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migratory response in NK and T cells while having no effect on monocytes and neutrophils.¹⁹ Thus, mechanisms are in place to mediate highly selective patterns of migration and recruitment of specific leukocyte subpopulations. The recirculation pattern of immune cells varies in a circadian pattem, which is dependent on neuroendocrine signals. In one study, a clear circadian rhythm was seen for T cell subsets, but not for NK cell ^5,21) whereas another study reported a clear increase of NK numbers and activity in the morning.²¹ It is believed that high levels of cortisol in the beginning of the day interfere with interleukin-2 production and enhance the migration of lymphocytes from the blood into tissues. Other mechanisms of inducing high levels of cortisol (stress, exercise),^22-24 as well as injection of hydrocortisone,²⁵ have similar inhibitory effects on lymphocyte migration. Importantly, species variations exist, and stress experiments in rodents cannot directly be compared to human studies. The different physiological responses to various stressors in the human system may be difficult to understand in the light of how apparently similar stressors are perceived in laboratory animals. The recruitment of NK cells is very sensitive to catecholamines, especially epinephrine.²⁶ The catecholamines have a negative effect on the adhesion of NK cells to the vessel walls, and cause the NK cells to detach. The changes in NK cell trafficking are not accompanied by changes in adhesion molecule expression on the circulating NK cells. The catecholamine-induced accumulation of NK cells in the blood was identical in normal and splenectomized donors, indicating that the spleen was not the relevant reservoir of NK cells.²⁷ Several studies have reported a stress-mediated increase in numbers of B and NK cells in blood.^28,29 Throughout the body, many nerve factors are able to function as chemokines, and immune cells express receptors for neurotransmitter molecules. Only some cytokines are regulated by cortisol, and a hierachy of cortisol-sensitivity has been proposed.³⁰ The bidirectional relationship between neuronal and immunological systems extends to the lymphoid tissues. In addition to the well-characterized central nervous system regulation of adrenals, nerve terminals invade all lymphoid tissue, and synapse-like ft)rmations can be seen between nerve endings and immune cells in bone marrow, lymph nodes, and spleen.31 Neumnal control of haematopoiesis has been studied in detail, and a complex feedback system exists, involving multiple cytokines and neurotransmitters.^32-33 Neuropeptide Y is an example of a neurotransmitter that is directly able to upregulate adhesion molecules on human endothelial cells.³⁴ The central nervous system regulation of immune surveillance is of functional importance. In mice, when signaling from the sympathetic nervous system to the periphery was interrupted prior to injection of NK-sensitive tumor cells, the number of metastases was significantly increased.³⁵ As neither the NK activity was altered, nor the ability to respond to tumor antigens, one possible explanation is that the sympathetic nervous system regulates either NK trafficking or matrix deposition in tissue, thereby regulating the ability of NK cells to migrate to the vicinity of tumors. This was partially confirmed by demonstrating that the sympathetic nervous system modulates lymphocyte recruitment into lymph nodes.³⁶ Consumption of the blue-green algae AFA has increased, and despite a large number of anecdotal reports of health benefits, studies of the exact mechanisms of AFA9s effects on immune function were needed. In a previous brief report, we presented preliminary data to show that AFA induced a rapid induction of NK cell recruitment into tissue in humans.³⁷ Since then, we have analyzed the migratory patterns of multiple white blood cell types in a total of 21 study subjects. Upon oral consumption of 1.5 grams AFA, we observed immediate changes in several specific immune parameters. MATERIALS AND METHODS: Subjects: Twenty-one non-hospitalized volunteers were analyzed in a double-blind crossover fashion, after signing an informed consent form. The volunteers had no known acute or chronic infections. Five were long-term AFA consumers, 2 were occasional AFA consumers, and the remaining 14 had never before consumed AFA. Occasional consumers had previously used AFA daily for at least 6 weeks continuously, but were not consuming AFA regularly during the weeks leading up to this study. No volunteer had taken AFA for at least 24 hours prior to being studied. Ten volunteers were male, and eleven were female. The age range was 20-52 years. Study design: Each volunteer was studied on two separate days. Each volunteer was always studied at the same time on the two study days, to eliminate the circadian influence on the data. The 'volunteers were asked to consume the same breakfasts at the same times on the two study days, and not to consume any other vitamin preparations or nutraceuticals for at least 12 hours before the study. The volunteers were required to sit quietly for 45 minutes prior to study start, so that no walking or other exercise could affect the relative proportions of leukocytes. The first blood sample was taken, and the substance was given. Until the drawing of the second blood sample 2 hours later, the volunteers were required to remain quiet and avoid any extensive walking. Consumables and reagents: Both AFA and placebo were provided by Cell Tech (Klamath Falls, Oregon). The dose given to the volunteers was 1.5 grams, which is the recommended dose for daily supplementation. A list of monoclonal antibodies used for immunostaining and flow cytometry is listed in Table 1.
