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Published in: Italian Journal of Pediatrics 1/2018

Open Access 01-12-2018 | Commentary

Low Dose Medicine: theoretical background and scientific evidence

Author: S. Bernasconi

Published in: Italian Journal of Pediatrics | Issue 1/2018

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The paper recently published by Carello R. et al. Long-term treatment with Low Dose Medicine in chronic childhood eczema. A double-blind two-stage randomized clinical trial (IJP 2017 43:78) highlights a new possible therapeutic approach for the treatment of chronic childhood eczema. It is based on the oral administration of low doses activated interleukin 12 and Interferon-γ in order to restore the immunologic balance, altered in the disease. This short commentary will briefly describe the theoretical background of Low Dose Medicine (LDM), with particular focus on the aspects linked with the efficacy and the safety of the LDM treatment. …
Literature
1.
2.
go back to reference Ader R, Felten D, Cohen N. Interactions between the brain and the immune system. Annu Rev Pharmacol Toxicol. 1990;30:561–602.CrossRefPubMed Ader R, Felten D, Cohen N. Interactions between the brain and the immune system. Annu Rev Pharmacol Toxicol. 1990;30:561–602.CrossRefPubMed
3.
go back to reference Ader R, Cohen N. Psychoneuroimmunology: conditioning and stress. Annu Rev Psychol. 1993;44:53–85.CrossRefPubMed Ader R, Cohen N. Psychoneuroimmunology: conditioning and stress. Annu Rev Psychol. 1993;44:53–85.CrossRefPubMed
4.
go back to reference Ader R, Cohen N, Felten D. Psychoneuroimmunology: interactions between the nervous system and the immune system. Lancet. 1995;345(8942):99–103.CrossRefPubMed Ader R, Cohen N, Felten D. Psychoneuroimmunology: interactions between the nervous system and the immune system. Lancet. 1995;345(8942):99–103.CrossRefPubMed
5.
go back to reference Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology. 2012;37(1):137–62.CrossRefPubMed Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology. 2012;37(1):137–62.CrossRefPubMed
6.
go back to reference Ngoc PL, Gold DR, Tzianabos AO, Weiss ST, Celedón JC. Cytokines, allergy, and asthma. Curr Opin Allergy Clin Immunol. 2005;5(2):161–6.CrossRefPubMed Ngoc PL, Gold DR, Tzianabos AO, Weiss ST, Celedón JC. Cytokines, allergy, and asthma. Curr Opin Allergy Clin Immunol. 2005;5(2):161–6.CrossRefPubMed
8.
go back to reference Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR Jr, et al. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev. 2012;33(3):378–455.CrossRefPubMedPubMedCentral Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR Jr, et al. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev. 2012;33(3):378–455.CrossRefPubMedPubMedCentral
9.
go back to reference Biancotto A, Wank A, Perl S, Cook W, Olnes MJ, et al. Baseline levels and temporal stability of 27 multiplexed serum cytokine concentrations in healthy subjects. PLoS One. 2013;8(12):e76091.CrossRefPubMedPubMedCentral Biancotto A, Wank A, Perl S, Cook W, Olnes MJ, et al. Baseline levels and temporal stability of 27 multiplexed serum cytokine concentrations in healthy subjects. PLoS One. 2013;8(12):e76091.CrossRefPubMedPubMedCentral
10.
go back to reference Reeves R, Leonard WJ, Nissen MS. Binding of HMG-I(Y) imparts architectural specificity to a positioned nucleosome on the promoter of the human interleukin-2 receptor alpha gene. Mol Cell Biol. 2000;20(13):4666–79.CrossRefPubMedPubMedCentral Reeves R, Leonard WJ, Nissen MS. Binding of HMG-I(Y) imparts architectural specificity to a positioned nucleosome on the promoter of the human interleukin-2 receptor alpha gene. Mol Cell Biol. 2000;20(13):4666–79.CrossRefPubMedPubMedCentral
11.
go back to reference Ishihara K, Hirano T. Molecular basis of the cell specificity of cytokine action. Biochim Biophys Acta. 2002;1592(3):281–96.CrossRefPubMed Ishihara K, Hirano T. Molecular basis of the cell specificity of cytokine action. Biochim Biophys Acta. 2002;1592(3):281–96.CrossRefPubMed
12.
go back to reference Commins SP, Borish L, Steinke JW. Immunologic messenger molecules: cytokines, interferons, and chemokines. J Allergy Clin Immunol. 2010;125(2 suppl 2):S53–72.CrossRefPubMed Commins SP, Borish L, Steinke JW. Immunologic messenger molecules: cytokines, interferons, and chemokines. J Allergy Clin Immunol. 2010;125(2 suppl 2):S53–72.CrossRefPubMed
13.
