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 Table of Contents  
Year : 2015  |  Volume : 2  |  Issue : 1  |  Page : 1-3

New scenarios in dermatology psychoneuroendocrine immunology and the low-dose medicine approach

Director of the Center for Interdisciplinary Studies of Regenerative Sciences; University of Rome "G. Marconi", Rome; Institute of Dermatology, Florence, Italy; World Health Academy Foundation, Zurich (CH), Switzerland

Date of Web Publication26-Jun-2015

Correspondence Address:
Torello Lotti
University of Rome "G.Marconi" Via Plinio 44, 00193 Rome, Italy

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2349-5847.159384

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How to cite this article:
Lotti T. New scenarios in dermatology psychoneuroendocrine immunology and the low-dose medicine approach. Pigment Int 2015;2:1-3

How to cite this URL:
Lotti T. New scenarios in dermatology psychoneuroendocrine immunology and the low-dose medicine approach. Pigment Int [serial online] 2015 [cited 2023 Mar 28];2:1-3. Available from: https://www.pigmentinternational.com/text.asp?2015/2/1/1/159384

  Psychoneuroendocrine Immunology and Low-Dose Medicine: Affirming the Model of Human Centered Medicine Top

From the second half of the 70 s, the development of psychoneuroendocrine immunology (P.N.E.I.): A discipline that studies the functional relationships between the nervous, immune, and endocrine systems) by Ader et al., offered the opportunity and the tools to study both physiological and pathological biologic processes in accordance with an unified vision of the body functions and to identify the P.N.E.I. mechanisms that manage the control of these functions. Taken together, the central nervous system, the autonomic nervous system, the endocrine and immune systems constitute the P.N.E.I. network. [1],[2],[3],[4]

The bi-directional cross-talk between the systems within P.N.E.I. network is managed by a relevant number of signaling molecules which are the carriers of the "biochemical information" necessary for the homeostatic regulation of all the biological responses within the network. A crush of the cross-talk due to an imbalance between specific signal molecules is fundamental for the onset of inflammatory, allergic, and autoimmune diseases. [5],[6]

In the last 30 years, the research in the fields of molecular biology and physiopathology identified in hormones, neuropeptides, cytokines, and growth factors the signaling molecules involved in both physiological and pathological biological processes in clear accordance with the principles of P.N.E.I.

Recently, a cutting-edge medical paradigm named low dose medicine (LDM) arose.

Low-dose medicine represents an innovative therapeutic approach based on the integration the most recent knowledge in the fields of molecular biology, P.N.E.I. and nano-concentrations research. LDM approach, based on oral systemic administration of low-dose messenger molecules, represents the best therapeutic tool for preservation and/or restoration of P.N.E.I. homeostatic equilibrium, pivotal point to guarantee the best physiological conditions of the human body.

Two main therapeutic strategies are based upon LDM approach:

  • Enhance a pathologically down-regulated cellular pathway administering cytokine, hormone, neuropeptides or growth factor physiologically linked with the altered signaling
  • Re-equilibrate a biological effect according to the principle of "opposing" molecules: Since different cytokines or hormones can have different effects on the same cell, that is, a cytokine can antagonize the effect of another one interleukin-4/interferon-gamma (IL-4/IFN-gamma) and a hormone can antagonize the effect of another one (progesterone/estrogens), both targeted at the same cell, in LDM antagonistic cytokines or hormones are utilized in order to break a biological effect. [7],[8]

Cytokines oral administration is proven to be effective in modulating immune response, as reported by scientific literature, but its efficacy is affected by the low bioavailability caused by the oral delivery route. [9] The only way to avoid this pitfall is represented by an innovative drug delivery system named sequential kinetic activation (SKA)-(GUNA Laboratories. Milan, Italy), which allows per OS administration of ultra-low doses of messenger molecules (in a range between picomolar and femtomolar concentration). Appling SKA technology, ultra-low concentrations of biologically active substances such as hormones, neuropeptides, cytokines, and growth factors are effective both in basic experimental assays and in clinical therapy even below the actually considered minimum effective dose. [10]