Table 1: List of monoclonal antibodies used in this study.	Purification of mononuclear cells: Fourteen ml of heparinized or EDTA blood was drawn from a peripheral vein. The blood was layered onto a Ficoll gradient and centrifuged to purify the peripheral blood mononuclear cells. Cells were washed, and used for direct immunofluorescence labeling. Samples were fixed in I % formalin and stored cold and dark prior to flow cytometric analysis. Flow cytometry: Data were acquired and stored on list mode for subsequent data analysis. The CellQuest software (Becton Dickinson) was used for acquisition and analysis. During analysis, electronic gating was used to eliminate red cells and clumps from the analysis. Data analysis: The relative proportions of monocytes, B and T lymphocytes, and T cell subsets were calculated based on positivity for the MoAbs listed in Table I. The relative proportion of NK cells was calculated by excluding monocytes and large granular cells from the analysis, then excluding the CD3+ cells, and evaluating the proportion of CD56+ cells in the sample. The number of CD3-CD56+ small lymphocytes was then related to the total number of peripheral blood mononuclear cells (PBMC). Changes were calculated by comparing the AFAand placebo-induced values for each volunteer. Figure 1 gives a representation of the various cell types tested, their relationship, and the marker used for quantification. By combining the relative proportions with actual cell counts, the absolute numbers of PBMC and polymorph nucleated
cells (PMN) were calculated in 12 volunteers. Also, the changes in absolute numbers of the following subpopulations were calculated: monocytes, CD3+ T cells, CD 19+ B cells, CD4+CD45RO-I+ and CD8+CD4SRO-I+ subsets. Purification of neutrophils: Seven ml of heparinized whole blood was mixed with 1.5 ml of 6% dextran 70 in 0.9% saline at room temperature. Sedimentation was allowed for 1 hour. The leukocyte-rich supernatant was harvested and the cells pelleted by centrifugation. The pellet was resuspended in 2 ml phosphate-buffered saline, which was then layered on top of 3 ml of Ficoll-Hypaque. Gradient centrifugation was performed, and the pellet was resuspended in 0.5 ml of phosphate-buffered saline. The remaining red blood cells were lysed by hypotonic shock for 25 seconds, after which isotonicity was restored. Cells were washed, resuspended in RPMI, and kept on ice until use. Assay for PMN phagocytic activity: The ability of PMN cells to kill Staphylococcus aureus bacteria was performed as follows: S aureus (frozen aliquots) were defrosted and washed. The bacteria were then opsonized with pooled human serum for 30 minutes in a 370C shaking water bath. PMN cells and bacteria were added to a series of tubes, and incubated in a 370C shaking water bath. At the following time points 5, 15, 30, and 45 minutes - a tube was removed, immediately placed on ice, and 0.5 ml icecold serum was added in order to stop further phagocytic activity. The tubes were centrifuged in the cold for 5 minutes at 3000 rpm, and the supernatant was decanted. The pellet was stained with Acridine Orange (14.4mg/L) for 1 minute. One ml of icecold buffer was added, and cells were washed 3 times. Cells were resuspended in cold buffer and kept on ice until microscopic examination. A wet mount slide was prepared from each tube for examination in a UV microscope at 100 times magnification. The proportion of phagocytic PMN was evaluated by counting 100 PMN, and counting how many of these cells contained at least 3 bacteria (whether bacteria were live or dead). During the examination, the number of live versus dead bacteria was counted in 50 PMN. Statistical