14.
go back to reference Weigent DA, Blalock JE. Associations between the neuroendocrine and immune systems. J Leukoc Biol. 1995;58(2):137–50.CrossRefPubMed Weigent DA, Blalock JE. Associations between the neuroendocrine and immune systems. J Leukoc Biol. 1995;58(2):137–50.CrossRefPubMed
15.
go back to reference Haddad JJ. On the mechanisms and putative pathways involving neuroimmune interactions. Biochem Biophys Res Commun. 2008;370(4):531–5.CrossRefPubMed Haddad JJ. On the mechanisms and putative pathways involving neuroimmune interactions. Biochem Biophys Res Commun. 2008;370(4):531–5.CrossRefPubMed
16.
go back to reference De la Fuente M. Editorial: crosstalk between the nervous and the immune systems in health and sickness. Curr Pharm Des. 2014;20(29):4605–7.CrossRefPubMed De la Fuente M. Editorial: crosstalk between the nervous and the immune systems in health and sickness. Curr Pharm Des. 2014;20(29):4605–7.CrossRefPubMed
17.
go back to reference Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S20–31.CrossRefPubMedPubMedCentral Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S20–31.CrossRefPubMedPubMedCentral
18.
go back to reference Bollyky PL, Bogdani M, Bollyky JB, Hull RL, Wight TN. The role of hyaluronan and the extracellular matrix in islet inflammation and immune regulation. Curr Diab Rep. 2012;12(5):471–80.CrossRefPubMedPubMedCentral Bollyky PL, Bogdani M, Bollyky JB, Hull RL, Wight TN. The role of hyaluronan and the extracellular matrix in islet inflammation and immune regulation. Curr Diab Rep. 2012;12(5):471–80.CrossRefPubMedPubMedCentral
19.
go back to reference Borroni EM, Mantovani A, Locati M, Bonecchi R. Chemokine receptors intracellular trafficking. Pharmacol Ther. 2010;127(1):1–8.CrossRefPubMed Borroni EM, Mantovani A, Locati M, Bonecchi R. Chemokine receptors intracellular trafficking. Pharmacol Ther. 2010;127(1):1–8.CrossRefPubMed
20.
go back to reference Farrell MS, Roth BL. Pharmacosynthetics: reimagining the pharmacogenetic approach. Brain Res. 2013;1511:6–20.CrossRefPubMed Farrell MS, Roth BL. Pharmacosynthetics: reimagining the pharmacogenetic approach. Brain Res. 2013;1511:6–20.CrossRefPubMed
21.
go back to reference Burnett AF, Biju PG, Lui H, Hauer-Jensen M. Oral interleukin 11 as a countermeasure to lethal total-body irradiation in a murine model. Radiat Res. 2013;180(6):595–602.CrossRefPubMedPubMedCentral Burnett AF, Biju PG, Lui H, Hauer-Jensen M. Oral interleukin 11 as a countermeasure to lethal total-body irradiation in a murine model. Radiat Res. 2013;180(6):595–602.CrossRefPubMedPubMedCentral
22.
go back to reference Hanson ML, Hixon JA, Li W, Felber BK, Anver MR, et al. Delivery of IL-27 recombinant bacteria attenuates immune colitis in mice. Gastroenterology. 2014;146(1):210–21.CrossRefPubMed Hanson ML, Hixon JA, Li W, Felber BK, Anver MR, et al. Delivery of IL-27 recombinant bacteria attenuates immune colitis in mice. Gastroenterology. 2014;146(1):210–21.CrossRefPubMed
23.
