Micrograph showing an opportunistic infection due to immunosuppression - large (blue) cell below-center-left infected with a polyomavirus. Urine cytology specimen.
Immunosuppression is a reduction of the activation or efficacy of the immune system.
Some portions of the immune system itself have immunosuppressive
effects on other parts of the immune system, and immunosuppression may
occur as an adverse reaction to treatment of other conditions.
AzathioprineWhite blood cells (and red blood cells)
Administration of immunosuppressive medications
or immunosuppressants is the main method for deliberately inducing
immunosuppression; in optimal circumstances, immunosuppressive drugs
primarily target hyperactive components of the immune system. People in remission from cancer who require immunosuppression are not more likely to experience a recurrence. Throughout its history, radiation therapy has been used to decrease the strength of the immune system. Dr. Joseph Murray of Brigham and Women's Hospital was given the Nobel Prize in Physiology or Medicine in 1990 for work on immunosuppression.
Steroids were the first class of immunosuppressant drugs
identified, though side-effects of early compounds limited their use.
The more specific azathioprine was identified in 1960, but it was the discovery of ciclosporin in 1980 (together with azathioprine) that allowed significant expansion of transplantation to less well-matched donor-recipient pairs as well as broad application to lung transplantation, pancreas transplantation, and heart transplantation. After an organ transplantation, the body will nearly always reject the new organ(s) due to differences in human leukocyte antigen
between the donor and recipient. As a result, the immune system detects
the new tissue as "foreign", and attempts to remove it by attacking it
with white blood cells,
resulting in the death of the donated tissue. Immunosuppressants are
administered in order to help prevent rejection; however, the body
becomes more vulnerable to infections and malignancy during the course
of such treatment.
Immunodeficiency is also a potential adverse effect of many immunosuppressant drugs, in this sense, the scope of the term immunosuppression in general includes both beneficial and potential adverse effects of decreasing the function of the immune system.
B cell deficiency and T cell
deficiency are immune impairment that individuals are born with or are
acquired, which in turn can lead to immunodeficiency problems. Nezelof syndrome is an example of an immunodeficiency of T-cells.
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.
Classification
Immunosuppressive drugs can be classified into five groups:
Glucocorticoids suppress cell-mediated immunity. They act by inhibiting gene expression of cytokines including Interleukin 1 (IL-1), IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF-alpha by binding to corticosteroid response elements on DNA. This decrease in cytokine production reduces T cell
proliferation. With decreased T cell proliferation there is decreased
production of IL-2. This further decreases the proliferation of T cells.
Glucocorticoids also suppress the humoral immunity, causing B cells to express smaller amounts of IL-2 and IL-2 receptors. This diminishes both B cell clone expansion and antibody synthesis.
Anti-inflammatory effects
Glucocorticoids influence all types of inflammatory events, no matter their cause. They induce the lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substratearachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect.
Cytostatics inhibit cell division.
In immunotherapy, they are used in smaller doses than in the treatment
of malignant diseases. They affect the proliferation of both T cells and
B cells. Due to their highest effectiveness, purine analogs are most frequently administered.
Methotrexate is a folic acid analogue. It binds dihydrofolate reductase and prevents synthesis of tetrahydrofolate.
It is used in the treatment of autoimmune diseases (for example
rheumatoid arthritis or Behcet's Disease) and in transplantations.
Azathioprine and mercaptopurine
Azathioprine
(Prometheus' Imuran), is the main immunosuppressive cytotoxic
substance. It is extensively used to control transplant rejection
reactions. It is nonenzymatically cleaved to mercaptopurine, that acts as a purine analogue and an inhibitor of DNA synthesis. Mercaptopurine itself can also be administered directly.
By preventing the clonal expansion of lymphocytes in the induction phase of the immune response, it affects both the cell and the humoral immunity. It is also efficient in the treatment of autoimmune diseases.
Antibodies
are sometimes used as a quick and potent immunosuppressive therapy to
prevent the acute rejection reactions as well as a targeted treatment of
lymphoproliferative or autoimmune disorders (e.g., anti-CD20 monoclonals).
Polyclonal antibodies
Heterologous polyclonal antibodies are obtained from the serum of animals (e.g., rabbit, horse), and injected with the patient's thymocytes or lymphocytes. The antilymphocyte (ALG) and antithymocyte antigens (ATG) are being used. They are part of the steroid-resistant acute rejection reaction and grave aplastic anemia
treatment. However, they are added primarily to other
immunosuppressives to diminish their dosage and toxicity. They also
allow transition to cyclosporin therapy.
