By Michael Lee, MD
Peer Reviewed
Clinical Case: Ms. A, an 84-year-old retired physician with a history of bronchiectasis of unclear etiology, is admitted with the chief complaint of chronic cough. Further inquiry into her medical history reveals that she contracted malaria as a child while living in Korea. She had been prescribed chloroquine by multiple doctors, but her symptoms of fevers and night sweats did not improve. It was a trial of acupuncture therapy, she says, that finally cured her of malaria.
Acupuncture refers to the act of inserting needles into specific locations on the body surface, known as acupoints or meridian points, in order to alleviate pain or treat various medical conditions [1, 2]. Acupuncture allegedly originates from ancient shamanic healing performances of the Neolithic Age (8000-5000 BC), and it was subsequently developed into formalized medical therapy in China, with the earliest description of needles’ therapeutic uses noted in 90 BC. Since the early 19th century, acupuncture has gained interest in the Western Hemisphere. Its popularity in the United States markedly grew in 1971 when an American journalist named James Reston wrote a story about receiving acupuncture for the New York Times [1]. Today, this ancient act of healing represents perhaps the most commonly practiced alternative medical therapy in the US, with approximately 2.1 million adult Americans receiving acupuncture each year [3]. While no large randomized studies have proven its efficacy, acupuncture continues to be utilized in a wide range of disorders, including cases as complex as post-stroke hemiplegia and mood disorders like anxiety and depression [3-5]. Acupuncture has been implemented even in developmental conditions, such as autism spectrum disorders [6].
Despite the popularization of acupuncture, its application in infectious conditions like malaria is not a widely accepted practice in Western medicine. A considerable volume of evidence, however, suggests that acupuncture could theoretically improve infectious, autoimmune, atopic, and even malignant conditions by modulating the immune system. Although there is a dearth of strong clinical trials supporting its efficacy, acupuncture and its permutations, such as electroacupuncture (wherein electric currents are applied through the acupuncture needle), have been used to treat bacterial infections and immunologic conditions, such as Hashimoto’s thyroiditis and ulcerative colitis [3]. These observations raise the following question: how might acupuncture affect the immune system and how convincing is the scientific evidence? Discussed below are the 2 most plausible theories explaining the potential immune-modulatory roles of acupuncture.
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1) Reinforcement of Innate Immunity through Natural Killer Cell Activation
One theorized mechanism of acupuncture-induced immune system enhancement involves activation of natural killer (NK) cells. Some of the earliest evidence suggesting this notion came from a study by Sato and colleagues, who showed that electroacupuncture may result in an increased level of NK cell activity in rats [7]. The investigators performed electroacupuncture on the rats’ anterior tibias, specifically at the location equivalent to the “Zusanli” or “ST36” acupoint of the human tibia. Stimulation of this acupoint is known to produce analgesic effects in animals and possibly humans, and it is one of the most commonly used acupoints in animal and clinical studies examining immune-modulatory roles of acupuncture [8]. The ST36 acupoint refers to the posterolateral region of the leg below the popliteal fossa in humans and the area 5 millimeters distal and lateral to the anterior tubercle in rats [9,10].
In this study, a total of 17 Wistar rats received 2 hours of daily electroacupuncture stimulation at the ST36 acupoint for 3 days, followed by splenectomy for NK cell analyses [7]. The isolated splenic NK cells (or, effector cells) were incubated in the presence of standardized target cells containing chromium-51. Subsequently, chromium-51 release assays were performed where the amount of chromium liberated from lysed target cells served as a surrogate marker for NK cell cytotoxicity against tumor cells. NK cell cytotoxic activity was significantly higher in the tibia-stimulated rats when compared to control rats that either were stimulated in the abdominal muscle (i.e., needle application to non-specific areas) or received no needle stimulation (percent lysis in tibia-stimulated rats vs. non-stimulated rats: 50.3 ± 1.9% vs. 42.3 ± 2.6% at effector cell to target cell ratio of 100:1; P < 0.05). This outcome suggests that acupuncture could enhance innate immunity through NK cell activation.
