Abstract
BackgroundThe phenomenon of hormesis, whereby small amounts of seemingly harmful or stressful agents can be beneficial for the health and lifespan of laboratory animals has been reported in literature. In particular, there is accumulating evidence that daily brief cold stress can increase both numbers and activity of peripheral cytotoxic T lymphocytes and natural killer cells, the major effectors of adaptive and innate tumor immunity, respectively. This type of regimen (for 8 days) has been shown to improve survival of mice infected with intracellular parasite Toxoplasma gondii, which would also be consistent with enhanced cell-mediated immunity.Presentation of the hypothesisThis paper hypothesizes that brief cold-water stress repeated daily over many months could enhance anti-tumor immunity and improve survival rate of a non-lymphoid cancer. The possible mechanism of the non-specific stimulation of cellular immunity by repeated cold stress appears to involve transient activation of the sympathetic nervous system, hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes, as described in more detail in the text. Daily moderate cold hydrotherapy is known to reduce pain and does not appear to have noticeable adverse effects on normal test subjects, although some studies have shown that it can cause transient arrhythmias in patients with heart problems and can also inhibit humoral immunity. Sudden immersion in ice-cold water can cause transient pulmonary edema and increase permeability of the blood-brain barrier, thereby increasing mortality of neurovirulent infections.Testing the hypothesisThe proposed procedure is an adapted cold swim (5–7 minutes at 20 degrees Celsius, includes gradual adaptation) to be tested on a mouse tumor model. Mortality, tumor size, and measurements of cellular immunity (numbers and activity of peripheral CD8+ T lymphocytes and natural killer cells) of the cold-exposed group would be compared to those of control groups (warm swim and no treatment). Cold-water stress would be administered twice a day for the duration of several months.Implications of the hypothesisIf the hypothesis is supported by empirical studies and the method is shown to be safe, this could lead to the development of an adjunctive immunotherapy for some (non-lymphoid) cancers, including those caused by viral infections.
Highlights
The phenomenon of hormesis, whereby small amounts of seemingly harmful or stressful agents can be beneficial for the health and lifespan of laboratory animals has been reported in literature
Numerous studies show that small amounts of harmful or stressful agents can be beneficial for the health of laboratory animals, the phenomenon that became known as hormesis, evidence for possible benefits in humans is lacking at present [1,2]
This paper presents theoretical evidence for immunomodulating properties of brief cold stress, as increasing evidence indicates that cold stress repeated daily can have a stimulating effect on cell-mediated immunity [3,4,5,6], while inhibiting humoral immunity to some extent [7,8]
Summary
Numerous studies show that small amounts of harmful or stressful agents (e.g. heat stress, cold stress, hypergravity) can be beneficial for the health of laboratory animals, the phenomenon that became known as hormesis, evidence for possible benefits in humans is lacking at present [1,2]. Effects on maturation and peripheral recruitment of CTLs Brief cold stress such as a cold swim has been reported to increase the level of peripheral T lymphocytes both in a transient manner after a single treatment (CD8+ T lymphocytes [11]) and in a sustained manner, when treatments are repeated daily or thrice per week (both CD4+ and CD8+ lymphocytes [3,12]) This could be mediated by the transient action of norepinephrine on β2-adrenergic receptors of CD8+ T lymphocytes [36,37,38] as a result of the activation of the SNS [39,40,41], which innervates both primary and secondary lymphoid organs and can stimu-. If the theory is confirmed by empirical studies and the proposed approach is shown to be safe, some form of cold hydrotherapy could potentially become a treatment option for some (non-lymphoid) cancers as an adjunctive immunotherapy
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