As of March 2005, there are two preparations available to the market: Atgam, obtained from horse serum, and Thymoglobuline,
obtained from rabbit serum. Polyclonal antibodies affect all
lymphocytes and cause general immunosuppression, possibly leading to post-transplant lymphoproliferative disorders (PTLD) or serious infections, especially by cytomegalovirus.
To reduce these risks, treatment is provided in a hospital, where
adequate isolation from infection is available. They are usually
administered for five days intravenously in the appropriate quantity.
Patients stay in the hospital as long as three weeks to give the immune
system time to recover to a point where there is no longer a risk of serum sickness.
Because of a high immunogenicity of polyclonal antibodies, almost all patients have an acute reaction to the treatment. It is characterized by fever, rigor episodes, and even anaphylaxis. Later during the treatment, some patients develop serum sickness or immune complex glomerulonephritis. Serum sickness arises seven to fourteen days after the therapy has begun. The patient has fever, joint pain, and erythema that can be soothed with the use of steroids and analgesics. Urticaria (hives) can also be present. It is possible to diminish their toxicity by using highly purified serum fractions and intravenous administration in the combination with other immunosuppressants, for example, calcineurin inhibitors, cytostatics, and corticosteroids.
The most frequent combination is to use antibodies and ciclosporin
simultaneously in order to prevent patients from gradually developing a
strong immune response to these drugs, reducing or eliminating their
effectiveness.
Monoclonal antibodies
Monoclonal antibodies are directed towards exactly defined antigens. Therefore, they cause fewer side-effects. Especially significant are the IL-2 receptor-
(CD25-) and CD3-directed antibodies. They are used to prevent the
rejection of transplanted organs, but also to track changes in the
lymphocyte subpopulations. It is reasonable to expect similar new drugs
in the future.
T-cell receptor directed antibodies
Muromonab-CD3 is a murine anti-CD3 monoclonal antibody of the IgG2a type that was previously used to prevent T-cell
activation and proliferation by binding the T-cell receptor complex
present on all differentiated T cells. As such it was one of the first
potent immunosuppressive substances and was administered to control the
steroid- and/or polyclonal antibodies-resistant acute rejection
episodes. As it acts more specifically than polyclonal antibodies it was
also used prophylactically in transplantations. However, muromonab-CD3
is no longer produced, and this mouse monoclonal antibody has been replaced in the clinic with chimeric, humanized, or human monoclonal antibodies.
The muromonab's mechanism of action is only partially understood.
It is known that the molecule binds TCR/CD3 receptor complex. In the
first few administrations this binding non-specifically activates
T-cells, leading to a serious syndrome 30 to 60 minutes later. It is
characterized by fever, myalgia, headache, and arthralgia.
Sometimes it develops in a life-threatening reaction of the
cardiovascular system and the central nervous system, requiring a
lengthy therapy. Past this period CD3 blocks the TCR-antigen binding and
causes conformational change
or the removal of the entire TCR3/CD3 complex from the T-cell surface.
This lowers the number of available T-cells, perhaps by sensitizing them
for the uptake by the epithelial reticular cells.
The cross-binding of CD3 molecules as well activates an intracellular
signal causing the T cell anergy or apoptosis, unless the cells receive
another signal through a co-stimulatory molecule. CD3 antibodies shift the balance from Th1 to Th2 cells as CD3 stimulates Th1 activation.
The patient may develop neutralizing antibodies
reducing the effectiveness of muromonab-CD3.
Muromonab-CD3 can cause excessive immunosuppression. Although CD3
antibodies act more specifically than polyclonal antibodies, they lower
the cell-mediated immunity significantly, predisposing the patient to opportunistic infections and malignancies.
IL-2 receptor directed antibodies
Interleukin-2
is an important immune system regulator necessary for the clone
expansion and survival of activated lymphocytes T. Its effects are
mediated by the trimer cell surface receptor IL-2a,
consisting of the α, β, and γ chains. The IL-2a (CD25, T-cell
activation antigen, TAC) is expressed only by the already-activated T
lymphocytes. Therefore, it is of special significance to the selective
immunosuppressive treatment, and research has been focused on the
development of effective and safe anti-IL-2 antibodies. By the use of recombinant gene technology,
the mouse anti-Tac antibodies have been modified, leading to the
presentation of two chimeric mouse/human anti-Tac antibodies in the year
1998: basiliximab (Simulect) and daclizumab
(Zenapax). These drugs act by binding the IL-2a receptor's α chain,
preventing the IL-2 induced clonal expansion of activated lymphocytes
and shortening their survival. They are used in the prophylaxis of the
acute organ rejection after bilateral kidney transplantation, both being similarly effective and with only few side-effects.
