Research Review

Sports Medicine 5: 248-267 (1988)

0112-1642/88/0004-0248/$10.00/0
© ADIS Press Limited
All rights reserved.

Exercise and the Immune Response

D. Keast, K. Cameron, and A.R. Morton
Department of Microbiology and Human Movement and Recreation Studies,
University of Western Australia, Nedlands, and Department of Physical Education,
Ballarat College of Advanced Education, Ballarat

Contents Summary ..................................................................................................................................... 248

I. The Immune System ............................................................................................................. 249
2. Immunity ................................................................................................................................ 249
2.1 Nonspecific Immunity .................................................................................................... 249
2.2 Acquired or Adaptive Immunity ................................................................................... 250
2.2.1 Antibody-Mediated Immunity .............................................................................. 250
2.2.2 Cell-Mediated Immunity ....................................................................................... 252
3. Factors that Modify Immune Mechanisms ......................................................................... 253
4. Exercise and Metabolism in the Immune System .............................................................. 254
4.1 Energy Supply and Fuel Utilisation by Lymphocytes .................................................. 254
5. Exercise and the Immune System ........................................................................................ 256
5.1 Effects on the Numbers of Circulating Lymphocytes .................................................. 256
5.2 Effects of Exercise on Lymphocyte Function ............................................................... 258
5.3 Effects of Exercise on Antibody Synthesis .................................................................... 259
5.4 Effects on the Phagocytic Cells ...................................................................................... 259
5.5 Effects on Natural Killer Cells ....................................................................................... 260
5.6 Effects on Platelets .......................................................................................................... 260
6. Exercise, Hormones and Immunity ..................................................................................... 260
6.1 Catecholamines and the Immune System in Exercise ................................................. 261
6.2 Glucocorticoids and the Immune System in Exercise ................................................. 261
7. Prostaglandins, Exercise and the Immune System ............................................................. 262
8. Conclusion .............................................................................................................................. 262

Summary A growing number of reports have become available which implicate infectious disease
with reduced performance in athletes.
The immune system consists of both nonspecific and specific components geared to
control infections. Adaptive immunity functions through both antibody-mediated and cell-
mediated compartments to establish and maintain long term immunity to infectious agents.
Evidence is accumulating to support the view that physical exercise can lead to modifi-
cation of the cells of the immune system. However, studies have often not been well de-
signed to control exercise protocols when examining the effects of exercise on the immune
system.
Large numbers of peripheral blood lymphocytes are mobilised with exercise and in
vitro tests indicate that temporarily these cells may not be capable of responding normally
to mitogens. These reactions appear to be influenced by hormones to some degree and
Exercise and the Immune Response 249

there are reports that the cells of the immune system are extremely active biochemically
and may depend on products from muscles to maintain their activity.
Specific populations within the circulating leucocyte pool vary significantly with ex-
ercise and there is some evidence that the T4iTs lymphocyte ratio may become signifi-
cantly reduced. This reduction in ratio may be related to the variable responses to T and
B cell mitogens recorded in vitro which overall suggests that a temporary immune suppres-
sion may exist following certain training or performance schedules. It is argued that this
may lead to a temporary susceptibility to infection and could result from overtraining.

