Physiological organization of immune response based on the homeostatic mechanism of matrix reprogramming: implication in tumor and biotechnology.

It is accepted that the immune system responds to pathogens with activation of antigen-independent innate and antigen-dependent adaptive immunity. However many immune events do not fit or are even inconsistent with this notion. We developed a new homeostatic model of the immune response. This model consists of four units: a sensor, a regulator, an effector and a rehabilitator. The sensor, macrophages or lymphocytes, recognize pathogenic cells and generate alarm signals. The regulator, antigen-presenting cells, Тregs and myeloid-derived suppressor cells, evaluate the signals and together with sensor cells program the effector. The effector, programmed macrophages and lymphocytes, eliminate the pathogenic cells. The rehabilitator, M2 macrophages, restrict inflammation, provide angiogenesis and reparation of tissue damage, and restore the homeostasis. We suggest the terms "immune matrix" for a biological template of immune responses to pathogens and "matrix reprogramming" for the interdependent reprogramming of different cells in the matrix. In an adequate immune response, the matrix forms a negative feedback mechanism to support the homeostasis. We defined the cellular and phenotypic composition of a tumor immune matrix. A tumor reprograms the homeostatic negative feedback mechanism of matrix into a pathogenic positive feedback mechanism. M2 macrophages play a key role in this transformation. Therefore, macrophages are an attractive target for biotechnology. Based on our hypotheses, we are developing a cell biotechnology method for creation of macrophages with a stable antitumor phenotype. We have shown that such macrophages almost doubled the survival time of mice with tumor.

Adaptation to intermittent hypoxia restricts nitric oxide overproduction and prevents beta-amyloid toxicity in rat brain.

This study tested the hypothesis that adaptation to intermittent hypoxia (AIH) can prevent overproduction of nitric oxide (NO) in brain and neurodegeneration induced by beta-amyloid (Aß) toxicity. Rats were injected with a Aß protein fragment (25-35) into the nucleus basalis magnocellularis. AIH (simulated altitude of 4000 m, 14 days, 4h daily) was produced prior to the Aß injection. A passive, shock-avoidance, conditioned response test was used to evaluate memory function. Degenerating neurons were visualized in stained cortical sections. NO production was evaluated in brain tissue by the content of nitrite and nitrate. Expression of nNOS, iNOS, and eNOS was measured in the cortex and the hippocampus using Western blot analysis. 3-Nitrotyrosine formation, a marker of protein nitration, was quantified by slot blot analysis. Aß injection impaired memory of rats; AIH significantly alleviated this disorder. Histological examination confirmed the protective effect of AIH. Degenerating neurons, which were numerous in the cortex of Aß-injected, unadapted rats, were essentially absent in the brain of hypoxia-adapted rats. Injections of Aß resulted in significant increases in NOx and in expression of all NOS isoforms in brain; AIH blunted these increases. NO overproduction was associated with increased amounts of 3-nitrotyrosine in the cortex and hippocampus. AIH alone did not significantly influence tissue 3-nitrotyrosine, but significantly restricted its increase after the Aß injection. Therefore, AIH affords significant protection against experimental Alzheimer's disease, and this protection correlates with restricted NO overproduction.

Possible use of adaptation to hypoxia in Alzheimer's disease: a hypothesis.

Disorders in memory and other cognitive functions in Alzheimer's disease (AD) may result from an exhaustion of adaptive reserves in the brain. Therefore it is a challenge to find methods to increase the adaptive reserve of the organism to combat AD. Excitotoxicity, Ca2+ homeostasis disruptions, oxidative stress, disturbed synthesis of NO, and impaired cerebral circulation are suggested as key pathogenic factors of AD. At present it appears that stimulation of the self-defense systems in neural cells is a promising strategy in restricting the progression of AD. These systems include those of antioxidants, heat shock proteins (HSPs), NO, and other so-called stress-limiting systems. Non-drug activation of these systems can be achieved most efficiently by adaptation of the organism to environmental challenges, such as hypoxia. In this paper the potential of methods used in adaptive medicine is explored. The protective mechanisms of adaptation to hypoxia may be related to restriction of oxidative stress in the hippocampus, the limitation of a decrease in NO production induced by beta-amyloid, and increased density of the vascular network in the brain. In this review we selectively present data that support the idea that adaptation to hypoxia is a possible non-drug means in the prevention of AD. In our opinion this strategy may provide a break-through in the clinical approach of this disease.