Like tacrolimus, ciclosporin (Novartis' Sandimmune) is a calcineurin
inhibitor (CNI). It has been in use since 1983 and is one of the most
widely used immunosuppressive drugs. It is a cyclic fungal peptide,
composed of 11 amino acids.
Ciclosporin is thought to bind to the cytosolic protein cyclophilin (an immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of ciclosporin and cyclophilin inhibits the phosphatase calcineurin, which under normal circumstances induces the transcription of interleukin-2. The drug also inhibits lymphokine production and interleukin release, leading to a reduced function of effector T-cells.
Ciclosporin is used in the treatment of acute rejection reactions, but has been increasingly substituted with newer, and less nephrotoxic, immunosuppressants.
Calcineurin inhibitors and azathioprine have been linked with post-transplant malignancies and skin cancers in organ transplant recipients. Non-melanoma skin cancer
(NMSC) after kidney transplantation is common and can result in
significant morbidity and mortality. The results of several studies
suggest that calcineurin inhibitors have oncogenic properties mainly
linked to the production of cytokines that promote tumor growth,
metastasis and angiogenesis.
This drug has been reported to reduce the frequency of regulatory T cells (T-Reg) and after converting from a CNI monotherapy to a mycophenolate monotherapy, patients were found to have increased graft success and T-Reg frequency.
The drug is used primarily in liver and kidney transplantations,
although in some clinics it is used in heart, lung, and heart/lung
transplantations. It binds to the immunophilin FKBP1A, followed by the binding of the complex to calcineurin and the inhibition of its phosphatase activity. In this way, it prevents the cell from transitioning from the G0 into G1 phase of the cell cycle. Tacrolimus is more potent than ciclosporin and has less pronounced side-effects.
Sirolimus (rapamycin, trade name Rapamune) is a macrolide lactone, produced by the actinomycete bacterium Streptomyces hygroscopicus.
It is used to prevent rejection reactions. Although it is a structural
analogue of tacrolimus, it acts somewhat differently and has different
side-effects.
Contrary to ciclosporin and tacrolimus, drugs that affect the
first phase of T lymphocyte activation, sirolimus affects the second
phase, namely signal transduction and lymphocyte clonal proliferation.
It binds to FKBP1A like tacrolimus, however the complex does not inhibit
calcineurin but another protein, mTOR.
Therefore, sirolimus acts synergistically with ciclosporin and, in
combination with other immunosuppressants, has few side effects. Also,
it indirectly inhibits several T lymphocyte-specific kinases and
phosphatases, hence preventing their transition from G1 to S
phase of the cell cycle. In a similar manner, Sirolimus prevents B cell
differentiation into plasma cells, reducing production of IgM, IgG, and
IgA antibodies.
It is also active against tumors that are PI3K/AKT/mTOR-dependent.
IFN-β suppresses the production of Th1 cytokines and the activation of monocytes. It is used to slow down the progression of multiple sclerosis. IFN-γ is able to trigger lymphocytic apoptosis.
Opioids
Prolonged use of opioids may cause immunosuppression of both innate and adaptive immunity.
Decrease in proliferation as well as immune function has been observed
in macrophages, as well as lymphocytes. It is thought that these effects
are mediated by opioid receptors expressed on the surface of these
immune cells.
These drugs may raise the risk of contracting tuberculosis
or inducing a latent infection to become active. Infliximab and
adalimumab have label warnings stating that patients should be evaluated
for latent TB infection and treatment should be initiated prior to
starting therapy with them.
TNF or the effects of TNF are also suppressed by various natural compounds, including curcumin (an ingredient in turmeric) and catechins (in green tea).
Mycophenolate
Mycophenolic acid acts as a non-competitive, selective, and reversible inhibitor of inosine-5′-monophosphate dehydrogenase (IMPDH), which is a key enzyme in the de novoguanosine
nucleotide synthesis. In contrast to other human cell types,
lymphocytes B and T are very dependent on this process. Mycophenolate
mofetil is used in combination with ciclosporin or tacrolimus in
transplant patients.