The study of the effect of physical exercise on
the immune system is of importance 'because of the
growing number of reports implicating mild infec-
tious disease with reduced performance of the ath-
lete. Historically, anecdotal information has sug-
gested that, in some instances, athletes undergoing
heavy and intensive training can become more sus-
ceptible to minor infections.
Limitations to the interpretations of much of
the current literature in this area exists because of
the variability of the intensity and duration of ex-
ercise and the fitness level of the subjects employed
to date. Despite this, major variations for the ma-
jority of cells of the immune network have been
recorded, along with often major changes in clas-
sical in vitro tests used as indicators of metabolic
responsiveness of the cells involved.
It is now possible to accurately prescribe exer-
cise protocols to selectively stress energy metab-
olism both on a short term and long term training
basis. Therefore, a more accurate delineation of the
true role of various types of exercise on immune
function should be possible. In addition, recent
technical advances allow the immune system to be
better defined into functional subpopulations. For
example, 2 of the subpopulations of lymphocytes
provide evidence that the T -helper: T-suppressor
ratio can be significantly changed following exer-
cise and we suggest this may result from physical
stress and indicate the presence of overtraining.
Many athletes are forced to temporarily with-
draw from sport during each season because of mi-
crobial infections. To-date claims by athletes of de-
creased resistance to minor infections and published
reports (Douglas & Hanson 1978; JokI 1974, 1977;
Nash 1986; Peter 1985; Roberts 1986) are largely
anecdotal. However, epidemiological studies
(Douglas & Hanson 1978; Heiss 1971; Peters &
Bateman 1983) lend some support to these obser-
vations and have been suggesting that serious ill-
ness and death have resulted from training in the
aftermath of virus infection (Roberts 1986). Many
of the proponents of exercise, however, see it as a
panacea and a means of increasing the functional
capacity of the immune system (Good & Fer-
nandes 1981; Green et al. 1981; Nash 1986). In the
last decade there has been an increasing interest in
the effects of regular vigorous exercise on the im-
mune system (Cameron et al. 1987; Lewicki et al.
1987; Nash 1986; Peter 1985).
A better understanding of the mechanisms in-
volved and how these can be influenced by phys-
ical training, provide a major challenge for future
research.
1. The Immune System
The immune system consists of 'all those phys-
iological mechanisms that endow the animal with
the capacity to recognise materials foreign to itself,
and includes nonspecific defense mechanisms'
(Bellanti 1985). Our interest mainly concerns ac-
quired or adaptive immunity.
2. Immunity
2.1 Nonspecific Immunity
Nonspecific immunity is a body's initial def-
ence mechanism against an invading micro-organ-
ism. It aims at preventing opportunists and/or pa-
thogens from entering the body while those that
Exercise and the Immune Response
escape and gain entry into the body activate the
specific immune defences. Nonspecific immunity
includes:
1. The ability of the skin to resist invasion both
by its mechanical properties and by the fact that it
excretes salts, long-chain fatty acids and other bac-
teriostatic and bactericidal materials on to the sur-
face.
2. The ability of the nose and mucous lining of
the respiratory tract to filter air entering the pul-
monary system.
3. The ability of the highly acidic digestive juices
in the stomach to destroy, to a large degree, in-
