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Cutaneous leishmaniasis is initiated by the bite of an infected sandfly and inoculation of Leishmania major parasites into the mammalian skin. Macrophages are known to playa central role in the course of infection because they are the prime host cells and funetion as antigen-presenting eells (APC) for induetion of the eell-mediated immune response. However, in addition to maerophages in the dermis. the skin eontains epidermal Langerhans eells (LC) which ean present antigen (Ag) to T cells. Therefore, using a murine model of cutaneous leishmaniasis, we analyzed the ability of epidermal cells to induce a T eell response to L.major. The results demonstrated that freshly isolated LC, but not cuItured LC, are highly active in presenting L.major Ag in vitro to T cells from primed mice and to a L.major-specific T cell clone. Furthermore, freshly isolated LC had the ability to retain L.major Ag in immunogenic form for at least 2 days. Their efficiency was much greater than that of irradiated spleen cells, a standard population of APC. LC stimulated both T cell proliferation and production of the Iymphokines interleukin (IL)-2 and IL-4. The response was Ag specific and could be induced by lysate of L. major parasites and by live organisms. The data suggest that epidermal LC are important APC in eutaneous leishmaniasis. They may perform a critical funetion by eapturing L.major Ag in the skin and presenting it either to quiescent T eells circulating through the draining lymph node or locally to T effector cells infiltrating the cutaneous lesion.
Ten monoclonal antibodies (McAbs) raised to Schistosoma japonicum eggs could be assigned using several serological and immunochemical techniques to 3 groups. The McAbs, termed A, B and C-McAbs, apparently recognize carbohydrate epitopes that can be located on the same antigen molecule. The antibodies, generally of IgM isotype, are idiotypically related. They are distinct from another IgM McAb (Group D-McAb) the carbohydrate target epitope of which can also be associated with the epitopes of A. B and C-McAbs. The McAbs produce large vacuolated bleb reactions in the circumoval precipitin test (COPT) and target epitopes have different representations in various life cycle stages such as immature and mature eggs, male and female worms (including S. mansoni). Antigens affinity purified on columns containing A, B, C and D-McAbs stimulate proliferation of T cells from egg-sensitized mice and elicit DTH reactions in such mice. This raises the possibility that the target antigens of these carbohydrate-reactive monoclonal antibodies are immunopathologic and involved in egg-induced granuloma formation.
Leishmanien besitzen eine Vielzahl von Mechanismen, die humorale und zelluläre Immunabwehr effektiv zu unterlaufen. Diese hängen eng mit der Expression von hauptsächlich zwei Glykokonjugaten auf der Parasitenoberfläche zusammen, dem gp63 und dem Lipophosphoglykan. Die Parasiten sind einerseits schlechte Aktivatoren des alternativen Komplementweges und umgehen damit ihre eigene extrazelluläre Lyse. Oberflächengebundene Komplementfaktoren fördern andererseits die Aufnahme der Leishmanien durch Makrophagen. Solange diese nicht durch T-Zellen aktiviert sind, dienen sie den Parasiten als "Refugium". Dies gilt insbesondere, als Leishmanien in der Lage sind, 1. den "oxidative burst" zu hemmen; 2. toxische Sauerstoffmetaboliten zu entgiften; 3. abbauende lysosomale Enzyme zu hemmen und 4. das saure Milieu in den Lysosomen für ihren eigenen Metabolismus auszunutzen. Schließlich unterlaufen Leishmanien die zelluläre Immunabwehr des Wirts, indem sie die Aktivierung von T-Lymphozyten hemmen und die Expansion von T-Zell-Sub-populationen bewirken, die für ihr eigenes Überleben nützlich sind.
