Rationale: A hallmark of pulmonary tuberculosis (TB) is the formation of granulomas. However, the immune factors that drive the formation of a protective granuloma during latent TB, and the factors that drive the formation of inflammatory granulomas during active TB, are not well defined. Objectives: The objective of this study was to identify the underlying immune mechanisms involved in formation of inflammatory granulomas seen during active TB. Methods: The immune mediators involved in inflammatory granuloma formation during TB were assessed using human samples and experimental models of Mycobacterium tuberculosis infection, using molecular and immunologic techniques. Measurements and Main Results: We demonstrate that in human patients with active TB and in nonhuman primate models of M. tuberculosis infection, neutrophils producing S100 proteins are dominant within the inflammatory lung granulomas seen during active TB. Using the mouse model of TB, we demonstrate that the exacerbated lung inflammation seen as a result of neutrophilic accumulation is dependent on S100A8/A9 proteins. S100A8/A9 proteins promote neutrophil accumulation by inducing production of proinflammatory chemokines and cytokines, and influencing leukocyte trafficking. Importantly, serum levels of S100A8/ A9 proteins along with neutrophil-associated chemokines, such as keratinocyte chemoattractant, can be used as potential surrogate biomarkers to assess lung inflammation and disease severity in human TB. Conclusions: Our results thus show a major pathologic role for S100A8/A9 proteins in mediating neutrophil accumulation and inflammation associated with TB. Thus, targeting specific molecules, such as S100A8/A9 proteins, has the potential to decrease lung tissue damage without impacting protective immunity against TB.Keywords: inflammation; tuberculosis; neutrophil; S100A8/A9 proteins; granuloma A hallmark of pulmonary tuberculosis (TB) in humans and experimentally infected animals is the formation of granulomas. However, the immune factors that drive the formation of the protective granuloma during latent TB, and the factors that drive the inflammatory granulomas formed during active TB, are not well defined. What This Study Adds to the FieldThis study demonstrates the dominant presence of neutrophils producing S100 proteins within the inflammatory lung granulomas of patients with active TB. This study also describes a link between S100A8/A9 protein induction, neutrophil accumulation, and pathology associated with the inflammatory granuloma formed during TB, because S100A8/A9 deficiency in mice reverses exacerbated inflammation during TB. In addition, this study demonstrates the potential use of S100A8/A9 proteins along with neutrophilattracting chemokines in serum as surrogate biomarkers to assess inflammation and disease severity in TB in humans.
Oropharyngeal candidiasis (OPC) is an opportunistic infection caused by Candida albicans. Despite its prevalence, little is known about C. albicans-specific immunity in the oral mucosa. Vaccines against Candida generate both Th1 and Th17 responses, and considerable evidence implicates IL-17 in immunity to OPC. However, IL-17 is also produced by innate immune cells that are remarkably similar to Th17 cells, expressing the same markers and localizing to similar mucosal sites. To date, the relative contribution(s) of Th1, Th17 and innate IL-17-producing cells in OPC have not been clearly defined. Here, we sought to determine the nature and function of adaptive T cell responses to OPC, using a new recall infection model. Mice subjected to infection and re-challenge with Candida mounted a robust and stable antigen specific IL-17 response in CD4+ but not CD8+ T cells. There was little evidence for Th1 or Th1/Th17 responses. The Th17 response promoted accelerated fungal clearance, and Th17 cells could confer protection in Rag1−/− mice upon adoptive transfer. Surprisingly, CD4 deficiency did not cause OPC, but was instead associated with compensatory IL-17 production by Tc17 and CD4-CD8-CD3+ cells. Therefore, classic CD4+Th17 cells protect from OPC, but can be compensated by other IL-17-producing cells in CD4-deficient hosts.
Summary Uveal melanoma is the most common intraocular malignancy though it is a rare subset of all melanomas. Uveal melanoma has distinct biology relative to cutaneous melanoma, with widely divergent patient outcomes. Patients diagnosed with a primary uveal melanoma can be stratified for risk of metastasis by cytogenetics or gene expression profiling, with approximately half of patients developing metastatic disease, predominately hepatic in location, over a 15 year period. Historically, no systemic therapy has been associated with a clear clinical benefit for patients with advanced disease and median survival remains poor. Here, as a joint effort between CURE OM and the National Cancer Institute, the current understanding of the molecular and immunobiology of uveal melanoma is reviewed, and on-going laboratory research into the disease is highlighted. Finally, recent investigations relevant to clinical management via targeted and immunotherpies are reviewed and next steps in the development of clinical therapeutics are discussed.
SUMMARYOral administration of antigen induces a state of tolerance that is associated with activation of CD8 T cells that can transfer unresponsiveness to naõ Ève syngeneic hosts. These T cells are not lytic, but they inhibit development of antibody, CD4T helper cell, and CD8 cytotoxic T lymphocyte (CTL) responses upon adoptive transfer into naõ Ève, syngeneic mice. In addition, we have shown that depletion of gd T cells by injection of the anti-d chain antibody (GL3) down modulates the expression of gd T-cell receptor (TCR) and inhibits the induction of oral tolerance to ovalbumin. Oral administration of antigen also fails to induce tolerance in TCR d-chain knockout mice suggesting that gd T cells play a critical, active role in tolerance induced by orally administered antigen. To further study the contribution of gd T cells to tolerance, murine gd T cells were isolated from intraepithelial lymphocytes (IEL) of the small intestine by stimulation with splenic ®ller cells, concanavalin A and growth factors. gd IEL lines demonstrated lytic activity in a redirected lysis assay. gd T-cell clones express different gd TCR genes and secrete large amounts of interleukin (IL)-10, but little or no IL-2, IL-4, or interferong. gd IEL clones expressed transforming growth factor-b1 and macrophage migration inhibitory factor, as well as IL-10, mRNA. Moreover, gd T-cell clones potently inhibited the generation of CTL responses by secreted molecules rather than by direct cell-to-cell contact.