gested organisms.
4. The lowering of iron levels in blood and in-
testinal fluid, which deprives pathogens of an ele-
ment that is required, to a large degree, for their
growth and replication.
5. Phagocytosis of unopsonised bacteria, vi-
ruses and other antigenic material by cells of the
reticuloendothelial system.
6. Triggering of inflammatory responses which
bring, along with other cells, macrophages to the
area of infection and/or cell damage. This results
from the activation and liberation of chemotactic
substances such as complement, properdin, hist-
amine, bradykinin and serotonin. The 2 complex
serum components known as complement and
properdin can be involved in several of these re-
actions while also taking part in specific antigen/
antibody reactions designed to inactivate and re-
move antigenic material and micro-organisms from
the system (Lentner 1984).
7. Secretion of antibacterial substances such as
lysozyme in tears, saliva and the mucous ofthe gut
and one or more of the a-interferons, which appear
to bind to cell surface receptors. One of the prop-
erties of the interferons is to instigate the produc-
tion of anti-viral proteins within cells, thus pre-
venting the synthesis of the macromolecules
required for virus replication.
2.2 Acquired or Adaptive Immunity
This type of immunity is referred to as 'specific
immunity' because this system relies upon the
body's ability to recognise foreign macromolecules
250
(antigens) of infectious agents and other immu-
nogenic materials. As the term 'acquired immu-
nity' implies, this type of immunity does not occur
until after the first exposure to the antigen.
There are 2 basic types of acquired immunity,
one termed antibody-mediated immunity or
humoral immunity and the other, cell-mediated
immunity (Bellanti 1985). Both systems involve
lymphocytes residing in structured depots around
the body such as the lymph nodes, spleen, sub-
mucosal areas of the gastrointestinal tract and to
some extent the bone marrow. In addition there
are relatively large numbers of lymphocytes dis-
tributed throughout the skin and a smaller pro-
portion in circulation in the blood and the lym-
phatics. Several subtypes of lymphocytes are now
known to exist that can be distinguished by mono-
clonal antibodies. Classically, the 2 main subgroups
that can be distinguished both by monoclonal anti-
bodies and by their functional characteristics are
the so-called B lymphocytes, which promote anti-
body-mediated immunity, and the T-Iymphocytes,
which promote cell-mediated immunity.
2.2.1 Antibody-Mediated Immunity
The B lymphocytes, as do the T lymphocytes,
develop from lymphocytic stem cells now consid-
ered to exist in the bone marrow in the mature
mammal. Just where in the body the B lympho-
cytes are first 'educated' into developing irrever-
sibly as B cells is uncertain; however, claims have
been made for either fetal liver, spleen or bone
marrow with the latter now being accepted as the
site for production of most lymphocyte precursors.
The B lymphocytes, when exposed to a specific
antigen and/or in cooperation with macrophages,
T lymphocytes and their soluble products in the
lymph node, replicate and subsequently mature into
plasma cells which synthesise and secrete mainly
glycoprotein molecules called antibodies (fig. 1).
This pool of replicating cells is specifically reactive
to the initiating antigen and the antibodies react
with and lead to the destruction of the antigen. The
antibodies formed by the plasma cells, and the more
mature B cells diffuse into the circulating lymph
and blood for transport to the site of infection where
Exercise and the Immune Response 251

