Mechanisms of acquired immunity in leishmaniasis

1984 ◽  
Vol 307 (1131) ◽  
pp. 87-98 ◽  
Keyword(s):  
T Cells ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Donovani ◽  
Inbred Mouse ◽  
Delayed Type Hypersensitivity ◽  
Acquired Immunity ◽  
Cell Mediated Immunity ◽  
Leishmania Tropica ◽  
Specific Suppression ◽  
Heat Stable

Self-curing cutaneous leishmaniasis depends on T cell-mediated immune activation of infected macrophages. Failure of immune control in inbred mouse models of metastasizing mucocutaneous and visceralizing forms of the disease involves, respectively, insusceptibility of the parasite and the generation of T cells that suppress a potentially curative response. Prophylactic immunization in man has so far been restricted to cutaneous leishmaniasis and based on inducing infection under controlled conditions with virulent Leishmania tropica major promastigotes. The feasibility of immunization against visceral leishmaniasis merits reconsideration. BALB/c mice are genetically vulnerable to L. tropica major , which produces a fatal visceralizing type of disease involving specific suppression of cell-mediated immunity. Potent and lasting protection can be induced by repeated intravenous immunization with irradiated promastigotes. The efficacy of this ‘vaccine’ is relatively heat-stable (1 h at 56 °C). Immunity is not attributable to antibody but to the generation of Lyt-1 + 2 - T cells which, although possessing helper and macrophage-activating functions, do not express classical delayed-type hypersensitivity. The immunological features of this system and its relevance to the possibility of protection against human Leishmania donovani infection are considered.

scholarly journals Immunological regulation of experimental cutaneous leishmaniasis. III. Nature and significance of specific suppression of cell-mediated immunity in mice highly susceptible to Leishmania tropica.

1980 ◽  
Vol 152 (3) ◽  
pp. 594-607 ◽  
Author(s):  
J G Howard ◽  
C Hale ◽  
F Y Liew
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Genetic Defect ◽  
Delayed Type Hypersensitivity ◽  
Cell Mediated Immunity ◽  
Leishmania Tropica ◽  
Self Healing ◽  
Cutaneous Lesions ◽  
Cell Mediated Immune Response ◽  
Lesion Growth

BALB/c mice have been an exceptional susceptibility to Leishmania tropica infection such that cutaneous lesions grow without restraint in all cases leading to fatal metastasis and visceralization in normal and x-irradiated, bone-marrow reconstituted (XBM) animals. Adult thymectomized, x-irradiated, bone marrow-reconstituted (ATxXBM) BALB/c mice, however, show pronounced retardation of lesion growth leading to some survival and even cures. A similar trend was also found in moderately susceptible (BALB/c X C57BL/6)F1 mice, in contrast with the "resistant" CBA strain, in which, as previously known, ATxXBM animals showed impairment of normal, spontaneous self-healing. These convere effects are paralleled by respective leishmania-specific delayed-type hypersensitivity (DTH) reactivities, prior thymectomy leading to diminution in CBA and augmentation in BALB/c and (BALB/c X C57BL/6)F1. Anti-leishmanial DTH responses, amplfiable by cyclophosphamide pretreatment, can be detected in BALB/c mice within 10 d of infection with 2 X 10(7) promastigotes, but becomes near-totally suppressed by day 25-35. No such suppressin is found in CBA, C57BL/6, or (BALB/c X C57BL/6)F1 mice together with varying degrees of immune control of lesion development or regression. Suppression of DTH in BALB/c mice is leishmania specific and does not extent to 2,4-dinitrofluorobenzene (DNFB) or sheep erythrocytes specificities. Spleen cells from suppressed L. tropica-infected mice when transferred to normal BALB/c mice impaired the induction of DTH to leishmanial antigen. This property resided in the T cell-enriched fraction and not in the T cell-depleted fraction. It is concluded that a major component of the striking inability of BALB/c mice to control L. tropica infection involves profound impairment of a potentially curative cell-mediated immune response by suppressor T cell generation. The possibility is discussed that this may be secondary to rapid amastigote (antigen) accumulation in macrophages expressing the primary genetic "defect."

scholarly journals PDL-1 Blockade Prevents T Cell Exhaustion, Inhibits Autophagy, and Promotes Clearance of Leishmania donovani