Small biological agents
Fingolimod is a synthetic immunosuppressant. It increases the expression or changes the function of certain adhesion molecules (α4/β7 integrin) in lymphocytes, so they accumulate in the lymphatic tissue
(lymphatic nodes) and their number in the circulation is diminished. In
this respect, it differs from all other known immunosuppressants.
Myriocin has been reported being 10 to 100 times more potent than Ciclosporin.
Treat some other non-autoimmune inflammatory diseases (e.g., long term allergic asthma control).
Side effects
A common side-effect of many immunosuppressive drugs is immunodeficiency, because the majority of them act non-selectively, resulting in increased susceptibility to infections, decreased cancer immunosurveillance and decreased ability to produce antibodies after vaccination.However, the vaccination status of patients taking immunosuppressive drugs for chronic diseases such as Rheumatoid arthritis or Inflammatory bowel disease should be investigated before starting any treatment, and patients should eventually be vaccinated against Vaccine-preventable disease. Some studies showed a low vaccination rate against some Vaccine-preventable disease among patients taking immunosuppressive drugs, despite a generally positive attitude towards vaccinations.
The main interests of PNI are the interactions between the nervous and immune systems and the relationships between mental processes and health.
PNI studies, among other things, the physiological functioning of the
neuroimmune system in health and disease; disorders of the neuroimmune
system (autoimmune diseases; hypersensitivities; immune deficiency); and the physical, chemical and physiological characteristics of the components of the neuroimmune system in vitro, in situ, and in vivo.
History
Interest
in the relationship between psychiatric syndromes or symptoms and
immune function has been a consistent theme since the beginning of
modern medicine.
Claude Bernard, the father of modern physiology, with his pupils
Claude Bernard, a French physiologist of the Muséum national d'Histoire naturelle (National Museum of Natural History in English), formulated the concept of the milieu interieur
in the mid-1800s. In 1865, Bernard described the perturbation of this
internal state: "... there are protective functions of organic elements
holding living materials in reserve and maintaining without interruption
humidity, heat and other conditions indispensable to vital activity.
Sickness and death are only a dislocation or perturbation of that
mechanism" (Bernard, 1865). Walter Cannon, a professor of physiology at Harvard University coined the commonly used term, homeostasis, in his book The Wisdom of the Body, 1932, from the Greek word homoios, meaning similar, and stasis, meaning position. In his work with animals, Cannon observed that any change of emotional state in the beast, such as anxiety, distress, or rage, was accompanied by total cessation of movements of the stomach (Bodily Changes in Pain, Hunger, Fear and Rage, 1915). These studies looked into the relationship between the effects of emotions and perceptions on the autonomic nervous system, namely the sympathetic and parasympathetic responses that initiated the recognition of the freeze, fight or flight response. His findings were published from time to time in professional journals, then summed up in book form in The Mechanical Factors of Digestion, published in 1911.
Hans Selye, a student of Johns Hopkins University and McGill University, and a researcher at Université de Montréal,
experimented with animals by putting them under different physical and
mental adverse conditions and noted that under these difficult
conditions the body consistently adapted to heal and recover. Several years of experimentation that formed the empiric foundation of Selye's concept of the General Adaptation Syndrome. This syndrome consists of an enlargement of the adrenal gland, atrophy of the thymus, spleen, and other lymphoid tissue, and gastric ulcerations.
Selye describes three stages of adaptation, including an initial
brief alarm reaction, followed by a prolonged period of resistance, and a
terminal stage of exhaustion and death. This foundational work led to a
rich line of research on the biological functioning of glucocorticoids.
Mid-20th century studies of psychiatric patients reported immune
alterations in psychotic individuals, including lower numbers of lymphocytes and poorer antibody response to pertussis vaccination, compared with nonpsychiatric control subjects. In 1964, George F. Solomon, from the University of California in Los Angeles,
and his research team coined the term "psychoimmunology" and published a
landmark paper: "Emotions, immunity, and disease: a speculative
theoretical integration."
