Sandra C Miller

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contents

Introduction

Evidence of a Prophylactic Role for Echinacea Echinacea Can Rejuvenate NK Cells in Elderly Animals Arabinogalactan Augments NK Cells

Echinacea Given to Leukemic Mice Enhances NK Cells and Increases Life Span Echinacea in Combination Therapy Enhances NK Cells and Increases Life Span of

Leukemic Mice References

Although herbal medicine was practiced by U.S. physicians in the 19th and early 20th centuries, Echinacea was never approved by the American Medical Association because rigorous experimental evidence of its medical efficacy did not exist, and in fact, the healing properties of this herb were virtually forgotten with the development of antibiotics (Combest and Nemecz, 1997). Subsequently, however, techniques for measuring the functional response of different immune cells, at least in vitro, led to herbs such as Echinacea being rediscovered and immune stimulation was advanced as a possible mechanism for their medicinal value. During the past 2 decades, much effort has been devoted to analyzing the many chemical compounds from this plant that may act on specific immune cells. These studies have indicated that such compounds include high molecular weight polysac-charides, inulin, heteroxylan, essential oils, alkyamides such as echinacein, isobutylamides (pen-tadecadienes and hexadecadienes), polyacetylene, tannins, vitamin C, and flavonoids. From this list, some important immunoenhancing elements may be those that interfere with prostaglandin formation, since prostaglandins are detrimental to natural killer (NK) cells. NK cells are fundamental as the first line of defense against a host of invading pathogens. We found some years ago that in vivo administration of an inhibitor of prostaglandin (i.e., indomethacin) significantly increased NK cells in leukemic mice, concomitant with cure and/or significantly longer life span (Christopher et al., 1991; Dussault and Miller, 1993). In the same way, the alkamide family of compounds within Echinacea inhibits the production of 5-lipoxygenase and cyclooxygenase (Muller-Jakic, 1994; Wagner et al., 1989), key enzymes in the production of prostaglandins, leading, thus, to an increase in the NK cell population, by reducing/removing the negative agent, prostag-landin. Thus, any treatment that would augment such cells would clearly be worthy of investigation for its therapeutic/prophylactic potential.

introduction

NK cells, unfortunately, decline with age, and correspondingly, several types of cancer increase with age in both mice and humans. This relationship is undoubtedly more than coincidental. Some years ago, we established the mechanism for the age-related decline in NK cells (Dussault and Miller, 1994) and found that it results from a least two phenomena: (1) reduced new cell production in the NK cell lineage in the bone marrow birth site, and (2) reduced efficiency of mature NK cells to bind to their target cells, hence preventing subsequent killing of the offensive target, such as virus-infected or cancer cells. Moreover, a growing body of anecdotal and experimental evidence suggested that certain phytochemicals in herbs might have the capacity to reduce tumors and virus infections (Bauer, 1996; Melchart et al., 1995; See et al., 1997). Considerable evidence had accumulated indicating the presence of immunostimulating compounds within Echinacea (Bauer, 1996; Muller-Jakic et al., 1994; Roesler et al., 1991a, 1991b; Steinmuller et al., 1993). One such compound is the complex carbohydrate, arabinogalactan. Macrophages, fundamentally important "helper" cells for the functional activity of NK cells, release numerous cytokines upon stimulation with purified polysaccharides such as and including arabinogalactan (Bauer, 1996; Leuttig et al., 1989; Stimpel et al., 1984). Among the resulting cytokine cascade produced by such stimulated macrophages are several powerful NK enhancers, such as interferon and TNF-a (Hauer and Anderer, 1993; Kelly, 1999; Leuttig et al., 1989; Rininger et al., 2000; Stein et al., 1999).

Thus, all these studies have collectively shown that while the polysaccharide, arabinogalactan, results in the production of NK stimulators, other Echinacea-derived phytochemicals (i.e., the alkamides) can release NK cells from their natural endogenous inhibitors, the prostaglandins. Consequently, a combination of all the positive data (anecdotal and experimental), emerging from the results of in vivo administration of Echinacea (Hill et al., 1996; Lersch et al., 1990, 1992; Roesler et al., 1991a, 1991b; Steinmuller et al., 1993; Stimpel et al., 1984; Tragni et al., 1985), led to our hypothesis that administration of Echinacea to leukemic mice may lead to the reduction and/or cure of these retrovirus-mediated cancers. Furthermore, we hypothesized that therapeutic intervention with Echinacea as an NK cell enhancer in combination therapy could be very successful in leukemia treatment. Antitumor immunotherapy, whereby immunization is combined with some pharmaceutical or secondary treatment, is coming into use clinically, and is in under considerable experimental testing.

