Psychoneuroimmunology Finds Acceptance As Science Adds Evidence

Despite some scientists' skepticism and funding shortages, the nascent field of psychoneuroimmunology (PNI) is gaining greater acceptance in the mainstream medical world. PNI seeks to understand the complex communications among the brain and the immune system, and their implications for health. Only within the past two decades have researchers begun to muster experimental evidence to figure it all out. Today, powerful new molecular techniques allow scientists to detail links between stress and disease immunity, pinpointing changes in hormone flow and immune system cells. According to Margaret Kemeny, an associate professor of psychiatry and biobehavioral science at the University of California, Los Angeles, PNI research has exploded in the last decade. Recent work has demonstrated that hormones and neurotransmitters released under stress can change immune cell behavior. These various cells actually have receptors to "hear" the signals, allowing the nervous, endocrine, and immune systems to "talk." At Ohio State University in Columbus, for example, researchers led by Janice Kiecolt-Glaser, a professor of psychology and psychiatry and director of the division of health psychology, and Ronald Glaser, a professor of medical microbiology and immunology, have shown that those who took care of a spouse or parent with Alzheimer's disease were more likely to have more severe colds than those who didn't have such responsibilities (J.K. Kiecolt-Glaser, Psychosomatic Medicine, 53:345-62, 1991). Other studies with a group of medical students focused on the effects of academic stress and a response to a hepatitis B vaccine, which would mimic response to an infectious agent. These studies showed antibody and immune cell response were diminished in those with more anxiety, higher stress and less social support (R. Glaser, Psychosomatic Medicine, 54:22-9, 1992). LOOK FOR A SIGN: Rochester's David Felten sees understanding biological signaling as key to advancing PNI. "One of the real strengths of the field is that in the last five years we've been concentrating on biological signaling-neurotransmitters and hormones talking to receptors, for example," observes David L. Felten, professor and chairman of the department of neurobiology and anatomy at the University of Rochester School of Medicine and Dentistry. Psychoneuroimmunology Resources Professional society: PsychoNeuroImmunology Research Society Keith W. Kelley, secretary-treasurer c/o Elaine Sampson Department of Animal Sciences University of Illinois 212 ERML, 1201 W. Gregory Dr. Urbana, Ill. 61801 (217) 244-3156 % Fax: (217) 244-5617 E-mail: esampson@uiuc.edu 300 members President: Suzanne Felten Internet site: An unmoderated forum for discussing PNI research may be found at PNI@ccat.sas.upenn.edu Journal: Brain, Behavior and Immunity Robert Ader, Editor-in-chief University of Rochester Medical Center Department of Psychiatry 300 Crittenden Blvd., Rochester, N.Y. 14642 (716) 275-5922 & Fax: (716) 271-1279 Meeting: Research Perspectives in Psychoneuroimmunology Boulder, Colo., June 4-8, 1997 For information, contact Keith W. Kelley c/o Elaine Sampson Department of Animal Sciences University of Illinois 212 ERML, 1201 W. Gregory Dr. Urbana, Ill. 61801 (217) 244-3156 % Fax: (217) 244-5617 E-mail: esampson@uiuc.edu "I don't think that there's any doubt today by immunologists that the central nervous system, the endocrine system, and stress can modulate the immune response," maintains Ohio State University's Glaser. "People are trying to understand those interactions at the molecular level. The last part is starting to play out: People are beginning to say, 'Sure, you see these effects on the immune system, but do they have health implications-are they biologically significant?' "In the last several years, we've begun to see health implications from stress changes on the immune system. As those studies continue to be published in good journals, those who are skeptical about the health implications may eventually buy into it," Glaser believes. Gaining Acceptance The field has taken its share of criticism. Many contend that the links between the various systems and the science supporting such connections are inconclusive. "Both scientists and the general public are interested [in PNI] because they always suspected it was true," notes Kiecolt-Glaser. "It has a high level of credibility [with the public], but the science hasn't been there." She says that critics often complain that "the science is soft, which it is in some studies, and the effects are marginal." Marvin Stein, an emeritus professor of psychiatry at Mount Sinai School of Medicine in New York, agrees. "We need to know more about how the brain and immune system talk," he says. "There's plenty of evidence about the effects of psychosocial factors in health-I don't think anyone disputes that. The question is, what's the clinical and biological relevance [of changes in the immune system]?" Some believe