analysis: Standard statistical analysis was performed using NNCS software. Paired t-test was used to determine statistical significance. Values that were outside two interquartile ranges from the 25th and 75th percentiles were considered extreme outliers and were removed from the analysis. The removal of outliers did not change the conclusions. RESULTS: Immediate mobilization of mononuclear cells into the blood: The absolute cell counts before and after consumption of either AFA or placebo were monitored in 12 volunteers. The consumption of AFA resulted in increased blood cell counts when compared to placebo. The PMN population did not change, whereas the lymphocyte (Ly) and monocyte (CDl4) subsets increased (Figure 2A). Within the lymphocyte subpopulation, the increase was observed in all of the following T cell subsets: CD3+, CD4+, CD8+, as well as in the CD 19+ B cell population (Figure 2B).
Figure 2A: AFA-induced changes in blood leukocyte populations. The histogram shows the % change of polymorph nucleated cells (PMN), monocytes (CD 14), and lymphocytes (Ly). Black columns represent the mean values of placebo, and the white columns represent the mean values of AFA. The bars indicate the standard error of the mean.	Figure 2B: AFA-induced changes in lymphocyte sub-populations. The histogram shows the % change of total T cells (CD3), T cell subsets (CD4, CD8), and B cell (CD19) lymphocyte populations. Black columns represent the mean values of placebo, and the white columns represent the mean values of AFA. The bars indicate the standard error of the mean.
The relative proportions between naïve (CD45A+) and memory (CD45RO+) T cells was monitored in all 21 subjects, for both the CD4+ helper and CD8+ cytotoxic T cell subsets. Despite a tendency for a shift towards less naive and more memory T cells in the blood, no significant changes were seen in naive versus memory T cell subsets. Specific recruitment of CD3- CD56+ small lymphocytes from the blood: In all 21 study subjects, the proportional changes of NK cells were examined. Two hours after AFA consumption, the relative proportion of CD3- CD56+ natural killer cells was decreased when compared to placebo (p<0.03). The effect was specific for small NK cells (low forward/side scatter properties), as the subset of cells defined as large granular lymphocytes (CDl4-negative, large granular cells) was not affected (data not shown). Long-term consumers produced a more pronounced response than naive volunteers. When the volunteers were grouped into long-term AFA consumers and naive volunteers, naive volunteers displayed a minor reduction in NK cells after AFA consumption, whereas long-term consumers displayed a pronounced reduction (p <0.005).
Figure 3: The relative changes in subpopulations of T cells is shown (mean and SEM for 21 volunteers). The helper (CD4+) T cell and cytotoxic (CD8+) T cell populations showed only a slight shift towards less naive and more activated/memory T cells in the circulation, and no statistical significance was reached.	Figure 4: Changes in natural killer cells (NK cells) in % of the starting value. Black columns represent the mean values of placebo, and the white columns represent the mean values of AFA. The bars indicate the standard enror of the mean. Figure 5: Western blotting of tyrosine phosphorylation of proteins extracted from unstimulated lymphocytes (lane I) versus lymphocytes incubated with Pokeweed Mitogen (PWM, positive control, lane 2) or AFA (lane 3: extract 1:5, lane 4: extract 1:25). Incubation of freshly purified human lymphocytes with AFA extract did not induce tyrosine phosphorylation. The data are representative of four similar experiments.