Of fundamental importance for the use of any agent, either prophylactically or therapeutically, especially over the long term, is that it not be, by itself, as deleterious (toxic) to the host as the disease(s) for which it is administered. In the case of Echinacea species, there is considerable evidence that, indeed, there appears to be no overdose/toxicity level as defined by assorted criteria (Lersch et al., 1992; Melchart et al., 1995; Mengs et al., 1991). Consequently, in our own studies, we chose a dose that was at the top of a dose-response curve prior to its plateau, as measured by progressive increases in the absolute numbers of NK cells. No further increase in NK cell numbers was found using a dose beyond 0.45mg/25g body weight per day, at least for the specific brand of E. purpurea employed throughout the studies discussed below.

evidence of a prophylactic role for ECHINACEA

We undertook a study a few years ago (Sun et al., 1999) to investigate the changes in immune system cells — as well as other hemopoietic cells — that may result from dietary intake of Echinacea. We added to the daily diet of inbred mice, for either 1 week or 2 weeks, E. purpurea extract from a commercial supplier (Phyto Adrien Gagnon, Santé Naturelle (A.G.) Ltée, La Prairie, QC, Canada), whose product is readily available in the marketplace and consumed by the general public. Thus, under controlled laboratory conditions, we analyzed the hemopoietic and immune cell populations in the spleen and bone marrow of normal, young adult mice, with and without E. purpurea in their daily diet for 1 week or 2 weeks. The spleen is a vast repository for cells mediating specific immunity (T and B lymphocytes), as well as nonspecific immunity (NK cells, mono-cytes/macrophages) and other cells involved in the generalized disease defense process (mature granulocytes). The bone marrow is the birth site of all abovementioned cells, and hence a repository of the precursor cells for all these lineages.

Our results indicated that mice fed E. purpurea daily for either 1 week or 2 weeks, had, in absolute numbers, significantly more NK cells (identified by immunoperoxidase labeling methods) in their bone marrow than did the bone marrow of mice consuming untreated chow (p < 0.01). The spleen (to which bone marrow-derived, new NK cells travel almost exclusively) had approximately 25% more NK cells in mice fed E. purpurea for 1 week, and significantly more NK cells (p < 0.01) after 2 weeks of daily dietary consumption of the herb. Moreover, monocytes/macrophages, accessory cells for NK cells, were approximately 25% more plentiful in both the bone marrow and spleen of mice consuming E. purpurea for 1 week, and were significantly more numerous in the spleen (p < 0.01) and bone marrow (p < 0.0l) of mice consuming the herb for 2 weeks. Especially important is the fact that increased NK cells in the bone marrow necessarily means that these new NK cells had been produced there under the influence of the dietary Echinacea, since NK cells do not recirculate back to the bone marrow once they exit that organ (Miller, 1982; Seaman et al., 1978; Zoller et al., 1982). In other words, increased NK cells in the bone marrow necessarily resulted from increased production of these cells, under the influence of E. purpurea. Strikingly, moreover, all other lymphocyte populations, as well as the mature granulocytes, granulocyte precursors, and red blood cell precursors, remained steadfastly at control (untreated chow) levels in both the spleen and the bone marrow, whether mice were fed E. purpurea for 1 week or 2 weeks. Therefore, this study, incorporating the parameters of herb exposure time, host animal pedigree, age, health, gender, and living environment, demonstrated singularly positive influences of E. purpurea on NK cells and their accessory cells, the monocytes/macrophages. This study represents the first quantitative in vivo analysis demonstrating the effects of Echinacea on the hemopoietic and immune cell populations in the organs of their birth (bone marrow) and function (spleen) under controlled laboratory conditions. The fact that these results were found in normal, healthy young adult animals indicates a potentially prophylactic role for E. purpurea.