2018 ◽  
Vol 86 (6) ◽  
Author(s):  
Samar Habib ◽  
Abdeljabar El Andaloussi ◽  
Khaled Elmasry ◽  
Aya Handoussa ◽  
Manar Azab ◽  
...  
Keyword(s):  
T Cells ◽  
Protective Immunity ◽  
Leishmania Donovani ◽  
Parasite Burden ◽  
Parasite Clearance ◽  
Interleukin 10 ◽  
Cell Mediated Immunity ◽  
Th1 Cell ◽  
Content Type

ABSTRACT Leishmania donovani is a causative pathogen of potentially fatal visceral leishmaniasis (VL). Therapeutic agents are available; however, their use is limited because of high cost, serious side effects, and development of antimicrobial resistance. Protective immunity against VL depends on CD4 + Th1 cell-mediated immunity. Studies have shown that progression of VL is due to exhaustion of T cells; however, the mechanism involved is not clearly understood. Here, we examined the role of PD1/PDL-1 in the pathogenesis of VL by using a murine model of VL. Our data indicate that L. donovani is able to elicit initial expansion of gamma interferon-producing CD4 + Th1 and CD8 + T cells at day 7 postinfection (p.i.); however, the frequency of those cells and inflammatory response decreased at day 21 p.i., despite persistence of parasites. Persistent infection-induced expansion of interleukin-10 + FOXP3 + Treg and CD4 + and CD8 + T cells expressing PD1. Blocking of PDL-1 signaling in vivo resulted in restoration of protective type 1 responses by both CD4 + and CD8 + T cells, which resulted in a significant decrease in the parasite burden. Mechanistically, PDL-1 blocking inhibited autophagy, a cellular degradation process hijacked by Leishmania to acquire host cell nutrients for their survival. Inhibition of autophagy was marked by decreased lipidation of microtubule-associated protein 1 light chain 3, a marker of autophagosome formation, and P62 accumulation. Together, our findings show for the first time that anti-PDL-1 antibody is an effective therapeutic approach for restoration of effector arms of protective immunity against VL and subsequent parasite clearance.

scholarly journals Tolerance to parenchymal self. Regulatory role of major histocompatibility complex-restricted, OX8+ suppressor T cells specific for autologous renal tubular antigen in experimental interstitial nephritis.

1985 ◽  
Vol 162 (6) ◽  
pp. 1892-1903 ◽  
Author(s):  
C J Kelly ◽  
W K Silvers ◽  
E G Neilson
Keyword(s):  
T Cells ◽  
Interstitial Nephritis ◽  
Clonal Expansion ◽  
Delayed Type Hypersensitivity ◽  
Cell Mediated Immunity ◽  
Suppressor T Cells ◽  
Rat Strains ◽  
Histocompatibility Complex ◽  
Renal Tubular

BN rats develop interstitial nephritis after immunization with rabbit, but not rat renal tubular antigen. Using RT1n rat strains that differentially express tubular antigen, we investigated the unresponsiveness of BN rats to BN tubular antigen (BN-TBM) using delayed-type hypersensitivity (DTH) responses to BN-TBM as a measure of cell-mediated immunity. Our results indicate that rat strains expressing tubular antigen respond to immunization with BN-TBM with the clonal expansion of antigen-specific, cyclophosphamide-sensitive, OX8+, MHC-restricted suppressor T cells. Such suppression appears to be relevant to the maintenance of tolerance to parenchymal self, since chronic cyclophosphamide therapy abrogates suppression and results in significant interstitial nephritis.

scholarly journals Evidence for mouse Th1- and Th2-like helper T cells in vivo. Selective reduction of Th1-like cells after total lymphoid irradiation.

1989 ◽  
Vol 170 (5) ◽  
pp. 1495-1511 ◽  
Author(s):  
H Bass ◽  
T Mosmann ◽  
S Strober
Keyword(s):  
T Cells ◽  
Selective Reduction ◽  
Adoptive Cell Transfer ◽  
Delayed Type Hypersensitivity ◽  
Cell Mediated Immunity ◽  
Spleen Cells ◽  
Total Lymphoid Irradiation ◽  
Early Return ◽  
Th1 And Th2

