Psychoneuroimmunology Finds Acceptance As  Science Adds Evidence

By Steven Benowitz
The Scientist 10[16]:14, Aug. 19, 1996    at www.Britannica.com
 
    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).

                          "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.

                          "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 themolecular 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."

    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.

                        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.

    "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.