Conclusion And Perspectives

MLT may be considered as a potential immunotherapeutic agent and an important endogenous neuroimmunomodulator. An hypothetical pineal gland-immune system physiological network might, therefore, take shape (Figure 1). The proper functioning of such network might be crucial in the adaptative response of the organism to environmental demands and, thus, in the maintenance of health. However, we are still far from a complete understanding of the mechanism underlying the immunological and hematopoietic action of MLT. For example, it is not clear whether MLT acts on Th1 or Th2 cells or on both. In addition, it is not known whether MLT may induce cytokine gene expression or whether its action is posttranslational only. These seem important questions as the Th1/Th2 balance and the resulting cytokines production are crucial for a successful immune response and may be relevant in immune-based pathologies (23). The stimulatory effect of MLT on IL-2 and gamma-IFN and the lack of influence on IL-4 suggests the involvement of Th1 cells. Perhaps, the same Th cell type may also produce MIO which are radically different from the enkephalin-containing molecules reported to be produced by Th2 cells (30). On the other hand, the dramatic protection exerted by MLT in experimental models of viral encephalitis and lethal bacterial infections as well as its capacity to restore depressed immune functions is consonant with a Th1 cells involvement as well as with the action of MLT on monocyte/macrophage cytokines (23). Physiologically, it seems possible to distinguish two different roles. The first one occurs in acute conditions during a viral or bacterial infection which produces a substantial activation of the immune system. In that condition, endogenous and/or exogenous MLT may optimize the immune response by sustaining Th cell and macrophage functions and production of cytokines, part of which (MIO, IL-6, IL-1) may also affect hematopoiesis. A second, more general role may be

Melatonin Macrophage

exerted at the hematopoietic-immune level by a chronic circadian resetting of the immunological machinery to maintain the immune homeostasis. This is suggested by the observation that in healthy mice, i.e. in absence of any infection and immunologi-cal activation, only the Th cells which sit in the bone marrow are sensitive to MLT (50,51). Products of this MLT-bone marrow Th cells interaction are the MIO which may affect hematopoiesis and thymocytes proliferation (50,51). Both the acute and chronic mechanisms might be exploited in the use of MLT as immunotherapeutic agent to correct secondary immunodeficiency or fight viral diseases. As we already stated in preceding reviews (56,57), we would like to stress the need for a large double blind study in human immunodeficiency virus (HIV)-positive patients. In presence of normal Th cell counts, the apparent ability of MLT to sustain Th cell functions and IL-2 and gamma-IFN production might result in delayed development or occurrence of AIDS. Reduction of plasma viremia was associated with an increased IL-2 mRNA expression in lymph nodes of HIV-infected patients (71). IL-2 is the most potent cytokine capable of inducing the CD8+ T cell -mediated inhibition of HIV replication which seems to override the ability of IL-2 to stimulate HIV expression (33). If effective, MLT administration would be a relatively cheap and safe prevention of this devastating disease. Alternatively, MLT might be associated with low-dose IL-2 which seems to be beneficial in HIV-associated malignancies (10) or with HIV protease inhibitors. The use of MLT in combination with IL-2 in cancer neuroimmunotherapy might prolong survival and improve the patients' quality of life (19). These encouraging results obtained by Lissoni and coworkers deserve, therefore, to be expanded and challenged in other studies. In addition, MLT might be useful in enhancing the immune response against tumor antigens, a promising therapeutic strategy for cancer vaccines. In regard to the use of MLT in combination with cancer chemotherapeutic drugs the results obtained so far are disappointing. MLT administered alone seems to worsen the bone marrow toxicity of common cancer chemotherapeutic regimens or, at best, be ineffective. This fact calls for further studies to understand the role of MLT in hematopoiesis and indicates that, in certain conditions, MLT may have adverse effects.

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