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1.  Immunotherapeutic strategies in autoimmune uveitis 
Autoimmunity Reviews  2014;13(9):909-916.
Autoimmune uveitis is an organ-specific disorder characterized by irreversible lesions to the eye that predominantly affect people in their most productive years and is among the leading causes of visual deficit and blindness. Currently available therapies are effective in the treatment of a wide spectrum of uveitis, but are often associated with severe side effects. Here, we review ongoing research with promising immunomodulatory therapeutic strategies, describing their specific features, interactions and the responses triggered by the targeted immune molecules that aim to minimize clinical complications and the likelihood of disease relapse. We first review the main features of the disease, diagnostic tools, and traditional forms of therapy, as well as the animal models predominantly used to understand the pathogenesis and test the novel intervention approaches aiming to control the acute immune and inflammatory responses and to dampen chronic responses. Both exploratory research and clinical trials have targeted either the blockade of effector pathways or of their companion co-stimulatory molecules. Examples of targets are T cell receptors (CD3), their co-stimulatory receptors (CD28, CTLA-4) and corresponding ligands (B7-1 and B7-2, also known as CD80 and CD86), and cytokines like IL-2 and their receptors. Here, we summarize the available evidence on effectiveness of these treatments in human and experimental uveitis and highlight a novel CD28 antagonist monovalent Fab′ antibody, FR104, which has shown preclinical efficacy suppressing effector T cells while enhancing regulatory T cell function and immune tolerance in a humanized graft-versus-host disease (GVHD) mice model and is currently being tested in a mouse autoimmune uveitis model with encouraging results.
doi:10.1016/j.autrev.2014.05.003
PMCID: PMC4181827  PMID: 24833504
Autoimmune uveitis; Experimental autoimmune uveitis; Costimulation blockade; Immune modulation; CD28 antagonists
2.  Challenge of Chronically Infected Mice with Homologous Trypanosoma cruzi Parasites Enhances the Immune Response but Does Not Modify Cardiopathy: Implications for the Design of a Therapeutic Vaccine 
Chagas disease is a Trypanosoma cruzi-induced zoonosis that has no natural cure. Local damage induced by the parasite and the immune response causes chronic heart and digestive lesions. Efforts to develop a therapeutic vaccine that boosts the immune response to completely clear the parasite are needed because there is no effective treatment for chronically infected patients. In an attempt to modify the host-parasite equilibrium to increase parasite destruction, we analyzed cardiopathy and the immune response in chronically infected mice that were challenged with live homologous parasites. Challenge with a single dose of parasite increased CD4+ and CD8+ T cell populations, gamma interferon (IFN-γ) production, and serum-specific IgG levels. However, subpatent parasitemias and cardiac tissue were not affected. Because of the short duration of the immune boost after a single challenge, we next evaluated the impact of four parasite doses, administered 3 weeks apart. At 1 to 2 months after the last dose, the numbers of CD4+ T cells and IFN-γ-producing CD4+ memory cells and the CD4+ T cell proliferative response to T. cruzi antigen were increased in the spleen. The frequency of IFN-γ-producing CD8+ memory cells in the blood was also increased. However, the sustained challenge did not favor TH1 development; rather, it induced an increase in serum-specific IgG1 levels and mixed TH1/TH2 cytokine production. Moreover, there were no significant changes in cardiac lesions and subpatent parasitemias. In conclusion, we believe that this study may help in elucidating the necessary elements for a successful therapeutic vaccine which may reduce cardiomyopathy in chronically infected human patients.
doi:10.1128/CVI.00032-12
PMCID: PMC3571278  PMID: 23254299
3.  Regulatory T Cells Accumulate in the Lung Allergic Inflammation and Efficiently Suppress T-Cell Proliferation but Not Th2 Cytokine Production 
Foxp3+CD25+CD4+ regulatory T cells are vital for peripheral tolerance and control of tissue inflammation. In this study, we characterized the phenotype and monitored the migration and activity of regulatory T cells present in the airways of allergic or tolerant mice after allergen challenge. To induce lung allergic inflammation, mice were sensitized twice with ovalbumin/aluminum hydroxide gel and challenged twice with intranasal ovalbumin. Tolerance was induced by oral administration of ovalbumin for 5 consecutive days prior to OVA sensitization and challenge. We detected regulatory T cells (Foxp3+CD25+CD4+ T cells) in the airways of allergic and tolerant mice; however, the number of regulatory T cells was more than 40-fold higher in allergic mice than in tolerant mice. Lung regulatory T cells expressed an effector/memory phenotype (CCR4highCD62LlowCD44highCD54highCD69+) that distinguished them from naive regulatory T cells (CCR4intCD62LhighCD44intCD54intCD69−). These regulatory T cells efficiently suppressed pulmonary T-cell proliferation but not Th2 cytokine production.
doi:10.1155/2012/721817
PMCID: PMC3227414  PMID: 22162718
4.  Cellular Renewal and Improvement of Local Cell Effector Activity in Peritoneal Cavity in Response to Infectious Stimuli 
PLoS ONE  2011;6(7):e22141.