The NK cell activation theory is also supported by a clinical trial in humans [11]. In a small crossover study, Yamaguchi and colleagues examined the effect of acupuncture on NK cell markers in 17 healthy human subjects with a mean age of 35.3 years. One hour after baseline blood sample collection, these subjects received acupuncture therapies at various acupoints, including, but not limited to, the ST36 acupoint. Post-procedural blood samples were obtained 1, 2, and 8 days after the acupuncture session. Flow cytometry showed no significant change in the mean absolute lymphocyte count after the acupuncture therapies, but there was a significant increase in the subset of lymphocytes expressing CD16 (0.8 ± 0.2% before acupuncture vs. 2.1 ± 0.4% 8 days after; P < 0.05) and CD56 (5.8 ± 0.7% before acupuncture vs. 11.2 ± 1.8% 8 days after; P < 0.01), which are markers representative of NK cells. Considering the role of NK cells in fighting viral infections, this study’s findings provide some rationale for the use of acupuncture in viral conditions like upper respiratory tract infections.
Subsequent murine studies following the aforementioned work by Sato provided few clues to the potential mechanism of acupuncture-induced NK cell activation. These studies showed that splenic extracts from tibia-stimulated rats had significantly (P < 0.01) higher levels of IL-2, IFN-gamma, and Beta-endorphin compared to abdomen-stimulated and non-stimulated rats [12, 13]. Moreover, in vivo administration of anti-IFN-gamma antibodies or naloxone seemed to abolish the NK cell-enhancing effect of electroacupuncture [12]. The authors speculated from these observations that electroacupuncture could activate NK cells via release of endogenous cytokines and opioids like IFN-gamma and Beta-endorphin. Although it has been further hypothesized that the hypothalamus, a site of beta-endorphin secretion, is involved in acupuncture-induced NK cell activation, no definitive data on this subject have been published to date [14].
2) Modulation of Th1/Th2 Balance
Traditionally, acupuncturists’ understanding of human health has been based on the notion of Yin and Yang, the equilibrium between two opposite yet interdependent forces [1]. Per this theory, offsetting this balance toward one side would result in an illness, and acupuncture could restore health by reinstating the equilibrium. This historical view of two distinct yet interrelated processes that contribute to one’s overall health can be compared to various concepts in modern medicine, such as the balance between the sympathetic and parasympathetic nervous systems.
Another example of equilibria influencing human health is the interplay between the Th1 and Th2 subtypes of CD4 T cells. Following the thymic positive and negative selections, naïve CD4 T cells commit to either the Th1 or the Th2 cell lineage, depending on the molecular milieu during the time of differentiation. Th1 CD4 cells are implicated in cell-mediated immunity, granuloma formation, and delayed type hypersensitivity, which are characterized by a spectrum of cytokines, including IL-2, IFN-gamma, and TNF-Beta. On the other hand, Th2 cells mediate humoral immunity and allergic reactions via IL-4, IL-5, IL-10, and IL-13. The Th1/Th2 modulation theory asserts that the clinical benefit of acupuncture may result from reinstituting the disrupted balance between Th1 and Th2 activities [14].
In 2004, Park and colleagues published data supporting this theory using a mouse model [9]. In this study, 10 mice were intraperitoneally immunized with a type of protein (DNP-KLH) known to induce Th2-skewed conditions in mice. Half of the immunized (i.e., Th2-skewed) mice were stimulated at the ST36 acupoint with electroacupuncture for twenty minutes, and this intervention was repeated daily for 21 days. At the 7, 14, and 21-day marks, serum samples and splenocytes were collected and analyzed for IgE and cytokine levels, respectively. The IgE and cytokine measurements served as surrogate markers for Th2 activity, and they were compared to values obtained from 5 other mice that had been immunized but did not undergo acupuncture. A separate group of 5 control mice received neither the immunization nor the acupuncture therapy.
Among the Th2-skewed mice, the average serum total IgE level was initially higher in the electroacupuncture group at the 7-day mark (P < 0.01), but after 14 (P < 0.05) and 21 (P < 0.001) days, electroacupuncture was associated with lower total-IgE levels [9]. Similarly, electroacupuncture resulted in significantly lower antigen-specific IgE levels at the 14 and 21-day marks. Splenic production of IL-4, a cytokine implicated in the differentiation and proliferation of Th2 lymphocytes, was also reduced in the electroacupuncture group compared to the no-acupuncture group. A subsequent study further suggested that the IgE and IL-4-lowering effects of electroacupuncture in Th2-skewed mice might be acupoint-specific; IgE and IL-4 productions were not suppressed when needles were inserted at non-specific locations [15]. Overall, these findings provide preliminary evidence for the possible therapeutic role of acupuncture in Th2-dominant conditions like allergic rhinitis.