Adhesion molecule expression on circulating leukocytes: We examined the expression of a series of adhesion molecules on the surface of monocytes, B, and T cells before and after AFA exposure in vivo and in vitro. The following adhesion molecules and subunits were examined: CD62L, CDlla, CDl lb, CDl8, CD29, CD44, and CD49d. The fluorescence intensity was monitored by % positive, as well as mean and median fluorescence values. Short-term incubation (90 minutes) in vitro with AFA extract resulted in a moderate loss of CD62L on B as well as T cells, and a weak upregulation of CDl lb, but no other changes in the expression of the following adhesion molecules: CD I 1 a, CDl8, CD29, CD44, and CD49d. Analysis of adhesion molecule expression on lymphocytes from volunteers 2 hours post AFA consumption showed moderate changes in CD62L expression, but no other changes (data not shown). AFA extract does not activate lymphocytes directly: We tested whether AFA extract could directly activate lymphocytes in vitro. When purified mononuclear cells were incubated with AFA extract, no activation was seen, as examined by tyrosine phosphorylation after 1-20 minutes of AFA exposure (Figure 5) and proliferative responses after 5 days of AFA exposure in vitro (Figure 6). Modulation of the phagocytic activity of polymorph nucleated (PMN) cells: The phagocytic activity of PMN cells was evaluated, using PMNs from blood samples drawn before and 2 hours after AFA consumption. The phagocytic activity was monitored at different times of incubation. When the study subjects had ingested placebo, no differences on in phagocytic activity were seen. In contrast, after consumption of AFA, a mild decrease in phagocytic activity was measured (Figure 7). This effect reached levels of significance only at longer incubation times (see legend to Figure 7).
Figure 6: Flow cytometric evaluation of lymphocyte proliferation after 5 days of culture with no stimulation (top), with AFA water extract (middle), and Pokeweed Mitogen (PWM, bottom). The X axis displays fluorescence intensity, where loss of fluorescence corresponds to proliferative activity. The proliferative index for each culture condition is displayed in upper right corner of each histogram. The experiment was conducted three times, where all cultures were performed in triplicate.	Figure 7: Phagocytic activity of polymorph nucleated cells (PMN) from volunteers before and after placebo or AFA ingestion. The phagocytic activity was unaffected by placebo, but was moderately reduced by AFA, thus resulting in a lower maximum phagocytic capacity, and a lower phagocytic rate.
DISCUSSION Based on the many case reports on beneficial neurological and immunological effects of consumption of the blue-green algae Aphanizomenon .fios-aquae, we studied the immune activation within 2 hours after ingestion of 1.5 grains AFA. (This dose is recommended for food supplementation.) We examined several aspects of immune cell migration and function. The data presented in this paper indicate a mild but consistent effect on the human immune system. The absolute numbers of circulating leukocyte subsets was increased. This effect was limited to lymphocytes and monocytes, whereas polymorph nucleated cells were not affected. This indicates a selective mobilization of lymphocytes and monocytes from primary or secondary lymphoid tissues, into the blood circulation. Thus, more monocytes, B, and T cells were released into the blood. In the preliminary study (involving 1 occasional and 4 regular AFA consumers), AFA consumption induced a substantial transient recruitment of NK cells in all five volunteers, peaking at 2 hours and rapidly declining.37 In the current analysis of 21 people, there was a specific recruitment from the blood of small NK cells. It could be argued that AFA only leads to margination (ie, lymphocytes sticking to the vessel walls without transmigration). However, margination is not a permanent phenomenon, and the on/off rate would allow us to sample some cells that have marginated and later released from the blood vessel wall. Such cells would likely demonstrate altered adhesion profiles, which we did not find. In addition, as the recruitment of cells from circulation into lymphoid tissue is highly cell-type specific, mediated in part by cell-type specific chemokines, transmigration would provide a more plausible explanation. Increase in adhesion molecule expression was previously observed in a small number of long term consumers.37 The present study reports data from a more thorough evaluation. When examining the profile of adhesion molecules on the surface of circulating lymphocyte