Origins
In 1975, Robert Ader and Nicholas Cohen, at the University of Rochester, advanced PNI with their demonstration of classic conditioning of immune function, and they subsequently coined the term "psychoneuroimmunology". Ader was investigating how long conditioned responses (in the sense of Pavlov's
conditioning of dogs to drool when they heard a bell ring) might last
in laboratory rats. To condition the rats, he used a combination of saccharin-laced water (the conditioned stimulus) and the drug Cytoxan, which unconditionally induces nausea and taste aversion
and suppression of immune function. Ader was surprised to discover that
after conditioning, just feeding the rats saccharin-laced water was
associated with the death of some animals and he proposed that they had
been immunosuppressed after receiving the conditioned stimulus. Ader (a
psychologist) and Cohen (an immunologist) directly tested this
hypothesis by deliberately immunizing conditioned and unconditioned
animals, exposing these and other control groups to the conditioned
taste stimulus, and then measuring the amount of antibody produced. The
highly reproducible results revealed that conditioned rats exposed to
the conditioned stimulus were indeed immunosuppressed. In other words, a
signal via the nervous system (taste) was affecting immune function.
This was one of the first scientific experiments that demonstrated that
the nervous system can affect the immune system.
In the 1970s, Hugo Besedovsky, Adriana del Rey and Ernst Sorkin,
working in Switzerland, reported multi-directional
immune-neuro-endocrine interactions, since they show that not only the
brain can influence immune processes but also the immune response itself
can affect the brain and neuroendocrine mechanisms. They found that the
immune responses to innocuous antigens triggers an increase in the
activity of hypothalamic neurons
and hormonal and autonomic nerve responses that are relevant for
immunoregulation and are integrated at brain levels (see review).
On these bases, they proposed that the immune system acts as a
sensorial receptor organ that, besides its peripheral effects, can
communicate to the brain and associated neuro-endocrine structures its
state of activity.
These investigators also identified products from immune cells, later
characterized as cytokines, that mediate this immune-brain communication.
In 1981, David L. Felten, then working at the Indiana University School of Medicine,
and his colleague JM Williams, discovered a network of nerves leading
to blood vessels as well as cells of the immune system. The researchers
also found nerves in the thymus and spleen terminating near clusters of lymphocytes, macrophages, and mast cells,
all of which help control immune function. This discovery provided one
of the first indications of how neuro-immune interaction occurs.
Ader, Cohen, and Felten went on to edit the groundbreaking book Psychoneuroimmunology in 1981, which laid out the underlying premise that the brain and immune system represent a single, integrated system of defense.
In 1985, research by neuropharmacologistCandace Pert, of the National Institutes of Health at Georgetown University, revealed that neuropeptide-specific receptors are present on the cell walls of both the brain and the immune system.The discovery that neuropeptides and neurotransmitters act directly upon the immune system shows their close association with emotions and suggests mechanisms through which emotions, from the limbic system, and immunology are deeply interdependent. Showing that the immune and endocrine systems are modulated not only by the brain but also by the central nervous system itself affected the understanding of emotions, as well as disease.
Contemporary advances in psychiatry, immunology, neurology,
and other integrated disciplines of medicine has fostered enormous
growth for PNI. The mechanisms underlying behaviorally induced
alterations of immune function, and immune alterations inducing
behavioral changes, are likely to have clinical and therapeutic
implications that will not be fully appreciated until more is known
about the extent of these interrelationships in normal and
pathophysiological states.
PNI research looks for the exact mechanisms by which specific
neuroimmune effects are achieved. Evidence for nervous-immunological
interactions exist at multiple biological levels.
The immune system and the brain communicate through signaling
pathways. The brain and the immune system are the two major adaptive
systems of the body. Two major pathways are involved in this cross-talk:
the Hypothalamic-pituitary-adrenal axis (HPA axis), and the sympathetic nervous system (SNS), via the sympathetic-adrenal-medullary axis (SAM axis). The activation of SNS during an immune response might be aimed to localize the inflammatory response.
The body's primary stress management
system is the HPA axis. The HPA axis responds to physical and mental
challenge to maintain homeostasis in part by controlling the body's cortisol
level. Dysregulation of the HPA axis is implicated in numerous
stress-related diseases, with evidence from meta-analyses indicating
that different types/duration of stressors and unique personal variables
can shape the HPA response. HPA axis activity and cytokines are intrinsically intertwined: inflammatory cytokines stimulate adrenocorticotropic hormone (ACTH) and cortisol secretion, while, in turn, glucocorticoids suppress the synthesis of proinflammatory cytokines.
Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis.
Like the stress response, the inflammatory reaction is crucial for
survival. Systemic inflammatory reaction results in stimulation of four
major programs:
These are mediated by the HPA axis and the SNS. Common human diseases such as allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro-inflammatory versus anti-inflammatory and T helper (Th1) versus (Th2) cytokine balance.