Pluripotent
Stem cell

Erythrocyte
~
Colony forming units ----- ~
;-
compartment .. .~phocyte
Megakaryocyte ~~ ~ , Large granular lymphocytes

!
r
• My~asy ~
~ pr~.e I~mphocyte ~
'i\~
Immature
Platelets
I \ Natural killer cell
Eosinophil Neutrophil MonJyte /
.. , (blood) \ ~. T-Killer cell
.. ~ Mature suppressor cell
l Macrophage
(tissue) lymphocyte T-Helper cell
(Phagocytosis)
I) (Cell-mediated immunity)

Fig. 1. The differentiation of cells of the immune system. The differentiation of myeloid,lymphoid and eythroid cells from a pluripotent
stem cell present in the bone marrow is illustrated. This differentiation occurs under the influence of soluble mediators such as
colony stimulating factors in the bone marrow and thymopoietin in the thymus. These and other maturational changes can now be
monitored by monoclonal antibodies through a series of well defined subsets of cells with outer membrane markers, 2 of which lead
to the T4 :CD4 and Ts:CDs T lymphocytes. Often cooperation between these cells and macrophages with concomitant production of
Iymphokines in particular interleukin 1-4 (IL-1 :IL-4) leads to antibody production.

they react with the antigen to form an antigen/anti-
body complex which can also include other serum
factors such as complement and properdin (Guy-
ton 1986; Lentner 1984). These reactions effec-
tively kill and assist in the removal of the invading
micro-organism or virally infected cells from the
body. An important component of the develop-
ment of the pool of antigen specific lymphocytes
is a group of 'memory' cells which form the basis
of long term immunity to the individual.
There are 5 classes of antibody which can be
synthesised, designated IgM, 19A, IgG, IgE and IgD
(Lentner 1984). These are immunoglobulins and
are classified by their molecular weights, their bio-
logical properties and sites of origin (Lentner 1984).
The IgM class of antibody is traditionally the best
activator of complement, although it is not as spe-
cific as the class IgG which is now known also to
weakly fix complement. The complement system
consists of some 20 reactive components, which
though usually inactive in the blood can be acti-
vated by 2 independent pathways, each leading to
a common terminal sequence of events. The 'al-
ternative' pathway involves the activation of pro-
Exercise and the Immune Response
perdin which subsequently stabilises components
of the complement system (Lentner 1984). While
the terminal sequence of events relies on cell mem-
brane attack, activation of complement results in
a cascade of interactions involving these proteins,
the end product of which is death of the micro-
organisms.
Complete or partial activation of the comple-
ment cascade can result in:
1. Coating of the micro-organism or immune
complexes, thus facilitating destruction via phag-
ocytosis.
2. Rupture of the cell membrane - lysis of the
cell.
3. Being a further aid to agglutination of micro-
organisms.
4. Neutralisation of viruses.
5. Chemotaxis of participating cells in the con-
trol of infection.
6. Rupture of basophils and mast cells, result-
ing in the release of histamine and other vaso-
reactive substances which playa major role in in-
flammation (Lentner 1984).
2.2.2 Cell-Mediated Immunity
Cell-mediated immunity following antigenic
challenge results from the formation of activated
T cells rather than antibodies. The reactive
lymphocytes have been previously modified or
processed (educated) in the thymus to form T
lymphocytes (fig. 1). The processing occurs shortly
before birth in most instances. The processed cells
form germinal centres in the lymph nodes and the
spleen and from these T lymphocytes repeatedly
circulate through the blood to the tissue spaces and
back. T cells become specifically sensitised by an
antigen following which they may develop the abil-
ity to attach themselves to the antigen and destroy
it or they may cooperate with macrophages and B-
lymphocytes to give impetus to antibody devel-
opment. This reactiveness stems from the fact that
several sub-types of T lymphocytes exist (Thomas
et al. 1981). Three ofthe more important sub-types
are: the cytotoxic T cells, the helper T cells
(T4 cells) and the suppressor T cells (T8 cells).
The cytotoxic T cells recognise and kill cells of
252
the body which may be abnormal antigenically and/
or infected with bacteria or viruses and are exhib-
iting newly induced antigenic markers on their sur-
faces. They can also lyse tumour cells which have
recognisable antigenic changes on their surfaces,
induced as part of their neoplastic changes.
The helper T cells facilitate the functioning of
the immune system. They accomplish this by hav-
ing the ability to be activated by much smaller
quantities of antigens than other cells in conjunc-
tion with interleukin I produced by antigen pro-
cessing macrophages. These activated T-helper cells
then themselves produce and release further lym-
phokines one of which, interleukin 2, appears to
increase the activity of the T cells to allow them