go back to reference Forster K, Goethel A, Chan CW, Zanello G, Streutker C, et al. An oral CD3-specific antibody suppresses T-cell-induced colitis and alters cytokine responses to T-cell activation in mice. Gastroenterology. 2012;143(5):1298–307.CrossRefPubMed Forster K, Goethel A, Chan CW, Zanello G, Streutker C, et al. An oral CD3-specific antibody suppresses T-cell-induced colitis and alters cytokine responses to T-cell activation in mice. Gastroenterology. 2012;143(5):1298–307.CrossRefPubMed
24.
go back to reference Yun Y, Cho YW, Park K. Nanoparticles for oral delivery: targeted nanoparticles with peptidic ligands for oral protein delivery. Adv Drug Deliv Rev. 2013;65(6):822–32.CrossRefPubMed Yun Y, Cho YW, Park K. Nanoparticles for oral delivery: targeted nanoparticles with peptidic ligands for oral protein delivery. Adv Drug Deliv Rev. 2013;65(6):822–32.CrossRefPubMed
25.
go back to reference Epstein OI. Release-activity: a long way from phenomenon to new drugs. Bull Exp Biol Med. 2012;154(1):54–8.CrossRefPubMed Epstein OI. Release-activity: a long way from phenomenon to new drugs. Bull Exp Biol Med. 2012;154(1):54–8.CrossRefPubMed
26.
go back to reference Gariboldi S, Palazzo M, Zanobbio L, Dusio GF, Mauro V, Solimene U, Cardani D, et al. Low dose oral administration of cytokines for treatment of allergic asthma. Pulm Pharmacol Ther. 2009;22(6):497–510.CrossRefPubMed Gariboldi S, Palazzo M, Zanobbio L, Dusio GF, Mauro V, Solimene U, Cardani D, et al. Low dose oral administration of cytokines for treatment of allergic asthma. Pulm Pharmacol Ther. 2009;22(6):497–510.CrossRefPubMed
27.
go back to reference D’Amico L, Ruffini E, Ferracini R, Roato I. Low dose of IL-12 stimulates T cell response in cul- tures of PBMCs derived from non small cell lung cancer patients. J Cancer Ther. 2012;3:337–42.CrossRef D’Amico L, Ruffini E, Ferracini R, Roato I. Low dose of IL-12 stimulates T cell response in cul- tures of PBMCs derived from non small cell lung cancer patients. J Cancer Ther. 2012;3:337–42.CrossRef
28.
go back to reference Cardani D, Dusio GF, Luchini P, Sciarabba M, Solimene U, Rumio C. Oral Administration of Interleukin-10 and anti-IL1 antibody ameliorates experimental intestinal inflammation. Gastroenterol Res. 2013;6(4):124–33. Cardani D, Dusio GF, Luchini P, Sciarabba M, Solimene U, Rumio C. Oral Administration of Interleukin-10 and anti-IL1 antibody ameliorates experimental intestinal inflammation. Gastroenterol Res. 2013;6(4):124–33.
29.
go back to reference Radice E, Miranda V, Bellone G. Low-doses of sequential-kinetic-activated interferon-gamma enhance the ex vivo cytotoxicity of peripheral blood natural killer cells from patients with early-stage colorectal cancer. A preliminary study intern. Immunopharmacology. 2014;19(1):66–73.CrossRef Radice E, Miranda V, Bellone G. Low-doses of sequential-kinetic-activated interferon-gamma enhance the ex vivo cytotoxicity of peripheral blood natural killer cells from patients with early-stage colorectal cancer. A preliminary study intern. Immunopharmacology. 2014;19(1):66–73.CrossRef
30.
go back to reference Roberti ML, Ricottini L, Capponi A, Sclauzero E, Vicenti P, Fiorentini E, Savoia C, et al. Im- munomodulating treatment with low dose inter- leukin-4, Interleukin-10 and Interleukin-11 in psoriasis vulgaris. J Biol Regul Homeost Agents. 2014;28(1):133–9.PubMed Roberti ML, Ricottini L, Capponi A, Sclauzero E, Vicenti P, Fiorentini E, Savoia C, et al. Im- munomodulating treatment with low dose inter- leukin-4, Interleukin-10 and Interleukin-11 in psoriasis vulgaris. J Biol Regul Homeost Agents. 2014;28(1):133–9.PubMed
31.
go back to reference Luchetti P. Increasing of visual function in patients with retinal atrophy treated with drugs of Low Dose Medicine. Monocentric retrospective observational study. Minerva Oftalmol. 2014;56(3–4):53–61. Luchetti P. Increasing of visual function in patients with retinal atrophy treated with drugs of Low Dose Medicine. Monocentric retrospective observational study. Minerva Oftalmol. 2014;56(3–4):53–61.