subsets, we found occasional shifts in adhesion molecule expression, confirming earlier observations, but in this larger study we found no consistent differences induced by AFA in vivo. This evaluation is hampered by the fact that we are not able to directly sample the cells that have left the circulation as a result of AFA. Thus, AFA did not uniformly affect the adhesion profile of all circulating lymphocytes. The low dose of AFA ingested and the rapidity of the observed effects do not support a direct effect, where bioactive molecules in AFA would be absorbed into the blood, and transported to the bone marrow and spleen, and there result in cellular changes leading to release of cells into the blood. A more plausible model for explanation is that neuro-or immune-active substances in AFA leads to triggering of a gut-to-brain activation. It has been reported that IL1 beta is able to mediate a gut-to-brain communication via the abdominal vagus nerve.38~39 Thus, in terms of rapid modulation of leukocyte recirculation, a gut-to-brain signal would result in brain-to-lymphoid-tissue signals, including the rapid release of chemokines. Many neuropeptides are either chemotactic or immunomodulatory. As nerve terminals wrap around the high endothelial regions of lymphocyte recruitment in the peripheral tissue, a central activation could rapidly amplify and alter cellular recruitment in a highly selective manner. In the bone marrow, nerve terminals come in close contact with developing and maturing cells, and could regulate the volume of cells released into the blood circulation.
Figure 8: Hypothetical model for AFA-induced immuno-modulation. 1) Ingestion of AFA, and release of bioactive phytochemicals in the stomach and/or upper intestine. 2) Release of cytokine(s) in the gut triggers vagus nerve signals from gut to CNS. 3) Central nervous system signals the peripheral lymphoid tissues, resulting in altered immune cell trafficking.	The rapid changes in leukocyte recirculation were stronger in long-term AFA consumers. Since the study design was double-blinded and randomized, the volunteers were not themselves aware of when they were receiving AFA versus placebo. Given the suggested CNS-mediated modulation of the immune system, a conditioning may have been established in which the CNS may have recognized the stimulation by AFA and in previously-exposed consumers added a conditioned component to the immune activation of cell trafficking. During our studies, we have been on guard for observations that could point in the direction of over-activation of the immune system. More is not always better. An over-activation of the immune system could be associated with circulating immune complexes and an increase in inflammatory processes that could be detrimental to health. We found no indications of a direct activation of any component of the immune system or a general activation of the immune system as a whole. The increased trafficking of immune cells should translate into better immune surveillance, ie, better and more efficient patrolling of microbial invaders, as well as virus-infected or transformed cells. We see this as very positive for the potential use of AFA in various clinical situations or as a nutritional support for the prevention of viral infections. This data also points to further research in a potential role for AFA in cancer prevention. ACKNOWLEDGEMENTS This study was funded by Cell Tech, Klamath Falls, Oregon, and performed in the laboratory of Dr. Gitte S. Jensen. We are grateful to Ann Griffith for her enthusiastic help with data entry and analysis, to Christine Ichim for technical assistance, and to Dr. David Schaeffer, University of Illinois, for statistical analysis. REFERENCES 1. Ostensvik 0, Skulberg OM, Underdal B, Hormazabal V. Antibacterial properties of extracts from selected plank-tonic freshwater cyanobacteria - a comparative study of bacterial bioassays. JAppl Microbiol 1998; 84(6): 1117-24. 2. Lahitova N, Doupovcova M, Zvonar J, Chandoga J, Hocman G. Antimutagenic properties of freshwater blue-green algae. Folia Microbiologica (Praha) 1994; 39(4):301 -3. 3. Hayashi K, Hayashi T, Kojima I. A natural sulfated polysaccharide, calcium spirulan, isolated from Spirulina platensis: in vitro and ex vivo evaluation of anti-herpes simplex virus and anti-human immunodeficiency virus activities. AIDS Res Hum Retroviruses 1996; 12(15):1463-71.
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Consumption of Aphanizomenon flos-aquae Has Rapid Effects on the Circulation and Function of Immune Cells in Humans

A novel approach to nutritional mobilization of the immune system