The purpose of these studies is to determine why an immunogenic tumor grows unchecked in the anterior chamber (a.c.) of the eye. The OVA-expressing EL4 tumor, E.G7-OVA, was injected into the a.c. or skin of immunocompetent and immunodeficient mice. Tumor growth and tumor-specific immune responses were monitored. Ocular tumor-infiltrating leukocytes were characterized phenotypically and functionally. Growth of E.G7-OVA was inhibited when limiting numbers of cells were injected in the skin but not in the a.c. of C57BL/6 mice, although both routes primed OVA-specific immune responses, which prevented the growth of a subsequent injection with E.G7-OVA in the skin or opposite eye. Tumor regression was OVA-specific because growth of the parental EL-4 tumor was not inhibited in primed mice. E.G7-OVA growth in the skin was not inhibited in immunodeficient Rag−/− or CD8 T cell-deficient mice, suggesting that CD8+ CTLs mediate tumor elimination. CD8+ T cell numbers were significantly increased in eyes of mice primed with E.G7-OVA, but few were detected in primary ocular tumors. Nevertheless, growth of E.G7-OVA was retarded in the a.c. of TCR-transgenic OT-I mice, and CD8+ T cell numbers were increased within eyes, suggesting that tumor-specific CD8+ CTLs migrated into and controlled primary ocular tumor growth. E.G7-OVA did not lose antigenicity or become immunosuppressive after 13 days of growth in the eye. However, CD11b+ cells accumulated in primary ocular tumors and contained potent immunosuppressive activity when assayed in vitro. Thus, CD11b+ cells that accumulate within the eye as tumors develop in the a.c. may contribute to immune evasion by primary ocular tumors by inhibiting CTLs within the eye.
To characterize mechanisms of CTL inhibition within an ocular tumor microenvironment, tumor-specific CTLs were transferred into mice with tumors developing within the anterior chamber of the eye or skin. Ocular tumors were resistant to CTL transfer therapy whereas skin tumors were sensitive. CTLs infiltrated ocular tumors at higher CTL/tumor ratios than in skin tumors and demonstrated comparable ex vivo effector function to CTLs within skin tumors indicating that ocular tumor progression was not due to decreased CTL accumulation or inhibited CTL function within the eye. CD11b+Gr-1+F4/80− cells predominated within ocular tumors, whereas skin tumors were primarily infiltrated by CD11b+Gr-1−F4/80+ macrophages (Mϕs), suggesting that myeloid derived suppressor cells may contribute to ocular tumor growth. However, CD11b+ myeloid cells isolated from either tumor site suppressed CTL activity in vitro via NO production. Paradoxically, the regression of skin tumors by CTL transfer therapy required NO production by intratumoral Mϕs indicating that NO-producing intratumoral myeloid cells did not suppress the effector phase of CTL. Upon CTL transfer, tumoricidal concentrations of NO were only produced by skin tumor-associated Mϕs though ocular tumor-associated Mϕs demonstrated comparable expression of inducible NO synthase protein suggesting that NO synthase enzymatic activity was compromised within the eye. Correspondingly, in vitro-activated Mϕs limited tumor growth when co-injected with tumor cells in the skin but not in the eye. In conclusion, the decreased capacity of Mϕs to produce NO within the ocular microenvironment limits CTL tumoricidal activity allowing ocular tumors to progress.
We tested the hypothesis that ␥␦ T cells are a component of an early immune response directed against preerythrocytic malaria parasites that are required for the induction of an effector ␣ T-cell immune response generated by irradiated-sporozoite (irr-spz) immunization. ␥␦ T-cell-deficient (TCR␦ ؊/؊ ) mice on a C57BL/6 background were challenged with Plasmodium yoelii (17XNL strain) sporozoites, and then liver parasite burden was measured at 42 h postchallenge. Liver parasite burden was measured by quantification of parasite-specific 18S rRNA in total liver RNA by quantitative-competitive reverse transcription-PCR and by an automated 5 exonuclease PCR. Sporozoite-challenged TCR␦ ؊/؊ mice showed a significant (P < 0.01) increase in liver parasite burden compared to similarly challenged immunocompetent mice. In support of this result, TCR␦ ؊/؊ mice were also found to be more susceptible than immunocompetent mice to a sporozoite challenge when blood-stage parasitemia was used as a readout. A greater percentage of TCR␦ ؊/؊ mice than of immunocompetent mice progressed to a blood-stage infection when challenged with five or fewer sporozoites (odds ratio ؍ 2.35, P ؍ 0.06). TCR␦ ؊/؊ mice receiving a single irr-spz immunization showed percent inhibition of liver parasites comparable to that of immunized immunocompetent mice following a sporozoite challenge. These data support the hypothesis that ␥␦ T cells are a component of early immunity directed against malaria preerythrocytic parasites and suggest that ␥␦ T cells are not required for the induction of an effector ␣ T-cell immune response generated by irr-spz immunization.
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