Since 2009, a growing body of scientific publications validated the principles of LDM; scientific data highlighted the efficacy and safety of low-dose SKA cytokines treatment in models of diseases presenting a pathologic Th1/Th2/Th17 switch. [11],[12],[13],[14],[15],[16]

  Low Dose Therapy: From Nano-concentrations a New Hope in Skin Diseases and Pigmentary Disorders Top

Low-dose medicine mainly highlights the role of inflammation and especially low-grade chronic inflammation in the etiopathogenesis of a wide spectrum of diseases. Some of the most dramatic dermatologic chronic inflammatory autoimmune diseases can today be approached with LDM. Considering these skin diseases as systemic diseases, acting on the bio-regulation of the immune system through oral systemic administration of signaling molecules, then only will be able to restore the cross-talk between immune cells and between these ones and the skin cells.

The loss of the immunologic balance is characterized by a shift between Th1- and Th2-mediated immune response due to an altered amplification of Th1 and Th2 lymphocyte subsets.

The Th1/Th2 switch results in the hyper-production of Th1-related cytokines. Skin diseases such as alopecia areata, vitiligo, and psoriasis present a characteristic expression of proinflammatory cytokines, mainly derived from Th1 lymphocytes, typical of organ-specific autoimmune diseases. [17],[18] Since the 70s, anti-cytokine therapy was proposed for the treatment of skin autoimmune diseases mainly counteracting the expression IFNs, IL-1, and tumor necrosis factor-alpha (TNF-α) Th1 proinflammatory cytokines; the therapeutic use of Th2 cytokines and specific antibodies was applied for alopecia areata, psoriasis, and atopic dermatitis treatment.

The most important and limiting pitfalls connected with the use of cytokines and other signal molecules are:

  • The need of high doses of active molecules
  • The low compliance of systemic administration performed by intravenous and subcutaneous injections.

A great number of dose-dependent side effects are linked with high doses of therapeutic cytokines, antibodies and growth factors. [19],[20]

The availability of low dose SKA signaling molecules (cytokines, growth factors, hormones, and neuropeptides) and the development of LDM approach make possible to use lower doses of activated molecules (active range between picomoles and femtomoles) with therapeutic outcomes comparable to those induced by high dosages but without side effects.

A multicenter double-blind placebo-controlled clinical study performed by Roberti et al.[15] described the efficacy specific low dose SKA cytokines (IL-4; IL-10; IL-11, at the concentration of 10 fg/ml - GUNA S.p.a., Milan, Italy) for the therapy of Psoriasis Vulgaris.

The two outcomes chosen for the evaluation of the treatment with low dose SKA cytokines were:

  • The presence and extension of psoriatic lesions
  • The improvement of the quality-of-life.

These two parameters were evaluated using the rating scales Psoriasis Area Severity Index and Dermatology Life Quality Index, respectively.

Roberti et al. clarified some aspects of low dose SKA cytokines action against Psoriasis Vulgaris and the results of the study allowed the researchers to confirm that low dose SKA cytokine administration is effective, safe, and long-lasting, which are crucial aspects for an hypothetic treatment of other chronic diseases such as Vitiligo. [21],[22],[23],[24],[25]

In Vitiligo, an imbalance in cytokine expression at cutaneous lesions level is observed, probably caused by a shift of the immune system with a prevalence of Th1/Th17 (high IL-1 and IL-17 levels) and a reduction of the Tregs/Th2-driven response (low IL-4 level); TNF-α also has a pivotal role in oxidative stress-mediated cytotoxicity directed against melanocytes and keratinocytes. [26],[27],[28] Loss of melanocytes exerts a central role in Vitiligo depigmentation. Increased melanocytes death rate is due to the disruption of the cross-talk between these cells and keratinocytes.