to secrete a further lymphokine, interleukin 3. To-
gether these reactions generate a pool of activated
lymphocytes which include T lymphocyte memory
cells which can become reactivated T cells at any
subsequent exposure to the given antigen. This
subsequent response occurs far more rapidly than
that following the initial exposure to antigen.
Suppressor T cells are downregulating cells and
appear to suppress and turn off both cytotoxic cells
and T-helper cells. It is thought that the suppressor
cells regulate the activity of other cells to prevent
undue damage to the body.
Most of these reactions are said to be genetically
restricted, indicating that the cellular cooperation
that is required to produce these reactions will only
occur between cells that are genetically identical.
This genetic restriction resides with what is known
as the major histocompatibility complex II, the
surface expression of genes closely associated with
the genes responsible for control of the immune
system.
For some 20 years or more a basic but contro-
versial proposition has been researched which pro-
poses that some type of cellular immune surveil-
lance exists as a primary defence, in particular
against cancer (Keast 1980). In the search for cells
which might mediate this surveillance a group of
so-called killer cells have been found which, while
appearing histologically similar to lymphoid cells,
do not carry any, or very little, of the normal sur-
face markers of the lymphocytes (Keast 1981).
Exercise and the Immune Response
Among the group of cells known as null cells is a
cell type which has been called the natural killer
cell, which has, in circulation in humans, an equiv-
alent known as the large granular lymphocyte cell
(Sakasela et a1. 1983).
Finally, there exists a group of cells, the mac-
rophages, whose prime function is to process anti-
gen to remove it from the body and to synthesise
interleukin I, which plays a prime role in activat-
ing the lymphocytes as described above (fig. I).
Subgroups of macrophages exist which can be dis-
tinguished by the presence or absence of a surface
marker, la. The la+ macrophage appears to be re-
sponsible for the synthesis of interleukin I.
The macrophages are involved in the gross de-
struction of invading micro-organisms and are large
phagocytic cells which are thought to develop from
the circulating monocytes which move out of the
blood to infiltrate the tissues. Historically these cells
then take on site specific names originally given to
them by histologists.
Macrophages in the liver sinuses are called
Kupffer cells, while those in the lungs are referred
to as alveolar or interstitial macrophages and tissue
histiocytes when located in the subcutaneous tis-
sues. In the skin there exists the Langerhans cells
and it is still unclear as to whether or not these are
metabolically modified macrophages or a specific
cell type closely resembling other dendritic mac-
rophages of the body. Macrophages in the lymph
nodes, spleen and bone marrow have been called
reticulum cells and the microglia are the macro-
phages of the brain.
3. Factors that Modify Immune
Mechanisms
Bellanti and Kadlec (1985) indicate that there
are a number of factors that can modify immunity.
Their list includes age, genetic, metabolic, envi-
ronmental, anatomical, physiological and micro-
bial factors.
The very young and the very old are more sus-
ceptible to infection due to lower levels of im-
munityat these ages. In the one instance the im-
mune system is immature, due in part to an initial
253
lack of antigenic challenge from the environment,
and in the other it is running down, due to a life-
time of antigenic assault.
Bellanti and Kadlec (1985) point out that meta-
bolic factors such as a depressed state of certain
hormonal systems result in an increased suscepti-
bility to infection. In particular, the depressed level
of hormonal secretions from the pancreas, the
adrenals, and the thyroid glands are presented as
examples. Genetic factors are important in the ef-
ficacy of the immune response and have been
shown to be involved in different levels of suscep-
tibility to certain infections that can exist within a
population. In humans some of the differences in
susceptibility are racially biased and probably rep-
resent to a large extent the natural selection pro-
cess.
Environmental and nutritional factors, in par-
ticular malnutrition, have long been recognised as
being associated with lowered immunity. As de-
scribed in section 2.1, certain anatomical barriers
to infection exist as a first line of defence. These
barriers include skin and the mucous membranes;
physical, nutritional and physiological damage to
these barriers result in an increased susceptibility
to infection. Other physiological factors which when
modified may result in significant changes to the
immune system, include the action of the cilia in
the respiratory tract, the peristaltic action of the
gut and the force of expression of urine. Dysfunc-
