Susceptibility to Infectious Diseases: Leishmania as a Paradigm (original) (raw)
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Experimental Parasitology, 2009
Anti mony resis tance is fre quently encoun tered dur ing treat ment of vis ceral leish man i a sis (VL) and the dif ferences are well char ac ter ized by inad e quate IFN-c dom i nant type-1 pro tec tion mech a nisms. The part played by Leish mania par a sites derived from anti mony treated patients in the out come of an immune response largely remains to be inves ti gated. In the pres ent study we observed that mac ro phages of BALB/c mice infected with anti mony non-responder (SAG-NR) iso lates had a greater amas ti gote bur den than anti mony responder (SAG-R) iso lates. Later it was observed that anti gen from SAG-NR and R L. dono van i iso lates elicit dif fer ent cyto kine responses in per i to neal blood mono nu clear cells (PBMCs) from patients with VL. The pro duc tion of IFN-c by T-cells in VL patients increased in response to Leish mania derived from responder patients but this response within same T-cells was lower when sen si tized from Leish mania from a non-responder VL patient. On the other hand, IL-4 and IL-10 expres sion was increased when primed with par a sites from non-responder VL source. Such a dif fer en tial pattern of cyto kine expres sion by the same T-cell pop u la tion pro duced to Leishmania from dif fer ent donors, needs fur ther explo ra tion.
Cd4+ T cell response to leishmania spp. in non-infected individuals
Human Immunology, 2000
T cell mediated immunity is known to play a central role in the host response to control intra-cellular pathogens. This work demonstrates the presence of specific CD4(+) T cells to Leishmania spp. antigens in peripheral mononuclear cells of naïve individuals (normal volunteers from non-endemic regions). The responder population was expanded by generation of antigen-specific T cell lines, which were produced by repeated stimulation with fixed promastigotes and autologous irradiated PBMC as antigen presenting cells. The leishmania-T cell lines were shown to proliferate in response to different species of the parasite (L. amazonensis, L. braziliensis, and L. donovani), but not to other recall antigens such as Candida albicans or tetanus toxoid. A preferential expansion of IFNgamma and IL-2 producing Th1-like T cells was observed. The leishmania-reactive cells were distributed between CD4(+) CD45RA(+) ("naïve") and CD4(+) CD45R0(+) ("memory") populations. Although limiting dilution analysis showed a precursor frequency 3 times lower within the naïve compartment, similar numbers of T cell lines were derived from both purified subpopulations. This study using leishmania-specific CD4(+) T cell lines produced from normal individuals should provide information on cellular immune responses that are triggered by the parasite and how infection impacts the naïve T cell repertoire.
Analysis of T helper cell responses during infection with Leishmania amazonensis
The American Journal of Tropical Medicine and Hygiene, 2002
Most inbred strains of mice are susceptible to Leishmania amazonensis infection and develop progressive cutaneous lesions. However, the role of Th subsets in the disease and the molecular basis of pathogenesis are unclear. To address this issue, we examined the frequency of cytokine-producing CD4 + T cells and the profile of ␣ T cell receptor (TCR) usage in infected BALB/c mice. At different infection stages, CD4 + cells of draining lymph nodes contained comparable frequencies of Th1 and Th2 cells, produced comparable levels of interleukin-4 (IL-4) and interferon-␥ in vitro, and showed no significant bias in ␣TCR usage. However, T cells became highly polarized to a Th2 phenotype (IL-4 + , IL-10 +) within a few cycles of in vitro restimulation. These Th2 cells preferentially expressed V␣2, V4, or V8.1/8.2, and significantly exacerbated disease in cell-transferred mice. Thus, unlike a Th2-dominant phenotype seen in L. major infection, a mixed Th1/Th2 response can be maintained in L. amazonensis-infected mice via an as-yet-unidentified mechanism.
Genes and Immunity, 2004
Severity of disease caused by Leishmania major depends on the genetics of the host. Early induction of T helper cell type 1 (Th1)-type responses in resistant C57BL/6 mice and T helper cell type 2 (Th2) in susceptible BALB/c mice is thought to determine cure or disease respectively. We have mapped three loci that confer susceptibility or resistance upon congenic mice on the C57BL/6 or BALB/c backgrounds. Here we examine the histopathology and production of interleukin 4 (IL-4) and interferon gamma (IFN-g) in the skin and draining lymph nodes in the congenic and parental mice. We show an evolving granuloma with a staged infiltration of inflammatory cells, but no difference between the groups. As an indication of an earlypolarised Th1/Th2 response we measured IFN-g and IL-4 in the lymph nodes and found no difference between any of the mice during the first 48 h. During infection, the level of IL-4 correlated with the lesion size, indicating that IL-4 reflects the disease severity rather than controls it. Considering this effect, B6.C(lmr1,lmr2) mice had similar cytokine levels to the parental C57BL/ 6 mice despite increased susceptibility and C.B6(lmr1,lmr2) were similar to BALB/c despite increased resistance. We conclude that the lmr loci affect disease severity by a mechanism independent of conventional helper T-cell responses.
