Dialyzable leukocyte extracts (DLE) transfer specific cell-mediated immune responses from sensitized donors to non-immune recipients. In addition, DLE have several immunomodulatory effects and are used for the treatment of several infectious and non-infectious diseases. Previous studies showed that human DLE obtained from virus-infected leukocytes and bovine DLE decrease the production of the pro-inflammatory cytokine TNF-α in response to bacterial lipopolysaccharide, in vitro and in vivo. In the present work, we inquire as to whether DLE from uninfected human leukocytes have the ability to regulate cytokine production in peripheral blood mononuclear cells (PBMC) in vitro. We observed that PBMC from healthy individuals were able to produce TNF-α, IL-12 and IL-10 after stimulation with DLE. Moreover, we identified monocytes as the main cell population that produced TNF-α after DLE stimulation. Interestingly, we found that DLE contain unidentified ligands that activate Toll-like receptor (TLR)-2. Finally, we observed that DLE directly activated monocytes through TLR-2. These results reveal a new biological activity of DLE, and suggest that part of the immunomodulatory properties of DLE could be attributed to TLR-2 activation on monocytes and to the induction of a pro-inflammatory environment that is crucial for control of infectious diseases.
(a) LandsteinerK., ChaseM.W. (1942) Experiments on transfer of cutaneous sensitivity to simple compounds. Proceedings of the Society for Experimental Biology and Medicine, 49, 688–690; (b) Lawrence HS. (1955) The transfer in humans of delayed skin sensitivity to Streptococcal M substance and to tuberculin with disrupted leucocytes. Journal of Clinical Investigation, 34, 219–230; (c) Lawrence HS, Al-Askari S, David J, Franklin EC, Zweiman B. (1963) Transfer of immunological information in humans with dialysates of leukocyte extracts. Transactions of the Association of American Physicians, 76, 84–89; (d) Lawrence HS, Valentine FT. (1970) Transfer factor and other mediators of cellular immunity. The American Journal of Pathology, 60, 437–452.
2.
(a) Estrada-ParraS., Chavez-SanchezR., Ondarza-AguileraR., Correa-MezaB., Serrano-MirandaE., Monges-NicolauA., Calva-PellicerC. (1995) Immunotherapy with transfer factor of recurrent herpes simplex type I. Archives of Medical Research, 26, S87–92; (b) Fabre RA, Perez TM, Aguilar LD, Rangel MJ, Estrada-Garcia I, Hernandez-Pando R, Estrada-Parra S. (2004) Transfer factors as immunotherapy and supplement of chemotherapy in experimental pulmonary tuberculosis. Clinical Experimental Immunology, 136, 215–223; (c) Wilson GB, Metcalf JF, Fudenberg HH. (1982) Treatment of Mycobacterium fortuitum pulmonary infection with “transfer factor” (TF): new methodology for evaluating TF potency and predicting clinical response. Clinical Immunology and Immunopathology, 23, 478–491; (d) Simon MR, Salberg DJ, Silva J, Jr., Ganji S, Desai S, Muller BF, Palutke M. (1981) Atypical mycobacterium infection treated with dialyzable leukocyte extracts: evidence for antigenic specificity. Clinical Immunology and Immunopathology, 20, 123–128; (e) Littman BH, Rocklin RE, Parkman R, David JR. (1978) Transfer factor treatment of chronic mucocutaneous candidiasis: requirement for donor reactivity to candida antigen. Clinical Immunology and Immunopathology.9. 97–110; (f) Delgado O, Romano EL, Belfort E, Pifano F, Scorza JV, Rojas Z. (1981) Dialyzable leukocyte extract therapy in immunodepressed patients with cutaneous leishmaniasis. Clinical Immunology and Immunopathology, 19, 351–359.
3.
(a) GallinJ.I., KirkpatrickC.H. (1974) Chemotactic activity in dialyzable transfer factor. Proceedings of the National Academy of Sciences of the United States of America, 71, 498–502; (b) Lang I, Nekam K, Gergely P, Petranyi G. (1982) Effect in vivo and in vitro treatment with dialyzable leukocyte extracts on human natural killer cell activity. Clinical Immunology and Immunopathology, 25, 139–144; (c) Vacek A, Barnet K, Hofer M, Cech K, Pekarek J, Schneiderova H. (1997) Stimulation of hemopoietic colony formation from mouse marrow cells in vitro using human dialyzable leukocyte extracts-IMMODIN-SEVAC. International Journal of Immunopharmacology, 19, 431–436.
4.
(a) Alvarez-ThullL., KirkpatrickC.H. (1999) Profiles of cytokine production in recipients of transfer factors. Biotherapy, 9, 55–59; (b) Ojeda Ojeda M, Fernandez Ortega CB, Arana Rosainz MJ. (1996) Dialysable leucocyte extract (DLE) reduces lipopolysaccharide-induced tumour necrosis factor secretion in human leucocytes. Biotherapy, 9, 163–170; (c) Franco-Molina MA, Mendoza-Gamboa E, Castillo-Leon L, Tamez-Guerra RS, Rodriguez-Padilla C. (2004) Bovine dialyzable leukocyte extract protects against LPS-induced, murine endotoxic shock. International Immunopharmacology, 4, 1577–1586.
5.
(a) ChalyY.V., PaleologE.M., KolesnikovaT.S., TikhonovI.I., PetratchenkoE.V., VoitenokN.N. (2000) Neutrophil alpha-defensin human neutrophil peptide modulates cytokine production in human monocytes and adhesion molecule expression in endothelial cells. European Cytokine Network, 11, 257–266; (b) Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM. (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature, 440, 228–232; (c) Kreckler LM, Wan TC, Ge ZD, Auchampach JA. (2006) Adenosine inhibits tumor necrosis factor-alpha release from mouse peritoneal macrophages via A2A and A2B but not the A3 adenosine receptor. The Journal of Pharmacology and Experimental Therapeutics, 317, 172–180.
6.
(a) WheelerD.S., DunsmoreK.E., DenenbergA.G., MuethingL., PoynterS.E., WongH.R. (2011) Biological activity of truncated C-terminus human heat shock protein 72. Immunology Letters, 135, 173–179; (b) Saenz R, Souza Cda S, Huang CT, Larsson M, Esener S, Messmer D. (2010) HMGB1-derived peptide acts as adjuvant inducing immune responses to peptide and protein antigen. Vaccine, 28, 7556–7562.
7.
Rivera-OrdazA., Gonzaga-BernachiJ., Serafin-LopezJ., Hernandez-PandoR., Van SoolingenD., Estrada-ParraS., Estrada-GarcíaI., Chacón-SalinasR. (2012) Mycobacterium tuberculosis Beijing genotype induces differential cytokine production by peripheral blood mononuclear cells of healthy BCG vaccinated individuals. Immunological Investigations, 41, 144–156.
8.
Maldonado-BernalC., KirschningC.J., RosensteinY., RochaL.M., Rios-SarabiaN., Espinosa-CantellanoM., BeckerI., EstradaI., Salazar GonzálezR.M., López-MacíasC., WagnerH., SánchezJ., IsibasiA. (2005) The innate immune response to Entamoeba histolytica lipopeptidophosphoglycan is mediated by toll-like receptors 2 and 4. Parasite Immunology, 27, 127–137.
