lactoferrin and Granuloma

There is great need for a therapeutic that would limit tuberculosis related pathology and thus curtail spread of disease between individuals by establishing a "firebreak" to slow transmission. A promising avenue to increase current therapeutic efficacy may be through incorporation of adjunct components that slow or stop development of aggressive destructive pulmonary pathology. Lactoferrin, an iron-binding glycoprotein found in mucosal secretions and granules of neutrophils, is just such a potential adjunct therapeutic agent. The focus of this review is to explore the utility of lactoferrin to serve as a therapeutic tool to investigate "disruption" of the mycobacterial granuloma. Proposed concepts for mechanisms underlying lactoferrin efficacy to control immunopathology are supported by data generated based on in vivo models using nonpathogenic trehalose 6,6'-dimycolate (TDM, cord factor).

Topics: Animals; Cord Factors; Granuloma; Humans; Lactoferrin; Mice; Tuberculosis

Infection with Mycobacterium tuberculosis (Mtb) results in the primary formation of a densely packed inflammatory foci that limits entry of therapeutic agents into pulmonary sites where organisms reside. No current therapeutic regimens exist that modulate host immune responses to permit increased drug penetration to regions of pathological damage during tuberculosis disease. Lactoferrin is a natural iron-binding protein previously demonstrated to modulate inflammation and granuloma cohesiveness, while maintaining control of pathogenic burden. Studies were designed to examine recombinant human lactoferrin (rHLF) to modulate histological progression of Mtb-induced pathology in a non-necrotic model using C57Bl/6 mice. The rHLF was oral administered at times corresponding to initiation of primary granulomatous response, or during granuloma maintenance. Treatment with rHLF demonstrated significant reduction in size of primary inflammatory foci following Mtb challenge, and permitted penetration of ofloxacin fluoroquinolone therapeutic to sites of pathological disruption where activated (foamy) macrophages reside. Increased drug penetration was accompanied by retention of endothelial cell integrity. Immunohistochemistry revealed altered patterns of M1-like and M2-like phenotypic cell localization post infectious challenge, with increased presence of M2-like markers found evenly distributed throughout regions of pulmonary inflammatory foci in rHLF-treated mice.

Topics: Animals; Fluoroquinolones; Granuloma; Humans; Inflammation; Lactoferrin; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis

Primary infection with

Topics: Animals; Cord Factors; Female; Fluoroquinolones; Granuloma; Humans; Inflammation; Lactoferrin; Mice; Mice, Inbred C57BL; Mycobacterium; Recombinant Proteins

Trehalose 6'6-dimycolate (TDM) is the most abundant glycolipid on the cell wall of Mycobacterium tuberculosis (MTB). TDM is capable of inducing granulomatous pathology in mouse models that resembles those induced by MTB infection. Using the acute TDM model, this work investigates the effect of recombinant human and mouse lactoferrin to reduce granulomatous pathology. C57BL/6 mice were injected intravenously with TDM at a dose of 25 μg·mouse

Topics: Administration, Oral; Animals; Cord Factors; Cytokines; Female; Granuloma; Humans; Lactoferrin; Lung Diseases; Macrophages; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Recombinant Proteins; Tuberculosis

Differentiation of tuberculous granuloma (TG) from non-tuberculous granuloma (NG) is histopathologically difficult. We evaluated the usefulness of selected immunohistochemical markers to differentiate tuberculous granuloma (TG) and non-tuberculous granuloma (NG). We selected six biomarkers (FoxP3, TNF-beta, E-selectin [ESEL], indoleamine 2,3-dioxygenase [IDO], lactoferrin [LACT], and tartrate-resistant acid phosphatase [TRAP]) and immunohistochemically analyzed their expression in the presence of two types of granulomatous tissue samples, TG (n = 36) and NG (n = 31), using a microarray format. Three of those six biomarkers (LACT, IDO, and TNF-beta) were moderately accurate in discriminating TG from NG, individually and in combination, according to ROC analysis (AUC = 0.7-0.89, sensitivity = 55.6-77.8%, specificity = 71.0-100%). Our data indicate that selected immunohistochemical markers (LACT, IDO, and TNF-beta) can be used in ancillary tests to differentiate TG from NG in tissue samples. Further large-scale studies are required to validate our results.