ECHINACEA can rejuvenate nk cells in elderly animals

The observations of our study above prompted a systematic investigation of the potential NK-stimulating role of E. purpurea in aging mice under the same conditions. Furthermore, since we had now demonstrated that NK cell production is augmented in the bone marrow in young adult mice in the presence of E. purpurea, we hypothesized that this may also occur in elderly mice, the latter group normally exhibiting little or no new NK cell production (Albright and Albright, 1983; Dussault and Miller, 1994; Ghoneum et al., 1991; Hanna, 1985; Krishnaraj, 1992; Kutza and Murasko, 1994). Consequently, we completed a study recently (Currier and Miller, 2000) which demonstrated that in healthy elderly mice, it was possible not only to increase NK cell numbers but their function as well by adding Echinacea purpurea to the daily diet of normal elderly mice for only 2 weeks. Both parameters (NK cell numbers and function) are diminished, or very reduced, in normal elderly humans as well as elderly mice. Indeed, this herbal addition to the diet of elderly mice returned their NK cell numbers and function to the levels of their young adult counterparts. In elderly humans, exogenous administration of various cytokines and growth factors results in little or no stimulatory influence on a variety of immune parameters (Kawakami and Bloom, 1988; Kutza and Murasko, 1994; Lerner et al., 1989). Similarly, we had previously found in healthy elderly mice that neither the cytokine, IL-2, nor the pharmaceutical agent, indomethacin (both potent stimulators of NK cells in the young adult animal), was able to stimulate its NK cell numbers or function (Dussault and Miller, 1994). Specifically, we found that giving this herb via the chow to old mice every day for 2 weeks resulted in an increase in absolute number of NK cells in the bone marrow, from almost undetectable numbers to significantly increased numbers (p < 0.004), equivalent to levels seen in young adult bone marrow. These results clearly indicate that this herb has been able to actually stimulate new NK cell production in the aged mice, after NK cells had undergone the natural age-related decline. Moreover, in the spleen, which is by far the major recipient organ for virtually all bone marrow-derived NK cells (Miller, 1982), the absolute numbers of NK cells were 30% greater than in control mice consuming untreated chow. However, no positive influence was found on the absolute numbers of the mature or precursor granulocytes, precursors to red blood cells, or immune cell (lymphocytic) populations after 2 weeks of ingesting E. purpurea, in either the spleen or the bone marrow in accordance with our previous observations in young adult mice (Sun et al., 1999).

Our study (Currier and Miller, 2000) also demonstrated that the actual lytic capacity, that is, ability to kill tumor cells, of this newly produced army of NK cells in these elderly mice was also returned to levels equal to those of young adults. In other words, we found that there was a consistent and statistically significant elevation in tumor killing (cytolytic) activity (p < 0.03 to 0.001) by NK cells taken from healthy aged mice that had been fed Echinacea for 2 weeks versus those fed regular untreated chow.

This study was especially pivotal since it demonstrated that the herb E. purpurea had the capacity to rejuvenate NK cells, a major element in the disease defense armament, in terms of both numbers and function. This rejuvenation ability could not be achieved by other NK-cell stimulants that were so successful in young adults.

arabinogalactan augments nk cells

In a recent study (Currier et al., 2002), we injected arabinogalactan intraperitoneally into young adult and elderly inbred mice once daily for either 1 week or 2 weeks. The specific arabinogalactan used is a water-soluble, complex carbohydrate form (L-arabino-D-galactans), a highly branched molecule with branched backbone chains of (1-3/6)-linked b-D-galactopyranosyl residues to which are attached side chains containing L-arabinofuranosyl, L-arabinopyranosyl residues. In striking contrast to our observations of increased NK cell numbers 1 week after daily administration of whole Echinacea (Sun et al., 1999), the results of administering arabinogalactan alone to healthy young adult mice for 1 week significantly decreased NK cell numbers in the bone marrow (p < 0.02), and resulted in no change from control numbers in the spleen (Currier et al., 2002). However, by 2 weeks after daily exposure to arabinogalactan, NK cell numbers in the bone marrow had risen to control levels and in the spleen they were significantly increased (p < 0.004), almost double the control numbers. Thus, unlike whole Echinacea, the effects of which were readily evident as stimulation of new NK cell production in the bone marrow by 1 week (Sun et al., 1999), it appeared that 2 weeks were needed to produce any stimulatory effect on NK cells when the polysaccharide alone was employed. Moreover, that observation appeared to be the only positive effect of this polysaccharide in these healthy young adult animals. The lymphocytes (T, B cells) were significantly decreased after 1 week (p < 0.004) and 2 weeks (p < 0.001) of arabinogalactan administration in bone marrow. With respect to the other hemopoietic cell lineages, arabinogalactan had no influence on them after 1 week, but after 2 weeks, in the spleen, mature granulocyte numbers, as well as their precursors and cells of the monocyte/macrophage lineage, were significantly reduced (p < 0.006, p < 0.043, and p < 0.001, respectively), while remaining unchanged in the bone marrow (Currier et al., 2002).

