliferation and interferon (IFN)-gamma production ex vivo by lymph node cells of protected mice were not reduced. However, the addition of rolipram directly to the culture suppressed IRBP-driven proliferation and IFN-gamma production by primed lymph node cells. Freshly explanted lymph node cells of treated mice showed inhibition of IFN-gamma mRNA but no parallel enhancement of IL-10 mRNA by quantitative polymerase chain reaction. Rolipram inhibited EAU in IL-10 knockout mice equally well compared with controls and suppressed their primed lymph node cells in culture. CONCLUSIONS: Rolipram appears to inhibit the expansion and effector function of uveitogenic T cells, raising the possibility that it may be useful for treatment of established disease. Contrary to expectations based on in vitro studies, the protective effects in vivo appear to be independent of IL-10. The observation that suppression of antigen-specific responses is demonstrable only in the physical presence of the drug suggests that, in a clinical setting, continuous administration of rolipram might be needed to sustain its therapeutic effect.

Adoptive Transfer↗
PubMed1998

Heterologous epitopes of IRBP protect against autoimmune uveitis induced by the autologous epitope.

Peptide 161-180 of human interphotoreceptor retinoid-binding protein (IRBP) contains a major uveitogenic epitope for mice of the H-2r haplotype. The human and bovine homologs differ from the autologous murine homolog by three and four amino acid residues, respectively. We compare the immunogenicity and pathogenicity of the three homologs, and investigate their ability to induce oral tolerance to experimental autoimmune uveoretinitis (EAU) induced by the autologous peptide. All three 161-180 homologs were pathogenic, with a hierarchy: human > murine > bovine. All crossreacted with each other and with IRBP. Feeding any of the three homologs (6 x 200 microg over 2 weeks) lowered antigen-specific responses and protected from EAU induced by the autologous homolog, and reduced EAU induced with whole IRBP. Peptide-fed mice had a reduced frequency of peptide-reactive T cells, suggesting a mechanism involving anergy and/or deletion. The results indicate that non-identical, but crossreactive, heterologous epitopes can protect against EAU induced by the corresponding autologous epitope, and even by the whole multi-epitope protein. These findings may impact on clinical trials in which uveitis patients are undergoing oral immunotherapy with bovine retinal antigens.

Administration, Oral↗
PubMed1998

A novel murine model of allergic conjunctivitis.

Allergic conjunctivitis affects over 40 million patients per year in the United States. Here we present the first murine model that incorporates the clinical, cellular, and humoral parameters of allergic conjunctivitis, including a ragweed-induced Th2-type cytokine production by lymphocytes. SWR/J mice were immunized with short ragweed pollen in aluminum hydroxide. Ten days after immunization, allergic conjunctivitis was induced by one topical application of ragweed pollen onto the eye. Immediate response was characterized by chemosis, redness of the conjuctiva, and lid edema. Histopathology and immunohistochemistry showed dense conjunctival infiltration with polymorphonuclear leukocytes, macrophages, and CD4+ T lymphocytes. In addition, ragweed-specific IgG1 and IgE serum levels were significantly higher in immunized animals, and high levels of IL-4 and IL-5 were detected in supernatants from ragweed-activated lymphocytes. This reproducible model is a well-suited instrument for testing the pathophysiology and future therapies of allergic conjunctivitis.

Allergens↗
PubMed1998

IL-10 has a protective role in experimental autoimmune uveoretinitis.

The role of IL-10 in the regulation of ocular autoimmune disease was studied in experimental autoimmune uveoretinitis (EAU) elicited in mice by immunization with the retinal antigen interphotoreceptor retinoid binding protein. IL-10-deficient mice were susceptible to EAU, indicating that pathogenesis can occur without presence of IL-10. Treatment of normal mice with IL-10 for 5 days after uveitogenic immunization ameliorated subsequent EAU scores, and down-regulated antigen-specific production of tumor necrosis factor-alpha and IFN-gamma. A concomitant treatment with IL-4 further reduced disease, and resulted in emergence of antigen-specific IL-4 and IL-10 production, as well as in enhancement of the IgG1 antibody isotype. IL-4 by itself was not protective. Only IL-10, but not IL-4, was able to inhibit the function of differentiated uveitogenic T cells in culture. Expression of mRNA for Th1 and Th2 cytokines in the eye during the course of EAU showed that while a Th1 pattern predominated early, IL-10 mRNA expression coincided with down-regulation of the Th1 response and resolution of EAU. Systemic neutralization of IL-10 during the expression phase of EAU resulted in elevated disease scores. Our results suggest that endogenous IL-10 limits expression of EAU and may play a role in the natural resolution of disease. The data further suggest that exogenous IL-10 may be useful in therapeutic control of autoimmune uveitis. While IL-10 by itself is sufficient to suppress Th1 effector development and function, a concomitant administration of IL-4 is required to shift the autoimmune response towards a non-pathogenic Th2 pathway.

Animals↗