PNI studies have little value. "Most of what PNI involves is the measurement of artifacts," says Wallace Sampson, a clinical associate professor of medicine at Stanford University and board chairman of the National Council against Health Fraud, a nonprofit organization in Loma Linda, Calif., that monitors alternative therapies. "The data are frequently in conflict with each other." When first discussed among scientists in the 1970s, the so-called crosstalk theory among the brain and immune system was clearly against immunology dogma. "It violated the basic assumptions underlying immunology, that it [the immune system] is an autonomous system," notes Glaser. Yet today, evidence supporting an intimate relationship between the brain and the immune system continues to mount, says Kemeny. As a result, she sees a greater willingness among scientists and physicians today to accept many of the findings of PNI. Glaser cites two of his team's studies published in prestigious journals as typical examples of the credibility the field has acquired in the mainstream medical profession. One is their paper in the British medical journal Lancet (J.K. Kiecolt-Glaser et al., 346:1194-6, 1995), which describes evidence that wound healing was much slower in psychologically stressed adult patients. He also cites an April paper in the Proceedings of the National Academy of Sciences (J.K. Kiecolt-Glaser et al., 93:3043-47, 1996) that shows stress lowers the ability to create disease-fighting antibodies from a flu vaccine. "These papers clearly demonstrated that these changes are biologically significant-that stress modifies an immune response-and [show] the way that these changes have health implications." In addition, Glaser points to the Ohio State studies that compared the health effects of stress on people who cared for parents or spouses with Alzheimer's disease with those who did not have such responsibilities. "We found that the care-givers, significantly more stressed than controls, also got more colds. That told us we had something significant here," he recalls. According to Glaser, two years after some of the participants' care-giving duties had stopped, their immune systems had not recovered to the controls' levels. "That has big-time health implications," says Glaser. The "million-dollar question in the field," he explains, is: "Are these observed immune system effects actually affecting health?" Whereas Glaser and others approach the field from the human angle, others are delving into the cellular and molecular mechanisms at work. Rochester's Felten points out that "because [PNI] involves biological signaling, it's more acceptable to even the skeptical immunologists. If you can measure receptors and second messenger effects, then you have good science, and no one can deny that." He recalls the early days of the field, when colleagues scoffed at the notion of the central nervous system affecting the immune system. Glaser also acknowledges that he wasn't convinced about PNI's potential until he began conducting studies. "Now the question becomes, 'Under what situations might this become important?'" asks Felten. "For example, we think that in older animals, which already have a less capable immune system, the nerve signaling may be critical." Felten, who studies biological signaling in mouse models under stress, points to a need for "careful and extensive epidemiological and intervention studies." TURN-ON: Pittsburgh's Bruce Rabin is using a rat model to find areas in the brain turned on by stress. Some scientists are examining how the brain is directly affected by stress. Bruce Rabin, a professor of pathology and psychiatry at the University of Pittsburgh School of Medicine, is using a rat model to identify the specific areas of the brain that are turned on under stress. "If we prevent some of those areas from being turned on, there are no immune changes when they are exposed to stress. "We also found that if we turn on specific areas of the brain without any stress, we can see similar immune system changes as if they were under stress," he says. "We believe that we are beginning to identify relevant areas of the brain that are associated with alterations of immune function under stress." In recent years, some researchers have started examining the connection between behavior and HIV infection. At the University of Miami, Neil Schneiderman and his colleagues showed that a 10-week stress management and relaxation training program with HIV-infected gay men helped increase patients' abilities to cope, decrease depression, and in many cases delayed onset of AIDS symptoms. Schneiderman notes that PNI might be part of an effective treatment for HIV-positive patients' disease progression. Many researchers describe a "difficult financial situation," particularly for newcomers to the field, a situation not altogether different from that of most research disciplines in general. "If funding is difficult to obtain, individuals will train in areas that have funding," Rabin