H-Y-specific and H-2Db-restricted, Lyt-1 "2+ T-cell clones (CTLL) with graded specific cytotoxic activities on male C57BL/6 (B6) target cells (1E3, +++; 2C5, ++; 2A5, +, 3E6, ±) were tested for their capacity to inhibit the generation of H-Y-specific cytotoxic T lymphocytes (CTL) in vitro. Addition of irradiated lymphocytes of CTLL 1E3 and CTLL 3E6 but not those of CTLL 2A5 or CTLL 2C5 abolished the generation of CTL from in vivo primed H-Y-specific precursor cells (CTLP) when added to fresh mixed-lymphocyte cultures (MLC). Exogenous sources of T-cell growth factors (TCGF) did not overcome suppression. Rather the presence of TCGF resulted in a further enhancement of suppressive activities in CTLL 1E3 and 3E6 and the induction of similar activities in cells from CTLL 2A5 and 2C5, which by themselves were not inhibitory. Moreover when added to similar MLC on Day 1 instead of Day 0, only irradiated cells of CTLL 3E6 but not those of the other three CTLL were suppressive. Induction of suppressive activities in H-Y-specific CTLL was independent of the appropriate male stimulator cells since it was also observed in MLC induced by irrelevant antigens (H-2, trinitrophenol). Furthermore at low cell numbers, irradiated lymphocytes from any of the CTLL consistently enhanced CTL activities generated from H-Y-specific CTLP. This augmenting activity, which was not TCGF, could be transferred by soluble mediators present in antigen-sensitized CTLL cultures. Thus, these data indicate (i) that cytotoxic effector cells can function as suppressor cells in the generation of CTL, (ii) that the cytotoxic activity of cloned CTL does not correlate with their capacity to suppress CTL responses, (iii) that the inhibition of CTL responses by CTLL is not due to simple consumption of T-cell growth factors produced in MLC, and (iv) that different CTL clones may interfere with the generation of CTL at different stages of their maturation. Moreover, the experiments suggest an antigen-independent enhancement of suppression by the interaction of CTL with lymphokines. Together with the augmenting activity evoked by cloned CTL the data provide strong evidence for the expression of multiple immunological functions by one particular subset of T cells and suggest that cytotoxic effector cells can differentially regulate the maturation and/or clonal expression of their precursor cells.
In this study we report that cloned Thy-l +, L3T4-, Lyt-l-, Lyt-2+, H-Y-specific and H-2Db-restricted cytotoxic T ce11 lines (CTLL) when indueed by lectin or antigen secrete a soluble mediator(s) (SF) that inhibits proliferation and generation of cytotoxic lymphocytes (CTL) in mixed lymphocyte cultures (MLC). The biological activity was separable by gel filtration and appeared as a broad peak in the moleeular mass range between 10000 and 50000 kDa. It was found that the suppressive activity released by CTLL neither strictly correlates with their cytotoxic potential nor with their ability to produce immune interferon or Iymphotoxin. SF was shown to elicitits activity in an antigen-nonspeeific manner in that it suppressed the maturation of T lymphocytes responding to both, the appropriate H-Y antigen as weH as to unrelated H_2d alloantigens or to the hapten 2,4,6-trinitrophenyl (TNP). The effect of SF on CTL responses was most pronounced in early phases of primary or secondary MLC. When analyzed for its inhibitory activity on precursor ceHs in populations selected for either Lyt-2- or L3T4- lymphocytes, it was found that SF interfered with the maturation of both subsets. The inhibition of CTL responses elicited by SF could not be reversed by the addition of exogenous interleukin 2. The findtng that SF also inhi. bited the proliferation of some but not a11 antigen-dependent cloned T ceHs with helper or eytc'toxic potential provides evidence that the faetor also may regulate effector lymphl)cytes. In addition, the results support the assumption that SF exerts its effect direetly on the responder rather than the stimulator population, and demonstrate that the development of CTL from their preeursor eeHs is contro11ed at least in part by the eytotoxic effeetor cells themselves via a soluble factor(s) that interferes with distinct stages of T ce11 maturation. These findings again emphasize the expression of multiple functions by CTL and indieate their possible role du ring the course of an immune response by their capability to eliminate target cells and to secrete a soluble product(s) that mediates feedback contro!.