tion in any of these parameters can lead to in-
creased incidence of infection often associated with
an overwhelming of the local immune system.
There are a number of other physiological func-
tions that help prevent infection which if changed
can change the effectiveness of the immune sys-
tem. These factors include certain bactericidal
compounds present in skin secretions, lysozyme
and naturally cross-reacting antibodies. Major
changes in the natural flora existing on and within
the body can lead to immune modulation. These
changes can be brought about by changes in diet,
environment and by the introduction of new mi-
cro-organisms into the body by, for example, travel
from one area of the world to another.
There is now an increasing acceptance that psy-
Exercise and the Immune Response
chological stress can be a major contributor to
modification of health but the role of the stress of
physical exercise, if any, in adding to the immune
modulation likely to occur from one or more of
the above factors is largely unexplored. It is clear
that extensive physical training induces major
physiological changes and often psychological
changes which have the potential to be expressed
in several of the above areas.
4. Exercise and Metabolism in the
Immune System
The accepted dogma of immune reactivity is that
the cellular components of the immune system are
activated by an antigen and transfer from a resting
state into one of high biochemical activity.
This activity involves rapid -cell division along
with the production of antigen specific antibodies,
the production of many mediators and chemical
signals including at least 4 interleukins, which serve
to amplify the immune response (Bellanti 1985).
Ardawi and Newsholme (1985) have presented evi-
dence that both the so-called 'resting' lymphocyte
and its antigenically stimulated counterpart are
extremely metabolically active. The study of the
demands of the immune system on the general
metabolism of the body is in an embryonic state.
It has been acknowledged, however, that its study,
integrated with the demands on metabolism of
physical exercise (Rybka & Novosad 1984) may be
a profitable means of exploring shared metabolism
on a tissue basis and the possible interdependence
of tissues on each other's metabolic products (Ar-
dawi & Newsholme 1985). These workers suggest
that there is ample evidence to indicate that, with
respect to amino acid metabolism, there is almost
certainly an interdependence between muscle and
the lymphocytes. Whether disturbance of this in-
terdependence leads to a lowering of immunity
in the 'training' athlete or not has yet to be ex-
plored, but represents an exciting prospect for the
future.
It has now been accepted that part of the phys-
iological process of training the athlete results in
an adaptation of the biochemistry of the active
254
muscles to the demands of the sport (Saltin 1986)
and much of the direction of sports dieting has also
been geared to boost pools of metabolic energy
which will come under demand. Yet, to date, there
is no clear evidence available as to whether or not
such metabolic demands can influence the func-
tion of the immune system. This most probably
comes from a lack of appreciation of the overall
metabolic demands of the immune system.
4.1 Energy Supply and Fuel Utilisation
by Lymphocytes
It is now acknowledged that there are at least 2
major sources for the provision of energy for
lymphocytes: these are glucose and glutamine (Ar-
dawi & Newsholme 1984; Hume & Weidemann
1980). The utilisation and relative contributions of
long chain fatty acids and ketone bodies as energy
sources in lymphocytes is far less clear, although it
is clear that ketone bodies alone cannot support
lymphocytes in culture (Ardawi & Newsholme
1984). However, the addition of oleate to isolated
lymphocytes in culture raised the oxygen con-
sumption significantly, indicating that fatty acids
can be utilised. While both of these substrates pro-
duced a glucose sparing effect, it was suggested that
this was not so important in conserving glucose in
the whole animal as in maintaining the concentra-
tions of glycolytic intermediates necessary for the
maintenance of cell proliferation (Ardawi &
Newsholme 1984). Other studies have suggested
that anaerobic (glycolytic) metabolism might be
more important than respiration (aerobic) for the
maintenance of energy metabolism in lymphocytes
and various other lymphoid tissues including thy-
mocytes (Kit 1976). Ardawi and N ewsholme (1985)
have recently reviewed much of the biochemical
literature on the metabolism of lymphocytes and
there is no evidence to date that human lympho-
cytes are different from those of other animals (Ar-
dawi 1987). Some important issues taken up in that
review follow. The low levels of phosphorylase ac-
tivity, which is less than that of hexokinase, sug-
gests that endogenous glycogen is not important as
a fuel to supply glucose for the lymphocyte, but
Exercise and the Immune Response 255