Recent studies show pro-inflammatory cytokine processes take place during depression, mania and bipolar disease, in addition to autoimmune hypersensitivity and chronic infections.
Chronic secretion of stresshormones, glucocorticoids (GCs) and catecholamines (CAs), as a result of disease, may reduce the effect of neurotransmitters, including serotonin, norepinephrine and dopamine, or other receptors in the brain, thereby leading to the dysregulation of neurohormones.
Under stimulation, norepinephrine is released from the sympathetic
nerve terminals in organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released norepinephrine, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells.
Glucocorticoids also inhibit the further secretion of corticotropin-releasing hormone from the hypothalamus and ACTH from the pituitary (negative feedback).
Under certain conditions stress hormones may facilitate inflammation
through induction of signaling pathways and through activation of the
corticotropin-releasing hormone.
These abnormalities and the failure of the adaptive systems to
resolve inflammation affect the well-being of the individual, including
behavioral parameters, quality of life and sleep, as well as indices of metabolic
and cardiovascular health, developing into a "systemic
anti-inflammatory feedback" and/or "hyperactivity" of the local
pro-inflammatory factors which may contribute to the pathogenesis of
disease.
This systemic or neuro-inflammation and neuroimmune activation have been shown to play a role in the etiology of a variety of neurodegenerative disorders such as Parkinson's and Alzheimer's disease, multiple sclerosis, pain, and AIDS-associated dementia. However, cytokines and chemokines
also modulate central nervous system (CNS) function in the absence of
overt immunological, physiological, or psychological challenges.
Psychoneuroimmunological effects
There
are now sufficient data to conclude that immune modulation by
psychosocial stressors and/or interventions can lead to actual health
changes. Although changes related to infectious disease and wound
healing have provided the strongest evidence to date, the clinical
importance of immunological dysregulation is highlighted by increased
risks across diverse conditions and diseases. For example, stressors can
produce profound health consequences. In one epidemiological study,
all-cause mortality increased in the month following a severe stressor –
the death of a spouse.
Theorists propose that stressful events trigger cognitive and affective
responses which, in turn, induce sympathetic nervous system and
endocrine changes, and these ultimately impair immune function. Potential health consequences are broad, but include rates of infection HIV progression cancer incidence and progression, and high rates of infant mortality.
Understanding stress and immune function
Stress is thought to affect immune function through emotional and/or behavioral manifestations such as anxiety, fear, tension, anger and sadness and physiological changes such as heart rate, blood pressure, and sweating. Researchers have suggested that these changes are beneficial if they are of limited duration, but when stress is chronic, the system is unable to maintain equilibrium or homeostasis;
the body remains in a state of arousal, where digestion is slower to
reactivate or does not reactivate properly, often resulting in
indigestion. Furthermore, blood pressure stays at higher levels.
In one of the earlier PNI studies, which was published in 1960,
subjects were led to believe that they had accidentally caused serious
injury to a companion through misuse of explosives.
Since then decades of research resulted in two large meta-analyses,
which showed consistent immune dysregulation in healthy people who are
experiencing stress.
In the first meta-analysis by Herbert and Cohen in 1993,
they examined 38 studies of stressful events and immune function in
healthy adults. They included studies of acute laboratory stressors
(e.g. a speech task), short-term naturalistic stressors (e.g. medical
examinations), and long-term naturalistic stressors (e.g. divorce,
bereavement, caregiving, unemployment). They found consistent
stress-related increases in numbers of total white blood cells, as well as decreases in the numbers of helper T cells, suppressor T cells, and cytotoxic T cells, B cells, and natural killer cells (NK). They also reported stress-related decreases in NK and T cell function, and T cell proliferative responses to phytohaemagglutinin [PHA] and concanavalin A [Con A]. These effects were consistent for short-term and long-term naturalistic stressors, but not laboratory stressors.
In the second meta-analysis by Zorrilla et al. in 2001,
they replicated Herbert and Cohen's meta-analysis. Using the same study
selection procedures, they analyzed 75 studies of stressors and human
immunity. Naturalistic stressors were associated with increases in
number of circulating neutrophils, decreases in number and percentages of total T cells
and helper T cells, and decreases in percentages of natural killer cell
(NK) cells and cytotoxic T cell lymphocytes. They also replicated
Herbert and Cohen's finding of stress-related decreases in NKCC and T
cell mitogen proliferation to phytohaemagglutinin (PHA) and concanavalin A (Con A).