Oxidative stress reactive oxygen species and other inflammatory triggers such as TNF-α induce keratinocytes apoptosis with consequent reduced production of keratinocytes-released factors stem cell factor, endothelins and above all, basic fibroblast growth factor (b-FGF) that negatively affects the vitality of melanocytes. Acting at the origin of the inflammatory phenomena counteracting pro-inflammatory cytokine with specific low dose SKA cytokines (IL-10, Anti-IL-1 and IL-4) and in the meantime, stimulating melanocytes to produce melanin via up-regulation of trans-membrane receptors through low dose SKA b-FGF represent the new LDM approach for vitiligo treatment.

  Conclusions Top

A large number of dermatological diseases have, among its etiological components, an altered immune response caused by the imbalance between Th1 and Th2-driven responses. An innovative strategy for the treatment of these diseases could be based on the rebalance of this altered cytokine profile. High doses of recombinant signal molecules such as cytokines, antibodies, and growth factors are effective against some immune aspects of skin autoimmune diseases but mild to severe dose-dependent and time-dependent side effects are still present.

The possibility of a fine adjustment of the immune response through the use of suitably identified signaling molecules is a good therapeutic opportunity for chronic inflammatory autoimmune diseases of the skin.

The availability of low-dose SKA-activated cytokines and the LDM approach (validated by an increasing number of scientific evidences in terms of efficacy and safety) induces us to postulate a new therapeutic approach based on systemic oral administration of low doses of activated cytokines and growth factors, which represents an innovative strategy for the treatment of dermatological diseases characterized by an immune Th1/Th2 imbalance such as Psoriasis Vulgaris and Vitiligo.