Interestingly, other murine studies suggest that acupuncture may also confer Th1-inhibitory effects. Using a murine model of ulcerative colitis, Tian and colleagues demonstrated a significant association between electroacupuncture and reductions in serum TNF-alpha and colonic TNF-alpha mRNA levels [16]. While ulcerative colitis is not considered a classic Th1-induced disease, TNF-alpha is closely related to Th1 activity, and the TNF-alpha lowering effect could explain the clinical benefit of acupuncture in true Th1-dominant entities, such as rheumatoid arthritis and delayed type hypersensitivities [14]. Another study of an inflammatory arthritic mouse model demonstrated a potential role of electroacupuncture in preventing joint destruction and suppressing serum IFN-gamma and TNF-alpha levels [17]. Again, considering that IFN-gamma and TNF-alpha are cytokines involved in the differentiation and proliferation of activated CD4 T cells into the Th1 subclass, a reduction of these cytokines could be a mechanism by which acupuncture might treat Th1-skewed disease entities [14].
These seemingly bi-directional effects of acupuncture on T helper cells are in line with clinical studies that suggest its efficacy in both Th1-dominant diseases like rheumatoid arthritis and Th2-dominant conditions like allergic rhinitis [18-20]. There remain, however, many unanswered questions regarding the Th1/Th2 modulation theory of acupuncture. Most importantly, mechanisms by which acupuncture affects helper T cells and their associated cytokines remain unclear [14]. The absence of plausible mechanisms is further confounded by the counterintuitive observation that 2 different outcomes (i.e., Th1 and Th2 suppression) may be achieved from stimulation of the same ST36 acupoint depending on the clinical circumstance. Moreover, potential differences between the murine immune system and that of humans must be considered when interpreting the animal data.
Numerous trials examining acupuncture’s role in various human diseases have been published [21]. An accurate assessment of its clinical efficacy, however, has proven to be extremely challenging as most of these clinical trials are underpowered [1]. More importantly, data from the small studies cannot be easily combined to construct meaningful meta-analyses as the individual studies greatly vary in their design. For instance, the types of investigated interventions range from traditional needle stimulation to electroacupuncture, and some trials involve even more advanced techniques like laser acupuncture, which delivers laser beams to acupoints without penetrating the skin barrier [1, 22]. Each of these interventions is administered for various durations and frequencies, and trials examining the same medical condition often involve different acupoints [1]. Overall, the small sample sizes and inter-study variations make it difficult to draw useful conclusions despite the abundance of clinical trials on acupuncture. As an example, 7 meta-analyses were published prior to 2005 looking at the role of acupuncture in treating headache syndromes. Of the 7 meta-analyses, 6 had inconclusive outcomes largely owing to substantial heterogeneities among the individual studies.
Progress has been made, nonetheless, in the field of clinical acupuncture trials. Sham acupuncture devices, which generate the sensation of needle insertion without physically penetrating the skin, became available in the late 1990s [23]. Although a number of studies using sham needles have undermined the true efficacy of acupuncture, the introduction of sham acupuncture has allowed for more objective, patient-blinded trials [1]. Moreover, adequately powered acupuncture trials are underway, obviating the need to draw conclusions from dissimilar and underpowered studies.
Whether acupuncture was responsible for Ms. A’s cure of malaria remains a mystery. Further clarification of potential mechanisms behind acupuncture-induced immune modulation, along with completion of robustly designed large clinical trials, may one day provide a full explanation of Ms. A’s acupuncture success story.
By Michael Lee, MD is a 2nd year resident at NYU Langone Medical Center
Peer Reviewed by Jason Siefferman, MD, Anesthesiology, Division of Pain Medicine, NYU Langone Medical Center
Image courtesy of Wikimedia Commons
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