32.
go back to reference Barygina V, Becatti M, Lotti T, Moretti S, Taddei N, Fiorillo C. Treatment with low-dose cytokines reduces oxidative-mediated injury in perilesional keratinocytes from vitiligo skin. J Dermatol Sci. 2015;79(2):163–70.CrossRefPubMed Barygina V, Becatti M, Lotti T, Moretti S, Taddei N, Fiorillo C. Treatment with low-dose cytokines reduces oxidative-mediated injury in perilesional keratinocytes from vitiligo skin. J Dermatol Sci. 2015;79(2):163–70.CrossRefPubMed
33.
go back to reference Lotti T, Hercogova J, Wollina U, Chokoeva AA, Zarrab Z, Gianfaldoni S, Roccia MG, et al. Viti- ligo: successful combination treatment based on oral low dose cytokines and different topical tre- atments. J Biol Regul Homeost Agents. 2015;29(1 Suppl):53–8.PubMed Lotti T, Hercogova J, Wollina U, Chokoeva AA, Zarrab Z, Gianfaldoni S, Roccia MG, et al. Viti- ligo: successful combination treatment based on oral low dose cytokines and different topical tre- atments. J Biol Regul Homeost Agents. 2015;29(1 Suppl):53–8.PubMed
34.
go back to reference Radice E, Bellone G, Miranda V. Enhancement of the Immunostimulatory functions of ex vi- vo-generated Dendritic cells from early-stage colon cancer patients by consecutive exposure to low doses of sequential-kinetic-activated IL-4 and IL-12. A Preliminary Study. Transl Oncol. 2015;8(4):327–38.CrossRefPubMedPubMedCentral Radice E, Bellone G, Miranda V. Enhancement of the Immunostimulatory functions of ex vi- vo-generated Dendritic cells from early-stage colon cancer patients by consecutive exposure to low doses of sequential-kinetic-activated IL-4 and IL-12. A Preliminary Study. Transl Oncol. 2015;8(4):327–38.CrossRefPubMedPubMedCentral
35.
go back to reference Lotti T. Successful combination treatment for psoriasis with phototherapy and low-dose cytoki- nes : a spontaneous, retrospective observational clinical study. Hautarzt. 2015;66(11):849–54.CrossRefPubMed Lotti T. Successful combination treatment for psoriasis with phototherapy and low-dose cytoki- nes : a spontaneous, retrospective observational clinical study. Hautarzt. 2015;66(11):849–54.CrossRefPubMed
36.
go back to reference Barygina V, Becatti M, Lotti T, Taddei N, Fiorillo C. Low dose cytokines reduce oxidative stress in primary lesional fibroblasts obtained from psoriatic patients. J Dermatol Sci. 2016;83(3):242–4.CrossRefPubMed Barygina V, Becatti M, Lotti T, Taddei N, Fiorillo C. Low dose cytokines reduce oxidative stress in primary lesional fibroblasts obtained from psoriatic patients. J Dermatol Sci. 2016;83(3):242–4.CrossRefPubMed
37.
go back to reference Fiorito F, Cantiello A, Granato GE, Navas L, Diffidenti C, De Martino L, Maharajan V, Fiorito F, et al. Clinical improvement in feline herpesvirus 1 infected cats by oral low dose of interleukin-12 plus interferon-gamma. Comparative Immuno- logy. Microbiol Infect Dis. 2016;48:41–7. Fiorito F, Cantiello A, Granato GE, Navas L, Diffidenti C, De Martino L, Maharajan V, Fiorito F, et al. Clinical improvement in feline herpesvirus 1 infected cats by oral low dose of interleukin-12 plus interferon-gamma. Comparative Immuno- logy. Microbiol Infect Dis. 2016;48:41–7.