Topics: Adolescent; Adult; Aged; Area Under Curve; Biomarkers; Child, Preschool; Diagnosis, Differential; Feasibility Studies; Female; Fixatives; Formaldehyde; Granuloma; Humans; Immunohistochemistry; Indoleamine-Pyrrole 2,3,-Dioxygenase; Lactoferrin; Lymphotoxin-alpha; Male; Middle Aged; Paraffin Embedding; Predictive Value of Tests; Retrospective Studies; ROC Curve; Tissue Array Analysis; Tissue Fixation; Tuberculosis; Young Adult

The immune system responds to tuberculosis (TB) infection by forming granulomas. However, subsequent immune-mediated destruction of lung tissue is a cause of significant morbidity and contributes to disease transmission. Lactoferrin, an iron-binding glycoprotein, has demonstrated immunomodulatory properties that decrease tissue destruction and promote T(H)1 immune responses, both of which are essential for controlling TB infection. The cord factor trehalose 6,6'-dimycolate (TDM) model of granuloma formation mimics many aspects of TB infection with a similar histopathology accompanied by proinflammatory cytokine production. C57BL/6 mice were injected intravenously with TDM. A subset of mice was given 1 mg of bovine lactoferrin 24 h post-TDM challenge. Lung tissue was analyzed for histological response and for the production of proinflammatory mediators. C57BL/6 mice demonstrated a granuloma formation that correlated with an increased production of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α,) IL-12p40, interferon-gamma (IFN-γ), and IL-10 protein. Mice treated with lactoferrin postchallenge had significantly fewer and smaller granulomas compared with those given TDM alone. Proinflammatory and T(H)1 cytokines essential to the control of mycobacterial infections, such as TNF-α and IFN-γ, were not significantly different in mice treated with lactoferrin. Furthermore, the anti-inflammatory cytokines IL-10 and transforming growth factor-β were increased. A potential mechanism for decreased tissue damage observed in the lactoferrin-treated mice is proposed. Because of its influence to modulate immune responses, lactoferrin may be a useful adjunct in the treatment of granulomatous inflammation occurring during mycobacterial infection.

Topics: Animals; Cord Factors; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Granuloma; Interleukin-10; Lactoferrin; Lung; Lung Diseases; Macrophages; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Protein Biosynthesis; Transforming Growth Factor beta; Tuberculosis

Immunohistochemical examination of iron-binding proteins was carried out in the formalin-fixed mesenteric lymph nodes of normal cattle and of cattle with paratuberculosis. Ferritin (FT) and lactoferrin (LF) were found in the granulomas in ileal lymph nodes from six infected cattle. A weak reaction for transferrin (TF) was found in granulomas of a lymph node from one of the infected cattle. FT was found in the macrophages in the medullary sinuses of normal and infected nodes; however, the reaction in infected nodes was generally stronger than that in normal ones. LF in the macrophages was found in only two infected nodes. Neutrophils in both normal and infected cattle always reacted strongly for LF. The TF was always found in the blood vessels and intracellular space. These results suggest that: (1) FT and LF may be important in vivo sources of iron for Mycobacterium paratuberculosis, since their own iron-binding compounds are considered to acquire iron from FT and LF in vitro; (2) the increase in FT and LF in the granulomas may be related to inflammatory hyposideraemia associated with paratuberculosis and (3) epithelioid and giant cells may have a different iron metabolism, from normal macrophages.

Topics: Animals; Carrier Proteins; Cattle; Cattle Diseases; Ferritins; Granuloma; Immunohistochemistry; Iron-Binding Proteins; Lactoferrin; Lymph Nodes; Lymphadenitis; Paratuberculosis; Tissue Distribution; Transferrin; Transferrin-Binding Proteins

Granulomatous lesions of bovine paratuberculosis contained ferritin, lactoferrin, and a small amount of transferrin, as demonstrated by the immunohistochemical method. Macrophages in the normal bovine ileum did not contain lactoferrin and transferrin; however, ferritin was found in individual macrophages of Peyer's patches. These results may help elucidate the relationship between intracellular growth of Mycobacterium paratuberculosis and the presence of iron-binding proteins in the granulomas.

Topics: Animals; Cattle; Cattle Diseases; Ferric Compounds; Ferritins; Granuloma; Immunochemistry; Lactoferrin; Lactoglobulins; Paratuberculosis; Transferrin