Purified CD4+ BALB/c spleen T cells obtained 4-6 wk after total lymphoid irradiation (TLI) helped normal syngeneic B cells to produce a vigorous antibody response to TNP keyhole limpet hemocyanin in adoptive cell transfer experiments. However, the same cells failed to transfer delayed-type hypersensitivity to the adoptive hosts as measured by a foot pad swelling assay. In addition, purified CD4+ cells from TLI-treated mice were unable to induce graft vs. host disease in lethally irradiated allogeneic C57BL/Ka recipient mice. In response to mitogen stimulation, unfractionated spleen cells obtained from TLI mice secreted normal levels of IL-4 and IL-5, but markedly reduced levels of IL-2 and INF-gamma. A total of 229 CD4+ clones from spleen cells of both normal and TLI-treated mice were established, and the cytokine secretion pattern from each clone was analyzed. The results demonstrate that the ratio of Th1- and Th2-like clones in the spleens of normal BALB/c mice is 1:0.6, whereas the ratio in TLI mice is approximately 1:7. These results suggest that Th2-like cells recover rapidly (at approximately 4-6 wk) after TLI treatment and account for the early return of antibody helper activity and secretion of IL-4 and IL-5, but Th1-like cells recover more slowly (in approximately 3 mo) after irradiation, and this accounts for the deficit in cell-mediated immunity and the reduced amount of IL-2 and IFN-gamma secretion.

scholarly journals POTENTIATION OF T-CELL-MEDIATED IMMUNITY BY SELECTIVE SUPPRESSION OF ANTIBODY FORMATION WITH CYCLOPHOSPHAMIDE

1974 ◽  
Vol 139 (6) ◽  
pp. 1529-1539 ◽  
Author(s):  
P. H. Lagrange ◽  
G. B. Mackaness ◽  
T. E. Miller
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antibody Formation ◽  
Specific Antigen ◽  
Cell Activity ◽  
Antigenic Stimulation ◽  
Delayed Type Hypersensitivity ◽  
Cell Mediated Immunity ◽  
Inhibitory Influence ◽  
Resting Cells

Delayed-type hypersensitivity (DTH) appears in mice immunized with less than an optimal immunogenic dose of sheep red blood cells (SRBC), but is blocked progressively as antibody production increases in response to larger doses of SRBC. Treatment with cyclophosphamide (CY) was shown to release T cells from this inhibitory influence of the humoral response, and cause enhancement of DTH. The magnitude of this enhancing effect on T-cell activity was markedly dependent on the time of treatment relative to the time of immunization, and on the time chosen for measuring DTH. The reasons for these pronounced effects of timing are threefold: (a) CY given before antigenic stimulation has a long-lasting effect on antibody formation, but no apparent effect on the precursors of activated T cells. (b) After antigenic stimulation, T cells also become susceptible to CY. (c) The production of a nonspecific participant (monocyte) in the DTH reaction is also suppressed by CY, though the supply of circulating monocytes is not immediately affected by the drug. The differential effect of CY on T and B lymphocytes depends on the differing physiological states of the majority of cells that make up these two populations. The former are resting cells that are insensitive to CY until exposed to specific antigen, while the latter are drawn from a rapidly replicating precursor pool and are susceptible to CY at all times.

The Role of Acquired Immunity and Periodontal Disease Progression

2003 ◽  
Vol 14 (4) ◽  
pp. 237-252 ◽  
Author(s):  
Yen-Tung A. Teng
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Periodontal Disease ◽  
Disease Progression ◽  
Periodontal Diseases ◽  
Delayed Type Hypersensitivity ◽  
Secretory Iga ◽  
Cell Mediated Immunity ◽  
Recent Advances