Immunological factors governing resistance and susceptibility of mice to Leishmania major infection
Revista latinoamericana de microbiología
Infection with Leishmania sp. is particularly suitable for the study of immunoregulatory mechanisms associated with host susceptibility or resistance. The clinical spectrum of this infection results from parasite virulence factors and host immune responses, some of which acting in a host protective manner while others exacerbate the disease. In the mouse model, factors governing resistance to Leishmania major infection mainly depends on the IFN-gamma activation of the leishmanicidal function of macrophages, and the Fas/ FasL-dependent T-cell cytotoxicity against infected macrophages. On the other hand, the immunological factors of susceptibility involve: I) the early upregulation of IL-4 production induced by the LACK antigen, II) the upregulation of IL-2 production, III) the high production of TGF-beta as macrophage deactivating factor, and IV) the production of IL-10 by the L. major infected macrophages, inhibited their microbicidal activity.
Role of CD4+ T cells in pathogenesis associated with Leishmania amazonensis infection
Journal of immunology (Baltimore, Md. : 1950), 1997
Most inbred strains of mice are susceptible to Leishmania amazonensis infection. We have examined the mechanism(s) underlying this generalized susceptibility using mice deficient in T cell development or in the expression of either MHC class I or class II. In contrast to wild-type C57BL/6 (B6) mice that uniformly developed large ulcerating lesions, mice lacking functional CD4+ T cells (due to targeted disruption of genes for either MHC class II trans-activator or I-A beta) showed no signs of lesion development for up to 12 to 14 wk postinfection and contained significantly lower numbers of parasites in lesions. Similarly, both B6 nude and RAG2 -/- mice failed to develop lesions. However, RAG2 -/- mice reconstituted with naive wild-type CD4+ T cells and beta2m -/- mice did develop lesions. Lesions of MHC class II -/- mice contained minimal numbers of CD8+ T cells, a marked reduction of monocytes/macrophages, and evident extracellular parasites. The inability to mount an inflammatory ...
Cytokines in Leishmaniasis: A Complex Network of Stimulatory and Inhibitory Interactions
Immunobiology, 1993
The work of immunologists, cell biologists and parasitologists in the field of leishmaniasis has not only provided important insights into the immunopathogenesis of this disease, but also yielded fundamental contributions to our understanding of basic immunological phenomena and of host-parasite interactions. The ability of recombinant interferon-y to induce the microbicidal activity of phagocytes and the opposite effect of inhibitory cytokines was first demonstrated with Leishmania-infected macrophages. The selective development of protective and disease-mediating CD4+ T lymphocytes as well as their differential influence on the course of the disease has been long investigated in the murine Leishmania major model and now represents one of the best examples for the in vivo induction of type 1 versus type 2 T helper lymphocytes. At the same time, this model has also been extensively used for immunization studies and cytokine therapy, which shed light on the functions of cytokines in vivo as well as on the mechanism(s) of disease resistance and susceptibility. In this review we will discuss the present picture of the cytokine network in murine L. major infections. Abbreviations: APC = antigen-presenting cell; ASF = activation suppression factor; CGRP = calcitonin-gene related peptide; GM-CSF = granulocyte macrophage colonystimulating factor; gp 63 = 63 kDa surface glycoprotein of Leishmania; lFN = interferon; IL = interleukin; iNOS = inducible nitric oxide synthase; LC = Langerhans cells; L. major = Leishmania major; L-NMMA = N G monomethyl-L-arginine; LPG = lipophosphoglycan; LPS = bacterial lipopolysaccharide; mAb = monoclonal antibody; MDF = macrophage-deactivating factor; NK cells = natural killer cells; NO = nitric oxide; RNl = reactive nitrogen intermediates; ROl = reactive oxygen intermediates; scid = severe combined immunodeficiency; sIL-4R = soluble IL-4 receptor; SLA = soluble leishmanial antigen; TCR = T cell receptor; Tho (ThI, Th2) = type 0 (type 1, type 2) T helper cells; TNF-a = tumor necrosis factor-a fected BALB/c mice into protected normal or nude BALB/c mice (34, 40, 42) (R, E) • transfer of CD4+ T cells from s.c. immunized BALBI c mice into naive BALB/c mice (48) (E)
Clinical and Experimental Immunology, 2004
SUMMARY Regulation of the immune response directed against Leishmania is critical for the establishment of effective control of the disease. It is likely that some types of immune responses directed against Leishmania can lead to more severe clinical forms of leishmaniasis causing a poor control of the pathogen and/or pathology, while others lead to resolution of the infection with little pathology as in cutaneous leishmaniasis. To gain a better understanding of the possible role that subpopulations of T cells, and their associated cytokines have on disease progression and/or protective immune responses to L. braziliensis infection, a detailed study of the frequency of activated and memory T cells, as well as antigen specific, cytokine producing T cells was carried out. Following the determination of cytokine producing mononuclear cell populations in response to total Leishmania antigen (SLA), and to the recombinant antigen LACK, correlation analysis were performed between specific ...