INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY
Vol. 22, no. 2, 0-0 (2009)
PIDOTIMOD: A REAPPRAISAL P. RIBOLDI, M. GEROSA and P.L. MERONI Allergy, Clinical Immunology and Rheumatology Unit, Istituto Auxologico Italiano Department of Internal Medicine, University of Milan, Milan, Italy Received September 26, 2008 – Accepted March 10, 2009 Pidotimod (Polimod ®) is a synthetic dipeptide molecule with biological and immunological activity on both the adaptive and the innate immune responses. In vitro studies, both from animal and human specimens, have documented a good activity on innate and adaptive immune responses and have been confirmed by in vivo studies. These activities have been applied in clinical studies demonstrating the efficacy of pidotimod in reducing the rate of recurrent infections of the upper respiratory and urinary tracts in children. The same results were obtained in recurrent respiratory tract infections in adults. Interestingly, these effects are more evident in the setting of immune defects such as senescence, Down’s syndrome, and cancer. Pidotimod (Polimod ®) is a synthetic dipeptide molecule with biological and immunological activity on both the adaptive and the innate immune responses (Fig. 1). In comparison with biological response modifiers of extractive origin, the synthetic process ensures a high purity product with a high reproducibility among batches. Pidotimod is rapidly absorbed by the gastrointestinal tract with a bioavailability of 45%. The plasma half life is 4 h with poor metabolism and renal elimination of the unmodified molecule . In vitro studies from both animal and human specimens have documented a good activity on innate and adaptive immune responses and have been confirmed by in vivo studies. These activities have been applied in clinical studies demonstrating the efficacy of pidotimod in reducing the rate of recurrent infections of the upper respiratory and urinary tract in children. The same results were obtained in recurrent respiratory tract infections
in adults. More importantly, these effects are more evident in the setting of immune defects such as senescence, Down’s syndrome, and cancer. The aim of this review is to analyze the effects of pidotimod on the innate and adaptive immunity and the studies of clinical efficacy. Animal studies The first experiments were designed to demonstrate a protective effect of pidotimod in experimental infections in mice. Mice injected intraperitoneally (i.p.) with P. mirabilis, P. vulgaris, S. aureus, K. pneumoniae or P. aeruginosa are protected from death when treated concomitantly with repeated injections of pidotimod. The protective effect reached a 100% survival with Proteus strains, 90% with S. aureus and 40% with more aggressive bacteria such as Pseudomonas and Klebsiella strains. This effect is dose-dependent and can be strengthened by a synergistic activity with beta-lactam antibiotics
Key words: pidotimod, innate immunity, recurrent infections, immunodeficiency Mailing address: Piersandro Riboldi MD, Istituto Auxologico Italiano, Via Spagnoletto 3, 20149 Milano, Italy Tel: ++39 02 61 911 2556 Fax: ++39 02 61 911 2559 e-mail [email protected]
Copyright © by BIOLIFE, s.a.s. This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties
P. RIBOLDI ET AL.
in this model of experimental infections in mice (1). The protective activity of pidotimod, in this experimental setting, is comparable with, or in some cases even better than, other immunomodulating molecules such as tuftsin, muramyl and bestatin (1). Pidotimod is able to reverse the immunodepression induced in mice by cyclophosphamide treatment by protecting mice from death in experimentally induced infections of strains of E. coli, Proteus, Morganella, and Pseudomonas (1). The survival time of mice experimentally infected with Mengovirus, Herpes simplex, influenza or Coxsackie viruses was significantly increased in a dose-dependent manner by pre-treatment with pidotimod. Such an effect was not related to any specific anti-viral activity of the compound (2-3). From these studies we can conclude that pidotimod protects against experimentally induced bacterial and viral infections. Since the compound does not display any antibiotic and/or direct antiviral activity, it has been suggested that its pharmacological activity may be related to its potentiating effect on the immune responses. These findings represent the rationale behind the studies planned to explore the pharmacological activity of pidotimod on innate and adaptive immune responses. Prednisolone-treated mice represent a model of experimentally-induced immunosuppression: in this setting the activity of pidotimod was evaluated on four parameters of innate immunity. Firstly, prednisolone induced a dramatic reduction of the number of peritoneal macrophages. Combined treatment of mice with prednisolone and pidotimod by intraperitoneal (i.p) injection or by oral administration normalized almost completely the number of peritoneal macrophages (4). Secondly, the production of superoxide anions by peritoneal macrophages is profoundly impaired by prednisolone treatment, and the addition of pidotimod by i.p injection or by oral route significantly increased the superoxide anion production (4). Thirdly, pidotimod fully restored tumor necrosis factor alpha (TNFα) secretion by peritoneal macrophages from mice treated with corticosteroids (4). Finally, pidotimod was able to potentiate the natural killer cell (NK) activity in ex vivo experiments both in young and old mice. The defective NK activity in aged mice was thought to represent an indirect parameter of age-
associated immune deficit (5). In conclusion, the experiments in mice demonstrated that pidotimod enhances the effectors of the innate immunity responses by potentiating different functions of the professional phagocytes and the NK cell activity. Several in vitro and in vivo studies in animal models have been performed to assess the effects of pidotimod on the different mechanisms involved in the adaptive immunity response by using different models of immunodepression. Pidotimod has been demonstrated to enhance the effectors of the adaptive immunity responses by restoring the proliferative response of T lymphocytes, the secretion of Th1 cytokines and by protecting thymocytes from apoptosis in in vivo experiments in mice previously treated with steroids, cyclophosphamide or methotrexate as immunosuppressant agents (6). Cell-mediated immune response was investigated in in vivo animal models as dinitrochlorobenzene (DNCB)-induced delayed hypersensitivity or as graft-versus-host (GvH) reaction in immunodepressed mice (6). Prednisolone, in addition to pidotimod or saline, was administered to mice subsequently exposed to DNCB on the ear skin. The immune response evaluated as ear weight was significantly higher in mice pre-treated with pidotimod than in controls. In the second experiment, a cellular suspension obtained from the spleen of C57BL/6 mice previously treated with pidotimod and subsequently immunodepressed with cyclophosphamide was injected into BDF1 mice and the immunological response against the infused donor cells was evaluated as “splenic index” (SI: ratio between splenic weight/treated mouse body weight and splenic weight/control mouse body weight). The twice-daily treatment with pidotimod significantly increased the GvH reaction (+21% in mice treated with oral pidotimod and +24% in mice treated with i.p. pidotimod) and partially restored the immune response of the immunocompromised mice (6). Further information on the effect of pidotimod on lymphocyte activity and proliferation was obtained by ex vivo studies. Splenic lymphocytes from mice treated with pidotimod by two different routes (i.p. or oral) and dosages and immunized with sheep erythrocytes were able to form an increased number of rosettes in comparison with saline treated mice (+38% and +45% for i.p.; +42% and +26% for
Int. J. Immunopathol. Pharmacol.
p.o. administration) (6). Both spontaneous blastogenesis and proliferation in response to mitogens were measured in cyclophosphamide-immunodepressed mice previously treated with pidotimod or saline. Pidotimod was able to restore spontaneous blastogenesis up to values near to controls (p