38.
go back to reference Genazzani AD, Prati A, Bonacini R, Despini G. Terapia integrativa e farmacologica dell'amenorrea ipotalamica da stress. Boll Ginecol Endocrinol. 2016;10:24–32. Genazzani AD, Prati A, Bonacini R, Despini G. Terapia integrativa e farmacologica dell'amenorrea ipotalamica da stress. Boll Ginecol Endocrinol. 2016;10:24–32.
39.
go back to reference Martin-Martin LS, Giovannangeli F, Bizzi E, Massafra U, Ballanti E, Cassol M, Migliore A. An open randomized active-controlled clinical trial with low-dose SKA cytokines versus DMARDs evaluating low disease activity maintenance in patients with rheumatoid arthritis. Drug Des Devel Ther. 2017;11:985–94.CrossRefPubMedPubMedCentral Martin-Martin LS, Giovannangeli F, Bizzi E, Massafra U, Ballanti E, Cassol M, Migliore A. An open randomized active-controlled clinical trial with low-dose SKA cytokines versus DMARDs evaluating low disease activity maintenance in patients with rheumatoid arthritis. Drug Des Devel Ther. 2017;11:985–94.CrossRefPubMedPubMedCentral
40.
go back to reference Castiglioni S, Miranda V, Cazzaniga A, Campanella M, Nichelatti M, Andena M, Maier JAM. Femtograms of Interferon-γ Suffice to Modulate the Behavior of Jurkat Cells: A New Light in Immunomodulation. Int J Mol Sci. 2017;18(12):2714-15. Castiglioni S, Miranda V, Cazzaniga A, Campanella M, Nichelatti M, Andena M, Maier JAM. Femtograms of Interferon-γ Suffice to Modulate the Behavior of Jurkat Cells: A New Light in Immunomodulation. Int J Mol Sci. 2017;18(12):2714-15.
41.
go back to reference Mancini F, Milardi D, Carfagna P, Grande G, Miranda V, De Cicco NA, Ricciardi D, Pontecorvi A, et al. Low-dose SKA progesterone and Interleukin-10 modulate the inflammatory pathway in endometriotic cell lines. Int Immunopharmacol. 2018;55:223–30.CrossRef Mancini F, Milardi D, Carfagna P, Grande G, Miranda V, De Cicco NA, Ricciardi D, Pontecorvi A, et al. Low-dose SKA progesterone and Interleukin-10 modulate the inflammatory pathway in endometriotic cell lines. Int Immunopharmacol. 2018;55:223–30.CrossRef
42.
go back to reference Humrich JY, von Spee-Mayer C, Siegert E, Alexander T, Hiepe F, Radbruch A, Burmester GR, et al. Rapid induction of clinical remission by low-dose interleukin-2 in a patient with refractory SLE. Ann Rheum Dis. 2015;74(4):791–2.CrossRefPubMed Humrich JY, von Spee-Mayer C, Siegert E, Alexander T, Hiepe F, Radbruch A, Burmester GR, et al. Rapid induction of clinical remission by low-dose interleukin-2 in a patient with refractory SLE. Ann Rheum Dis. 2015;74(4):791–2.CrossRefPubMed
43.
go back to reference Jyonouchi S, Gwafila B, Gwalani LA, Ahmad M, Moertel C, Holbert C, Kim JY, et al. Phase I trial of low-dose interleukin 2 therapy in patients with Wiskott-Aldrich syndrome. Clin Immunol. 2017;179:47–53.CrossRefPubMed Jyonouchi S, Gwafila B, Gwalani LA, Ahmad M, Moertel C, Holbert C, Kim JY, et al. Phase I trial of low-dose interleukin 2 therapy in patients with Wiskott-Aldrich syndrome. Clin Immunol. 2017;179:47–53.CrossRefPubMed
Metadata
Title
Low Dose Medicine: theoretical background and scientific evidence
Author
S. Bernasconi
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Italian Journal of Pediatrics / Issue 1/2018
Electronic ISSN: 1824-7288
DOI
https://doi.org/10.1186/s13052-018-0460-6

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