Abstract
In the murine model of Leishmania major infection, resistance or susceptibility to the parasite has been associated with the development of a Th1 or Th2 type of immune response. Recently, however, the immunosuppressive effects of IL-10 have been ascribed a crucial role in the development of the different clinical correlates of Leishmania infection in humans. Since T cells and professional APC are important cellular sources of IL-10, we compared leishmaniasis disease progression in T cell-specific, macrophage/neutrophil-specific and complete IL-10-deficient C57BL/6 as well as T cell-specific and complete IL-10-deficient BALB/c mice. As early as two weeks after infection of these mice with L. major, T cell-specific and complete IL-10-deficient animals showed significantly increased lesion development accompanied by a markedly elevated secretion of IFN-γ or IFN-γ and IL-4 in the lymph nodes draining the lesions of the C57BL/6 or BALB/c mutants, respectively. In contrast, macrophage/neutrophil-specific IL-10-deficient C57BL/6 mice did not show any altered phenotype. During the further course of disease, the T cell-specific as well as the complete IL-10-deficient BALB/c mice were able to control the infection. Furthermore, a dendritic cell-based vaccination against leishmaniasis efficiently suppresses the early secretion of IL-10, thus contributing to the control of parasite spread. Taken together, IL-10 secretion by T cells has an influence on immune activation early after infection and is sufficient to render BALB/c mice susceptible to an uncontrolled Leishmania major infection.
Author Summary
The clinical symptoms caused by infections with Leishmania parasites range from self-healing cutaneous to uncontrolled visceral disease and depend not only on the parasite species but also on the type of the host's immune response. It is estimated that 350 million people worldwide are at risk, with a global incidence of 1–1.5 million cases of cutaneous and 500,000 cases of visceral leishmaniasis. Murine leishmaniasis is the best-characterized model to elucidate the mechanisms underlying resistance or susceptibility to Leishmania major parasites in vivo. Using T cell-specific and macrophage-specific mutant mice, we demonstrate that abrogating the secretion of the immunosuppressive cytokine IL-10 by T cells is sufficient to render otherwise susceptible mice resistant to an infection with the pathogen. The healing phenotype is accompanied by an elevated specific inflammatory immune response very early after infection. We further show that dendritic cell-based vaccination against leishmaniasis suppresses the early secretion of IL-10 following challenge infection. Thus, our study unravels a molecular mechanism critical for host immune defense, aiding in the development of an effective vaccine against leishmaniasis.
Actinomycetes are prolific producers of pharmacologically important compounds accounting for about 70% of the naturally derived antibiotics that are currently in clinical use. In this study, we report on the isolation of Streptomyces sp. strains from Mediterranean sponges, on their secondary metabolite production and on their screening for anti-infective activities. Bioassay-guided isolation and purification yielded three previously known compounds namely, cyclic depsipeptide valinomycin, indolocarbazole alkaloid staurosporine and butenolide. This is the first report of the isolation of valinomycin from a marine source. These compounds exhibited novel anti-parasitic activities specifically against Leishmania major (valinomycin IC50 < 0.11 μM; staurosporine IC50 5.30 μM) and Trypanosoma brucei brucei (valinomycin IC50 0.0032 μM; staurosporine IC50 0.022 μM; butenolide IC50 31.77 μM). These results underscore the potential of marine actinomycetes to produce bioactive compounds as well as the re-evaluation of previously known compounds for novel anti-infective activities.
Freshly isolated human T lymphocytes were tested for their response to mycobacteria, mycobacteriallysates, 2 dimensional (2D) PAGE separated mycobacteriallysates, leishmania and defined leishmanial antigen preparations. While,o T cells proliferated vigourously in the presence of mycobacteria and mycobacteria derived lysates, a significant stimulation from 2 D gel separated lysates was not detected. In addition '10 T cells failed to respond towards leishmania or leishmanial components. In the ab T cell compartment some donors, presumably according to their state of immunity against mycobacteria, responded to mycobacteria, mycobacterial lysates and 2 D gel separated mycobacterial lysates. Neither freshly isolated '10 T cells nor ab T cells from naive donors did mount a significant immune response against leishmania.