concedes. What's more, he adds, the National Institutes of Health frequently focuses on diseases, and "diseases have lobbies; PNI doesn't have a lobby. When you're dealing with health, funding agencies have less interest." That's not to say that NIH hasn't supported PNI studies, according to Ellen Stover, who heads the Office on AIDS at the National Institute of Mental Health (NIMH). Stover's institute; the National Institute on Aging; and the National Heart, Lung and Blood Institute, among others, have supported PNI research. TOUGH CALL: Evaluating PNI research requires broad expertise, says Rochester's Robert Ader Robert Ader, George L. Engel Professor of Psychosocial Medicine at Rochester, cites "the problem in communicating across disciplines, such as psychology and immunology." Ader notes that funding mechanisms parallel disciplines, and those who judge research proposals tend to be expert in only one particular field. New and interdisciplinary research projects are difficult to fund because the merits of both risky science and science that crosses disciplines are difficult to evaluate. Some look at NIH as both a benefactor and an obstacle. "Our biggest impediment to progress in the field is the ultraconservative study-section and peer-review process at NIH, which has retrenched to funding the most mundane, very safest research," comments Felten. He notes, however, that NIMH overall has been responsive to the field's needs, but the study sections have fallen short because it's difficult to find the necessary interdisciplinary expertise in endocrinology, immunology, neuroscience, and behavior. "A study section needs to attract those with the broad multidisciplinary expertise," Felten suggests. Fred Altman, acting chief of NIMH's basic prevention and behavioral medicine research branch, doesn't see a problem with the available study section expertise for judging the merit of research proposals. Says Altman: "I think we're well equipped to evaluate proposals." Felten is convinced that public interest in PNI is growing, particularly with programs such as Bill Moyers's public television series "Healing and the Mind." "Gradually, it has gained acceptance with the scientific community as the scientific data has grown," Felten comments. "Criticism comes from bad science." Promising Future The University of Pittsburgh's Rabin argues that there is much less scientific and public skepticism about PNI than there was a decade ago. "The quality of the research is much higher today and much less anecdotal. "In addition, people have lost some faith in physicians' abilities to manage disease and have a marked increase in the interest in preventive medicine," he says. He notes that the U.S. health care system "has brought this on by the reduction in quality of diagnosing and treating disease because of cost containment and managed care." Blue Cross/Blue Shield of Massachusetts, in fact, is hoping that behavioral intervention might help keep breast cancer patients healthier longer. Blue Cross is sponsoring a PNI research project in conjunction with the American Psychological Association (APA) to see whether counseling can improve breast cancer patients' recovery. TALKING IT OUT: APA's Geoffry Reed asks if counseling aids in recovery. "We hope to translate what we see scientifically to procedures in a real world setting as part of health care," says study director Geoffrey Reed, assistant executive director for professional development at APA's practice directorate, headquartered in Washington, D.C. In the project, one group of 60 women will receive group therapy as part of their standard treatment, while another group will receive only standard medical treatment. Psychological measures such as attitude, medicine, and healthy behavior compliance, in addition to immune function, will be studied. PNI has attracted a sizable public following and is of "considerable theoretical interest to researchers,"says Reed. However, he notes, it "hasn't had a large-scale impact on health care delivery. Until we test these [kinds of theories] out, we won't have an impact." While many researchers are optimistic about the field's expansion and see an eventual widespread acceptance, others have reservations. "In some ways we have too much acceptance in the mainstream and not enough critical review," says Suzanne Felten, president of the PsychoNeuroImmunology Research Society, based in Urbana, Ill. "It's common to find charlatans who want to charge outlandish sums of money for nothing. On the other hand, the field has taken leaps in studies linking bereavement and [lowered] immune function, for example, and by developing animal models and interventions that may be important clinically." She says understanding the immune system, especially regarding behavior and aging, could have serious implications for medicine and immunology. "These are well received [by scientists]," she notes.

Psychoneuroimmunology Finds Acceptance As Science Adds Evidence

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