Our understanding of the pathogenesis in human periodontal diseases is limited by the lack of specific and sensitive tools or models to study the complex microbial challenges and their interactions with the host’s immune system. Recent advances in cellular and molecular biology research have demonstrated the importance of the acquired immune system not only in fighting the virulent periodontal pathogens but also in protecting the host from developing further devastating conditions in periodontal infections. The use of genetic knockout and immunodeficient mouse strains has shown that the acquired immune response—in particular, CD4+ T-cells—plays a pivotal role in controlling the ongoing infection, the immune/inflammatory responses, and the subsequent host’s tissue destruction. In particular, studies of the pathogen-specific CD4+ T-cell-mediated immunity have clarified the roles of: (i) the relative diverse immune repertoire involved in periodontal pathogenesis, (ii) the contribution of pathogen-associated Th1-Th2 cytokine expressions in periodontal disease progression, and (iii) micro-organism-triggered periodontal CD4+ T-cell-mediated osteoclastogenic factor, ‘RANK-L’, which is linked to the induction of alveolar bone destruction in situ. The present review will focus on some recent advances in the acquired immune responses involving B-cells, CD8+ T-cells, and CD4+ T-cells in the context of periodontal disease progression. New approaches will further facilitate our understanding of their underlying molecular mechanisms that may lead to the development of new treatment modalities for periodontal diseases and their associated complications. Abbreviations used in the paper are as follows: Antibody, Ab; antigen, Ag; antigen-presenting cells, APC; Actinobacillus actinomycetemcomitans, A. actinomycetemcomitans or Aa; β2-microglobulin, β2m; cytotoxic CD8+ αβ T-lymphocytes, CTL; dendritic cells, DC; delayed-type hypersensitivity, DTH; immunoglobulin, Ig; Fc receptor, Fc-R; interferon-γ, IFN-γ; receptor activator of NF-κB ligand, RANK-L; molecular weight, MW; Porphyromonas gingivalis, P. gingivalis or Pg; localized juvenile periodontitis, LJP; lipopolysaccharide, LPS; mouse mammalian tumor virus, MMTV; non-obese diabetic and severe combined immunodeficiency mice, NOD/SCID mice; osteoclast, OC; T-helper cells, Th; superantigen, SAg; transforming growth factor-β, TGF-β; secretory-IgA, s-IgA; T-cell receptor, TCR; T cytotoxic-1 cells, Tc1; and T cytotoxic-2 cells, Tc2.

scholarly journals Impaired Th1 Response Is Associated With Therapeutic Failure in Patients With Cutaneous Leishmaniasis Caused by Leishmania braziliensis

2020 ◽  
Author(s):  
Augusto M Carvalho ◽  
Luiz H Guimarães ◽  
Rúbia Costa ◽  
Maíra G Saldanha ◽  
Iana Prates ◽  
...  
Keyword(s):  
T Cells ◽  
Cutaneous Leishmaniasis ◽  
Cd8 T Cells ◽  
Clinical Presentation ◽  
Granzyme B ◽  
Therapeutic Failure ◽  
Response To Therapy ◽  
Delayed Type Hypersensitivity ◽  
Leishmania Braziliensis ◽  
Th1 Response

Abstract Background Leishmania skin test (LST) evaluates the delayed type hypersensitivity to Leishmania antigens (LA) and has been used for diagnosis of cutaneous leishmaniasis (CL). In CL patients LST is usually positive but a small percentage have negative LST. The aim of this study was to determine the clinical and immunologic features and response to antimony therapy in LST-negative CL patients. Methods We compare the clinical presentation, response to therapy, and immune response of CL patients with negative vs positive LST. Results The clinical presentation was similar in both groups but LST-negative patients had a lower cure rate. In the lesions, LST-negative patients displayed less inflammation and necrosis, and higher frequency of CD8+ T cells. Mononuclear cells from LST-negative patients had a poor T helper 1 cell (Th1) response but levels of interleukin-1β (IL-1β), IL-6, IL-17, granzyme B, and metalloproteinase-9 (MMP-9) were similar to the LST-positive group upon stimulation with LA. Leishmania internalization and killing by macrophages were similar in both groups. Cure of disease was associated with restoration of Th1 response. Conclusions In LST-negative patients, impaired Th1 response is associated with therapeutic failure. Increased frequency of CD8+ T cells and high production of inflammatory cytokines, granzyme B, and MMP-9 contributes to immunopathology.

scholarly journals RESTORATION OF CELL-MEDIATED IMMUNITY TO ANIMALS BLOCKED BY A HUMORAL RESPONSE

1974 ◽  
Vol 140 (3) ◽  
pp. 865-870 ◽  
Author(s):  
George B. MacKaness ◽  
Philippe H. Lagrange
Keyword(s):  
T Cells ◽  
Antibody Response ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Humoral Response ◽  
Delayed Type Hypersensitivity ◽  
Cell Mediated Immunity ◽  
Continuous Exposure ◽  
Long Period ◽  
Blocking Factors

The T cells which mediate delayed-type hypersensitivity (DTH) to sheep red blood cells (SRBC) are blocked by a normal humoral response and cannot be made to function by further immunization. They can be rescued to some extent by treatment with immunopotentiating agents such as cyclophosphamide (CY) which suppresses the antibody response selectively, or by BCG which interferes with the action of serum blocking factors. These two agents together can restore cell-mediated immunity completely, but a further antigenic stimulus is needed to reestablish DTH in mice blocked by a long period of continuous exposure to SRBC.

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