The peritoneal cavity (PerC) is a singular compartment where many cell populations reside and interact. Despite the widely adopted experimental approach of intraperitoneal (i.p.) inoculation, little is known about the behavior of the different cell populations within the PerC. To evaluate the dynamics of peritoneal macrophage (MØ) subsets, namely small peritoneal MØ (SPM) and large peritoneal MØ (LPM), in response to infectious stimuli, C57BL/6 mice were injected i.p. with zymosan or Trypanosoma cruzi. These conditions resulted in the marked modification of the PerC myelo-monocytic compartment characterized by the disappearance of LPM and the accumulation of SPM and monocytes. In parallel, adherent cells isolated from stimulated PerC displayed reduced staining for β-galactosidase, a biomarker for senescence. Further, the adherent cells showed increased nitric oxide (NO) and higher frequency of IL-12-producing cells in response to subsequent LPS and IFN-γ stimulation. Among myelo-monocytic cells, SPM rather than LPM or monocytes, appear to be the central effectors of the activated PerC; they display higher phagocytic activity and are the main source of IL-12. Thus, our data provide a first demonstration of the consequences of the dynamics between peritoneal MØ subpopulations by showing that substitution of LPM by a robust SPM and monocytes in response to infectious stimuli greatly improves PerC effector activity.
doi:10.1371/journal.pone.0022141
PMCID: PMC3142143  PMID: 21799778
5.  The Spleen CD4+ T Cell Response to Blood-Stage Plasmodium chabaudi Malaria Develops in Two Phases Characterized by Different Properties 
PLoS ONE  2011;6(7):e22434.
The pivotal role of spleen CD4+ T cells in the development of both malaria pathogenesis and protective immunity makes necessary a profound comprehension of the mechanisms involved in their activation and regulation during Plasmodium infection. Herein, we examined in detail the behaviour of non-conventional and conventional splenic CD4+ T cells during P. chabaudi malaria. We took advantage of the fact that a great proportion of CD4+ T cells generated in CD1d-/- mice are I-Ab-restricted (conventional cells), while their counterparts in I-Ab-/- mice are restricted by CD1d and other class IB major histocompatibility complex (MHC) molecules (non-conventional cells). We found that conventional CD4+ T cells are the main protagonists of the immune response to infection, which develops in two consecutive phases concomitant with acute and chronic parasitaemias. The early phase of the conventional CD4+ T cell response is intense and short lasting, rapidly providing large amounts of proinflammatory cytokines and helping follicular and marginal zone B cells to secrete polyclonal immunoglobulin. Both TNF-α and IFN-γ production depend mostly on conventional CD4+ T cells. IFN-γ is produced simultaneously by non-conventional and conventional CD4+ T cells. The early phase of the response finishes after a week of infection, with the elimination of a large proportion of CD4+ T cells, which then gives opportunity to the development of acquired immunity. Unexpectedly, the major contribution of CD1d-restricted CD4+ T cells occurs at the beginning of the second phase of the response, but not earlier, helping both IFN-γ and parasite-specific antibody production. We concluded that conventional CD4+ T cells have a central role from the onset of P. chabaudi malaria, acting in parallel with non-conventional CD4+ T cells as a link between innate and acquired immunity. This study contributes to the understanding of malaria immunology and opens a perspective for future studies designed to decipher the molecular mechanisms behind immune responses to Plasmodium infection.
doi:10.1371/journal.pone.0022434
PMCID: PMC3141041  PMID: 21814579
6.  Comparative Analysis of Activation Phenotype, Proliferation, and IFN-γ Production by Spleen NK1.1+ and NK1.1− T Cells During Plasmodium chabaudi AS Malaria 
The NK1.1 molecule participates in NK, NKT, and T-cell activation, contributing to IFN-γ production and cytotoxicity. To characterize the early immune response to Plasmodium chabaudi AS, spleen NK1.1+ and NK1.1− T cells were compared in acutely infected C57BL/6 mice. The first parasitemia peak in C57BL/6 mice correlated with increase in CD4+NK1.1+TCR-αβ+, CD8+NK1.1+TCR-αβ+, and CD4+NK1.1−TCR-αβ+ cell numbers per spleen, where a higher increment was observed for NK1.1+ T cells compared to NK1.1− T cells. According to the ability to recognize the CD1d-α-GalCer tetramer, CD4+NK1.1+ cells in 7-day infected mice were not predominantly invariant NKT cells. At that time, nearly all NK1.1+ T cells and around 30% of NK1.1− T cells showed an experienced/activated (CD44HICD69HICD122HI) cell phenotype, with high expression of Fas and PD-L1 correlating with their low proliferative capacity. Moreover, whereas IFN-γ production by CD4+NK1.1+ cells peaked at day 4 p.i., the IFN-γ response of CD4+NK1.1− cells continued to increase at day 5 of infection. We also observed, at day 7 p.i., 2-fold higher percentages of perforin+ cells in CD8+NK1.1+ cells compared to CD8+NK1.1− cells. These results indicate that spleen NK1.1+ and NK1.1− T cells respond to acute P. chabaudi malaria with different kinetics in terms of activation, proliferation, and IFN-γ production.