More recently, there has been increasing interest in the links
between interpersonal stressors and immune function. For example,
marital conflict, loneliness, caring for a person with a chronic medical
condition, and other forms on interpersonal stress dysregulate immune
function.
Communication between the brain and immune system
Stimulation of brain sites alters immunity (stressed animals have altered immune systems).
Damage to brain hemispheres alters immunity (hemispheric lateralization effects).
Immune cells produce cytokines that act on the CNS.
Immune cells respond to signals from the CNS.
Communication between neuroendocrine and immune system
Glucocorticoids and catecholamines influence immune cells.
Hypothalamic Pituitary Adrenal axis releases the needed hormones to support the immune system.
Activity of the immune system is correlated with neurochemical/neuroendocrine activity of brain cells.
Connections between glucocorticoids and immune system
Anti-inflammatory hormones that enhance the organism's response to a stressor.
Prevent the overreaction of the body's own defense system.
Overactivation of glucocorticoid receptors can lead to health risks.
Regulators of the immune system.
Affect cell growth, proliferation and differentiation.
Cause immunosuppression which can lead to an extended amount of time fighting off infections.
High basal levels of cortisol are associated with a higher risk of infection.
Furthermore, stressors that enhance the release of CRH suppress the
function of the immune system; conversely, stressors that depress CRH
release potentiate immunity.
Central mediated since peripheral administration of CRH antagonist does not affect immunosuppression.
HPA axis/stress axis responds consistently to stressors that are new, unpredictable and that have low-perceived control.
As cortisol reaches an appropriate level in response to the
stressor, it deregulates the activity of the hippocampus, hypothalamus,
and pituitary gland which results in less production of cortisol.
Relationships between prefrontal cortex activation and cellular senescence
For example, SSRIs, SNRIs and tricyclicantidepressants acting on serotonin, norepinephrine, dopamine and cannabinoid receptors
have been shown to be immunomodulatory and anti-inflammatory against
pro-inflammatory cytokine processes, specifically on the regulation of
IFN-gamma and IL-10, as well as TNF-alpha and IL-6 through a
psychoneuroimmunological process. Antidepressants have also been shown to suppress TH1 upregulation.
Tricyclic and dual serotonergic-noradrenergic reuptake inhibition by SNRIs (or SSRI-NRI combinations), have also shown analgesic properties additionally. According to recent evidences antidepressants also seem to exert beneficial effects in experimental autoimmune neuritis in rats by decreasing Interferon-beta (IFN-beta) release or augmenting NK activity in depressed patients.
These studies warrant investigation of antidepressants for use in
both psychiatric and non-psychiatric illness and that a
psychoneuroimmunological approach may be required for optimal pharmacotherapy in many diseases.
Future antidepressants may be made to specifically target the immune
system by either blocking the actions of pro-inflammatory cytokines or
increasing the production of anti-inflammatory cytokines.
The endocannabinoid system
appears to play a significant role in the mechanism of action of
clinically effective and potential antidepressants and may serve as a
target for drug design and discovery. The endocannabinoid-induced
modulation of stress-related behaviors appears to be mediated, at least
in part, through the regulation of the serotoninergic system, by which
cannabinoid CB1 receptors modulate the excitability of dorsal raphe serotonin neurons. Data suggest that the endocannabinoid system in cortical
and subcortical structures is differentially altered in an animal model
of depression and that the effects of chronic, unpredictable stress
(CUS) on CB1 receptor binding site density are attenuated by antidepressant treatment while those on endocannabinoid content are not.
The increase in amygdalar CB1 receptor binding
following imipramine treatment is consistent with prior studies which
collectively demonstrate that several treatments which are beneficial to
depression, such as electroconvulsive shock and tricyclic antidepressant treatment, increase CB1 receptor activity in subcorticallimbic structures, such as the hippocampus, amygdala and hypothalamus. And preclinical studies have demonstrated the CB1 receptor is required for the behavioral effects of noradrenergic based antidepressants but is dispensable for the behavioral effect of serotonergic based antidepressants.
Extrapolating from the observations that positive emotional
experiences boost the immune system, Roberts speculates that intensely
positive emotional experiences—sometimes brought about during mystical
experiences occasioned by psychedelic medicines—may boost the immune
system powerfully. Research on salivary IgA supports this hypothesis,
but experimental testing has not been done.