In striking contrast to our observations on elderly mice given whole Echinacea (Currier and Miller, 2000), administration of arabinogalactan alone for 2 weeks was completely ineffective in augmenting NK cells in either the bone marrow or spleen, and was similarly ineffective in augmenting other non-NK lymphocytes (Currier et al., 2002). This analysis has demonstrated that although a single phytocompound, in this case, a complex carbohydrate of the type contained in Echinacea species, is capable of enhancing NK cells, the time taken to do so is longer (2 weeks) and, moreover, there is by this time a negative influence on other important disease-defense cell lineages (granulocytes, monocyte/macrophages). Furthermore, it appears that arabinogalactan administered to normal elderly mice is incapable of stimulating NK cells in either the bone marrow or spleen, and has no influence on all other immune and hemopoietic cells in these organs.

Thus, in the long run, it may be more efficacious in terms of prophylaxis and/or therapy to administer whole Echinacea rather than isolated phytochemicals contained therein. Whole product contains multiple compounds, each serving either different or synergistically acting physiologically significant functions. The possibility that the collective whole may indeed be better than any single derivative is supported by circumstantial evidence provided by others (Rininger et al., 2000; Voaden et al., 1972).

ECHINACEA given to leukemic mice enhances nk cells and increases life span

Before 2001, the literature contained no information concerning the status of immune cells and other hemopoietic cells in leukemic (or any tumor-bearing) animals or humans given therapy involving herbals or derived phytocompounds. We recently undertook a study to investigate the role of dietary Echinacea in leukemic mice (Currier and Miller, 2001). The study was completed under controlled laboratory conditions, including the use of (1) inbred mice of identical strain, age, and gender; (2) regulated dose and known exposure times of E. purpurea; (3) known stage of leukemia development; and (4) standardized housing conditions throughout the investigation for all treated and untreated (control) leukemic mice. Leukemias and lymphomas have long been known to be readily killed by NK cells (Biron and Welsh, 1982; Hefeneider et al., 1983; Itoh et al., 1982; Kalland, 1987; Kasai et al., 1981; Keissling et al., 1975; Koo and Manyak, 1986; Lotzova et al., 1986). Moreover, these tumors are virus associated, and virus-infected cells are prime targets for NK cells. We hypothesized, consequently, that any agent that enhances NK cells should be expected to be effective in leukemia abatement. Thus, E. purpurea was given via the daily diet from the day of tumor onset (instigated by injection of 3 x 106 live, FLV-induced leukemia cells) and concluding approximately 3 months later.

The results were strikingly positive. NK cell numbers 9 days after the onset of the leukemia were very significantly elevated over those of leukemic mice fed untreated chow (p < 0.000007). Three months after leukemia onset — long after all the leukemic mice fed untreated chow had died (27 days after tumor onset) — the absolute numbers of NK cells in the treated mice were recorded at more than twice the level found in normal mice of the same age. Moreover, an analysis of all the hemopoietic cell populations in the bone marrow of these leukemic mice at 3 months after leukemia onset revealed that the cell numbers in all major cell lineages were virtually indistinguishable from our previously established findings in normal mice. Thus, this fundamental study demonstrated first, that in the presence of dietary E. purpurea, resumption of normal hemopoiesis and lymphopoiesis in these leukemic mice had occurred (at 3 months), concomitant with the significant increase in the leukemia-fighting NK cells. Second, the life-span analysis revealed that approximately one-third of leukemic mice not only survived until 3 months, but went on to long-term survival and normal life span (Currier and Miller, 2001). The data, when analyzed by Kaplan-Meier Statistics software, revealed that the survival advantage provided by adding E. purpurea to the diet of leukemic mice compared to mice consuming the control diet was statistically significant (p < 0.022). Nevertheless, survival frequency could undoubtedly be improved even more by manipulation of dose/frequency/duration regimens of E. purpurea in the diet.