  References Top

Ader R, Cohen N. Psychoneuroimmunology: Conditioning and stress. Annu Rev Psychol 1993;44:53-85.  Back to cited text no. 1
Ader R, Cohen N, Felten D. Psychoneuroimmunology: Interactions between the nervous system and the immune system. Lancet 1995;345:99-103.  Back to cited text no. 2
Brazzini B, Ghersetich I, Hercogova J, Lotti T. The neuro-immuno-cutaneous-endocrine network: Relationship between mind and skin. Dermatol Ther 2003;16:123-31.  Back to cited text no. 3
Lotti T, Bianchi B, Ghersetich I, Brazzini B, Hercogova J. Can the brain inhibit inflammation generated in the skin? The lesson of gamma-melanocyte-stimulating hormone. Int J Dermatol 2002;41:311-8.  Back to cited text no. 4
Ngoc PL, Gold DR, Tzianabos AO, Weiss ST, Celedón JC. Cytokines, allergy, and asthma. Curr Opin Allergy Clin Immunol 2005;5:161-6.  Back to cited text no. 5
Lourenço EV, La Cava A. Cytokines in systemic lupus erythematosus. Curr Mol Med 2009;9:242-54.  Back to cited text no. 6
Cooke A. Th17 cells in inflammatory conditions. Rev Diabet Stud 2006;3:72-5.  Back to cited text no. 7
Bettelli E, Korn T, Kuchroo VK. Th17: The third member of the effector T cell trilogy. Curr Opin Immunol 2007;19:652-7.  Back to cited text no. 8
Renukuntla J, Vadlapudi AD, Patel A, Boddu SH, Mitra AK. Approaches for enhancing oral bioavailability of peptides and proteins. Int J Pharm 2013;447:75-93.  Back to cited text no. 9
Lotti T, Perra A. Bases and principles of low dose medicine and P.N.E.I. Foundations of Low Dose Pharmacology. Pigmentary Dis 2014;1:e101.  Back to cited text no. 10
Gariboldi S, Palazzo M, Zanobbio L, Dusio GF, Mauro V, Solimene U, et al. Low dose oral administration of cytokines for treatment of allergic asthma. Pulm Pharmacol Ther 2009;22:497-510.  Back to cited text no. 11
D'Amico L, Ruffini E, Ferracini R, Roato I. Low dose of IL-12 stimulates T Cell response in cultures of PBMCs derived from non small cell lung cancer patients. J Cancer Ther 2012;3:337-42.  Back to cited text no. 12
Cardani D, Dusio GF, Luchini P, Sciarabba M, Solimene U, Rumio C. Oral administration of Interleukin-10 and Anti-IL-1 antibody ameliorates experimental intestinal inflammation. Gastroenterol Res 2013;6:124-33.  Back to cited text no. 13
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. Immunopharm 2014;19:66-73.  Back to cited text no. 14
Roberti ML, Ricottini L, Capponi A, Sclauzero E, Vicenti P, Fiorentini E, et al. Immunomodulating treatment with low dose interleukin-4, interleukin-10 and interleukin-11 in psoriasis vulgaris. J Biol Regul Homeost Agents 2014;28:133-9.  Back to cited text no. 15
Lotti T, Hercogova J. Successful treatment of psoriasis with low-dose per os interleukins 4, 10, and 11. Dermatol Ther 2015;28:1-2.  Back to cited text no. 16
Skurkovich S, Korotky NG, Sharova NM, Skurkovich B. Treatment of alopecia areata with anti-interferon-gamma antibodies. J Investig Dermatol Symp Proc 2005;10:283-4.  Back to cited text no. 17
Numerof RP, Asadullah K. Cytokine and anti-cytokine therapies for psoriasis and atopic dermatitis. BioDrugs 2006;20:93-103.  Back to cited text no. 18
Wallis RS. Reactivation of latent tuberculosis by TNF blockade: The role of interferon gamma. J Investig Dermatol Symp Proc 2007;12:16-21.  Back to cited text no. 19
Guerra I, Algaba A, Pérez-Calle JL, Chaparro M, Marín-Jiménez I, García-Castellanos R, et al. Induction of psoriasis with anti-TNF agents in patients with inflammatory bowel disease: A report of 21 cases. J Crohns Colitis 2012;6:518-23.  Back to cited text no. 20
Valle Y, Lotti TM, Hercogova J, Schwartz RA, Korobko IV. Multidisciplinary approach to R and D in vitiligo, a neglected skin disease. Dermatol Ther 2012;25 Suppl 1:S1-9.  Back to cited text no. 21
Parsad D. A new era of vitiligo research and treatment. J Cutan Aesthet Surg 2013;6:63-4.  Back to cited text no. 22
[PUBMED]  Medknow Journal  
Lotti T, Zanardelli M, D'Erme AM. Vitiligo: What's new in the psycho-neuro-endocrine-immune connection and related treatments. Wien Med Wochenschr 2014;164:278-85.  Back to cited text no. 23
Lotti T, D'Erme AM. Vitiligo as a systemic disease. Clin Dermatol 2014;32:430-4.  Back to cited text no. 24
Lotti T, Hercogova J, Schwartz RA. Vitiligo; What's New, What's True-Zurich (CH). Zurich: WHA Publishing House, VR Foundation; 2014.  Back to cited text no. 25
Sandoval-Cruz M, García-Carrasco M, Sánchez-Porras R, Mendoza-Pinto C, Jiménez-Hernández M, Munguía-Realpozo P, et al. Immunopathogenesis of vitiligo. Autoimmun Rev 2011;10:762-5.  Back to cited text no. 26
Kumar R, Parsad D. Melanocytorrhagy and apoptosis in vitiligo: Connecting jigsaw pieces. Indian J Dermatol Venereol Leprol 2012;78:19-23.  Back to cited text no. 27
[PUBMED]  Medknow Journal  
Laddha NC, Dwivedi M, Mansuri MS, Gani AR, Ansarullah M, Ramachandran AV, et al. Vitiligo: Interplay between oxidative stress and immune system. Exp Dermatol 2013;22:245-50.  Back to cited text no. 28


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