doi:10.1089/jir.2009.0095
PMCID: PMC2893693  PMID: 20187775
7.  The Liver Plays a Major Role in Clearance and Destruction of Blood Trypomastigotes in Trypanosoma cruzi Chronically Infected Mice 
Intravenous challenge with Trypanosoma cruzi can be used to investigate the process and consequences of blood parasite clearance in experimental Chagas disease. One hour after intravenous challenge of chronically infected mice with 5×106 trypomastigotes, the liver constituted a major site of parasite accumulation, as revealed by PCR. Intact parasites and/or parasite remnants were visualized at this time point scattered in the liver parenchyma. Moreover, at this time, many of liver-cleared parasites were viable, as estimated by the frequency of positive cultures, which considerably diminished after 48 h. Following clearance, the number of infiltrating cells in the hepatic tissue notably increased: initially (at 24 h) as diffuse infiltrates affecting the whole parenchyma, and at 48 h, in the form of large focal infiltrates in both the parenchyma and perivascular spaces. Phenotypic characterization of liver-infiltrating cells 24 h after challenge revealed an increase in Mac1+, CD8+ and CD4+ cells, followed by natural killer (NK) cells. As evidence that liver-infiltrating CD4+ and CD8+ cells were activated, increased frequencies of CD69+CD8+, CD69+CD4+ and CD25+CD122+CD4+ cells were observed at 24 and 48 h after challenge, and of CD25−CD122+CD4+ cells at 48 h. The major role of CD4+ cells in liver protection was suggested by data showing a very high frequency of interferon (IFN)-γ-producing CD4+ cells 24 h after challenge. In contrast, liver CD8+ cells produced little IFN-γ, even though they showed an enhanced potential for secreting this cytokine, as revealed by in vitro T cell receptor (TCR) stimulation. Confirming the effectiveness of the liver immune response in blood parasite control during the chronic phase of infection, no live parasites were detected in this organ 7 days after challenge.
Author Summary
Chagas disease, a Latin American illness caused by the protozoan parasite Trypanosoma cruzi, has only rare spontaneous cure, and in most patients a small number of parasites persists for life in the blood and tissues, leading to chronic disorders such as cardiomyopathy. In a murine model of chronic T. cruzi infection we observed that the liver plays an important role in the clearance of blood-circulating parasites. Moreover, parasite accumulation in this organ is followed by their elimination, an effect that is not immediate but seems to depend on the recruitment of leukocytes and on the local production of IFN-γ, a cytokine known to increase the T. cruzi-killing capacity of phagocytes. Our findings contribute to the knowledge of T. cruzi-host interaction, showing the participation of a non-lymphoid organ in parasite control. In addition, they contribute to understanding the multifaceted role the liver plays in the immune response.
doi:10.1371/journal.pntd.0000578
PMCID: PMC2793026  PMID: 20052269
8.  Contribution of NK, NK T, γδ T, and αβ T Cells to the Gamma Interferon Response Required for Liver Protection against Trypanosoma cruzi  
Infection and Immunity  2006;74(4):2031-2042.
In the present work, we show that intracellular Trypanosoma cruzi is rarely found in the livers of acutely infected mice, but inflammation is commonly observed. The presence of numerous intrahepatic amastigotes in infected gamma interferon (IFN-γ)-deficient mice corroborates the notion that the liver is protected by an efficient local immunity. The contribution of different cell populations was suggested by data showing that CD4- and CD8-deficient mice were able to restrain liver parasite growth. Therefore, we have characterized the liver-infiltrating lymphocytes and determined the sources of IFN-γ during acute T. cruzi infection. We observed that natural killer (NK) cells increased by day 7, while T and B cells increased by day 14. Among CD3+ cells, CD4+, CD8+, and CD4− CD8− cell populations were greatly expanded. A large fraction of CD3+ cells were positive for PanNK, a β1 integrin expressed by NK and NK T cells. However, these lymphocytes were not classic NK T cells because they did not express NK1.1 and showed no preferential usage of Vβ8. Otherwise, liver NK T (CD3+ NK1.1+) cells were not increased in acutely infected mice. The majority of PanNK+ CD4+ and PanNK+ CD8+ cells expressed T-cell receptor αβ (TCRαβ), whereas PanNK+ CD4− CD8− cells were positive for TCRγδ. In fact, γδ T cells showed the most remarkable increase (40- to 100-fold) among liver lymphocytes. Most importantly, intracellular analysis revealed high levels of IFN-γ production at day 7 by NK cells and at day 14 by CD4+, CD8+, and CD4− CD8− TCRγδ+ cells. We concluded that NK cells are a precocious source of IFN-γ in the livers of acutely infected mice, and, as the disease progresses, conventional CD4+ and CD8+ T cells and γδ T cells, but not classic NK-T cells, may provide the IFN-γ required for liver protection against T. cruzi.
doi:10.1128/IAI.74.4.2031-2042.2006
PMCID: PMC1418886  PMID: 16552032

Results 1-8 (8)