Thus, it is clear that phytocompounds contained in E. purpurea, and possibly other Echinacea species, may be profoundly valuable tools, at least in combating leukemia and likely in the amelioration of other types of tumors yet untested. Clearly, the therapeutic potential of this herb suggests that it could have a formal and fundamental role to play in modern antitumor therapy, either alone or in combination protocols.

ECHINACEA in combination therapy enhances nk cells and increases life span of leukemic mice

In other experiments, we co-administered to leukemic, E. purpurea-consuming mice (as above), the pineal gland hormone melatonin from leukemia onset. This substance is a neuroimmunomod-ulator, a biogenic indoleamine (N-acetyl-5 methoxytryptamine), long known to be a chronomod-ulator in biologic systems and, more recently, identified as a powerful immunostimulant, specifically involving NK cells (Demas and Nelson, 1998; Guerrero and Reiter, 1992; Liebmann et al., 1997; Maestroni et al., 1996; Poon et al., 1994; Yu et al., 2000). We found (Currier and Miller, 2001) that the combination of melatonin and E. purpurea co-administered in the diet of leukemic, young adult mice increased the survival rate from the approximately 33% achieved by E. purpurea alone, to 40%, such that Kaplan-Meier statistical analysis of survival indicated significance atp < 0.00035 when the two agents were administered together versus that found by giving E. purpurea alone (p < 0.022). Thus, at least in leukemic animals, adding a second NK stimulant (melatonin) proved to be more efficacious than therapy employing E. purpurea alone.

In a sequel to the study above, we assessed the effect of combination therapy using immunization with killed leukemia cells prior to the onset of leukemia, followed by dietary administration of E. purpurea (Currier and Miller, 2002). Studies involving tumor immunization have employed a wide variety of protocols, including genetic engineering of tumor cells with and without viral modification or injecting killed tumor cells or their extract (Carr-Brendel et al., 1999; Charles et al., 2000; Li et al., 1998, Okamoto et al., 2000; Schirrmacher et al., 1998, 1999; Simons et al., 1999). We postulated that the combination of immunization against leukemia together with dietary E. purpurea could be substantially more therapeutic than either E. purpurea alone or immunization alone. Thus, inbred mice of identical strain, age, and gender were given killed leukemia cells 5 weeks before injecting them with 3 x 106 live leukemia cells to initiate tumor onset. The results indicated that immunization therapy alone produced a survival rate and life span increment similar to that provided by administering E. purpurea alone, that is, approximately one-third of the treated population survived long term (Currier and Miller, 2001, 2002). When E. purpurea was added to the diet from tumor onset to these immunized mice, the survival rate and life span increment nearly doubled to almost 60% (Currier and Miller, 2002). When NK cells were assessed at 3 months after tumor onset in these mice receiving combination therapy, it was found that the absolute numbers of NK cells in the bone marrow rose to almost three times that of immunized mice not consuming E. purpurea (p < 0.003), while the numbers of NK cells in the spleens of immunized mice consuming E. purpurea rose to almost twice (p < 0.00l) the levels of immunized mice that did not consume the herb. Moreover, by 3 months, the presence of E. purpurea in the diet had no influence on the lymphocytes (T, B cells), monocytes, mature granulocytes, or their precursors in either the spleen or the bone marrow, again demonstrating the primary and positive influence of Echinacea on NK cells.

These results indicate that combination therapy can have profoundly positive results, where one of the agents is E. purpurea, as long as the other agent is neither cytotoxic nor immunosup-pressive. For example, agents such as cyclophosphamide, methotrexate, and a battery of other chemotherapy poisons that indiscriminately kill vast numbers of normal cells along with their tumor targets, must be excluded from any combination therapy with E. purpurea or other Echinacea species.

We have thus established under formal experimental conditions that using Echinacea alone, or even more effectively, in combination treatment with an appropriate secondary treatment, signifi cantly increases survival rate and life span, at least in mice, and would appear to warrant further investigation in larger mammals and humans. Both E. purpurea and melatonin are commercially available and ready options for leukemia-afflicted humans, especially where other forms of therapy have proven to be too toxic to endure, or have become ineffective.

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