Stimulating effect of tuftsin and its analogues on the defective monocyte chemotaxis in systemic lupus erythematosus

Lukács, Katalin; Szabó, Gyöngyi; Sonkoly, I; Vegh, Eva; Gács, János; Szekerke, M.; Szegedi, Gyula

doi:10.1016/0162-3109(84)90034-1

Cited by 18 publications

(10 citation statements)

References 15 publications

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“…This peptide activates several components of the immune system, including granulocytes and macrophages [22]. Tuftsin derivatives also stimulates phagocytosis and cell migration [23], human tuftsin and its analogues have a chemotactic effect on monocytes [24,25].…”

Section: Introductionmentioning

confidence: 99%

In vitro biological evaluation of new antimycobacterial salicylanilide-tuftsin conjugates

Baranyai

Krátký

Vosátka

et al. 2017

European Journal of Medicinal Chemistry

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Tuberculosis is caused by Mycobacterium tuberculosis, an intracellular pathogen that can survive in host cells, mainly in macrophages. An increase of multidrug-resistant tuberculosis qualifies this infectious disease as a major public health problem worldwide. The cellular uptake of the antimycobacterial agents by infected host cells is limited. Our approach is to enhance the cellular uptake of the antituberculars by target cell-directed delivery using drug-peptide conjugates to achieve an increased intracellular efficacy. In this study, salicylanilide derivatives (2-hydroxy-N-phenylbenzamides) with remarkable antimycobacterial activity were conjugated to macrophage receptor specific tuftsin based peptide carriers through oxime bond directly or by insertion of a GFLG tetrapeptide spacer. We have found that the in vitro antimycobacterial activity of the salicylanilides against M. tuberculosis HRv is preserved in the conjugates. While the free drug was ineffective on infected macrophage model, the conjugates were active against the intracellular bacteria. The fluorescently labelled peptide carriers that were modified with different fatty acid side chains showed outstanding cellular uptake rate to the macrophage model cells. The conjugation of the salicylanilides to tuftsin based carriers reduced or abolished the in vitro cytostatic activity of the free drugs with the exception of the palmitoylated conjugates. The conjugates degraded in the presence of rat liver lysosomal homogenate leading to the formation of an oxime bond-linked salicylanilide-amino acid fragment as the smallest active metabolite.

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Section: Introductionmentioning

confidence: 99%

In vitro biological evaluation of new antimycobacterial salicylanilide-tuftsin conjugates

Baranyai

Krátký

Vosátka

et al. 2017

European Journal of Medicinal Chemistry

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“…While the mechanism of action of TPC has not yet been elucidated fully, tuftsin or tuftsin-like peptides have been shown to exert immune-stimulatory effects such as phagocytosis and cell migration [11,[28][29][30]. In addition, it has been well established that helminth infections induce an immune response that shifts the host system towards T helper type 2 (Th2)-like phenotype.…”

Section: Discussionmentioning

confidence: 99%

Tuftsin–phosphorylcholine (TPC) equally effective to methylprednisolone in ameliorating lupus nephritis in a mice model

Shemer

Kivity

Shovman

et al. 2018

Clinical and Experimental Immunology

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The role of helminth treatment in autoimmune diseases is growing constantly. Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with challenging treatment options. Tuftsin-phosphorylcholine (TPC) is a novel helminth-based compound that modulates the host immune network. This study was conducted to evaluate the potential value of TPC in ameliorating lupus nephritis in a murine model and specifically to compare the efficacy of TPC to the existing first-line therapy for SLE: corticosteroids (methylprednisolone). Lupus-prone NZBxW/F mice were treated with TPC (5 µg/mouse), methylprednisolone (MP; 5 mg/body weight) or phosphate-buffered saline (PBS) (control) three times per week once glomerulonephritis, defined as proteinuria of grade > 100 mg/dl, was established. Levels of anti-dsDNA autoantibodies were evaluated by enzyme-linked immunosorbent assay (ELISA), splenic cytokines were measured in vitro and the kidney microscopy was analysed following staining. TPC and MP treatments improved lupus nephritis significantly and prolonged survival in NZBxW/F mice. TPC-treated mice showed a significantly decreased level of proteinuria (P < 0·001) and anti-dsDNA antibodies (P < 0·001) compared to PBS-treated mice. Moreover, TPC and MP inhibited the production of the proinflammatory cytokines interferon IFN-γ, interleukin IL-1β and IL-6 (P < 0·001) and enhanced expression of the anti-inflammatory cytokine IL-10 (P < 0·001). Finally, microscopy analysis of the kidneys demonstrated that TPC-treated mice maintained normal structure equally to MP-treated mice. These data indicate that the small molecule named TPC hinders lupus development in genetically lupus-prone mice equally to methylprednisolone in most of the cases. Hence, TCP may be employed as a therapeutic potential for lupus nephritis.

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“…The average accessibility of the whole molecule is taken as 100%. 37 sin and some of its analogues possess chemoatractant properties and stimulate the chemotaxis of defective monocytes derived from SLE 34 and Hodgkin patients. 35 Preincubation of monocytes with these peptides also enhance their random migration.…”

Section: Chemotaxismentioning

confidence: 99%

“…34 MTT was obtained from Sigma (St. Louis, MO, USA). This assay is based on the measurements of mitochondrial succinyl dehydrogenase activity.…”

Section: ϫ6mentioning

confidence: 99%

Synthesis, conformation, and immunoreactivity of new carrier molecules based on repeated tuftsin‐like sequence

et al. 2004

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Sequential oligopeptides based on a pentapeptide (TKPKG) derived from tuftsin with different lengths were synthesized by stepwise solid phase methodology. These highly soluble oligomers were nontoxic on mouse spleen cells, and other biological data suggested that tuftsin-like properties were also presented. The (TKPKG)n (n=2,4,6,8) oligopeptides were not immunogenic; however, they increased sheep red blood cells (SRBC) antigen specific antibody response in mice, demonstrating their immunostimulatory effect. Chemotactic activity was also found on J774 monocyte cells, while MRC5 fibroblasts were chemotactically nonresponders to the tested forms of tuftsin. These oligomers showed unordered and flexible structure by CD measurements, confirmed by computer modeling studies indicating also a fairly good accessibility of the epsilon-amino group of each lysine residue. Data suggest that these new oligotuftsin derivatives can be considered as promising carriers for synthetic vaccine.

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Stimulating effect of tuftsin and its analogues on the defective monocyte chemotaxis in systemic lupus erythematosus

Cited by 18 publications

References 15 publications

In vitro biological evaluation of new antimycobacterial salicylanilide-tuftsin conjugates

In vitro biological evaluation of new antimycobacterial salicylanilide-tuftsin conjugates

Tuftsin–phosphorylcholine (TPC) equally effective to methylprednisolone in ameliorating lupus nephritis in a mice model

Synthesis, conformation, and immunoreactivity of new carrier molecules based on repeated tuftsin‐like sequence

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