".. Span of TCA

CYCle
2-0xoglutarate
\

'---- ®~ 1
1
~ @Malate

Aspartate oxaloacetate;/"

\ -L,,:,. (~o
Lymphocyte

Pyruvate _ Lactate

Fig. 2. The proposed pathway for the partial oxidation of glutamine in lymphocytes. 1 = glutaminase; 2 = aspartate amino-
transferase; 3 = malate dehydrogenase (NAD+-linked); 4 = malic enzyme [NAD(P)+-linked]; 5 = phosphoenolpyruvate
carboxykinase; 6 = pyruvatekinase; 7 = lactate dehydrogenase. Modified from Ardawi and Newsholme (1985).

that glucose is an important substrate mainly
metabolised by glycolysis (Newsholme & Leech
1983).
The Kreb's cycle is fully functional in lympho-
cytes and the fact that it increases substantially in
activity when lymphocytes are responding to im-
munological challenge indicates its importance in
cell division for these cells (Ardawi & Newsholme
1982).
Glutamine has been known for some time to be
an important fuel in a number of rapidly dividing
cells and lymphocytes (Ardawi & Newsholme
1983), although classically glutamine is considered
to contribute nitrogen-containing precursors for the
synthesis of macromolecules, including purine and
pyrimidine nucleotides, amino sugars and some
amino acids (Tate & Meister 1973). More recently,
Ardawi and Newsholme (1985) have proposed that,
in vivo. the glutamine pathway in lymphocytes may
be under external regulation and that this may be
with respect to the supply of the glutamine itself
(fig. 2). This raises important issues from the ath-
letes' viewpoint because muscle is a major site for
the synthesis of glutamine (Ardawi & Newsholme
1985). These authors have suggested that some of
the anecdotal evidence that well trained athletes
may be more susceptible to minor infections may
stem from the fact that under intense physical ex-
ercise the demands on muscle and other organs for
glutamine are such that the lymphoid system may
be forced into a glutamine debt which temporarily
affects its function.
Exercise and the Immune Response
5. Exercise and the Immune System
It soon became obvious on exploring the liter-
ature that much of the research into the effects of
physical exercise on the immune system has been
carried out with little systematic regard for the
various types and amounts of stress that can be
applied to the body by sports exertion. Thus, while
some emphasis has been placed on differences
which might exist between responses seen, within
the immune system, at the beginning of a training
period and that seen in the entrained athlete, there
has been little regard given to the different exertion
patterns that different sports activities may place
on the athlete. It is difficult, therefore, to begin to
link any of the now many changes that have been
recorded to occur within the immune system with
any specific physiological or biochemical mech-
anisms, such as the effects of aerobic as opposed
to glycolytic demands of certain physical exercise
patterns.
5.1 Effects on the Numbers of
Circulating Lymphocytes
It is now well established that in most studies
on the effects of physical exercise on the immune
system the number of circulating leucocytes has
been shown to increase as a result of a wide range
of exercise stresses (Bieger et at. 1980; Busse et at.
1980; Cameron et at. 1987; De Lanne et al. 1960;
Edwards et al. 1984; Eskola et al. 1978; Hedfors et
al. 1976; Moorthy & Zimmerman 1978; Nguyen et
al. 1984; Soppi et al. 1982; Steel et al. 1964). The
exact time of onset of the leucocytosis during ex-
ercise has not been extensively studied, but De
Lanne et al. (1960) detected a significant elevation
of leucocyte numbers within 5 minutes of begin-
ning submaximal exercise and most studies have
indicated the leucocytosis to be well established and
maintained for at least 15 minutes after cessation
of exercise with the numbers still significantly raised
for at least 3 hours after marathon runners had
completed their competition (Eskola et al. 1978).
More recently Cameron et at. (1987) have shown
that the leucocytosis is well established at sampling
256
some 5 to 10 minutes after exercise protocols de-
signed specifically to stress the 3 main energy sys-
tems used in sport. We have also shown recently
that the performance of the closed sport of archery
by trained archers is sufficient to induce a leuco-
cytosis within 15 to 20 minutes of commencement
of competition (Keast & Morton, unpublished).
More detailed analysis of the extent and the
duration times for the leucocytosis is required as
there is some small amount of evidence that these
may be related to the degree of stress experienced
by the individual (Eskola et at. 1976; Hedfors et
at. 1976; Moorthy & Zimmerman 1978; Soppi et
al. 1982). This appears not to be related to the type
of energy system under stress (Cameron et al. 1987).
There is some evidence that the magnitude of the
leucocytosis may be inversely proportional to the
degree of previous training (Moorthy & Zimmer-
man 1978; Soppi et at. 1982); although it is also
possible that the magnitude of any leucocytosis
could be related to raised levels of circulating cate-
cholamines, since the infusion of catecholamines
does give rise to a leucocytosis (Crary et al. 1983;
Eriksson & Hedfors 1977; Mishler & Sharp 1976;
Steel et al. 1971) and it has been established that
the levels of catecholamines increase with intensity
and duration of physical exercise (Galbo 1983).
The picture remains far from clear when the cell
types that are contributing to the leucocytosis are
investigated. The differential mobilisation of all
leucocyte subsets have been reported as well as sit-
uations when specific subset cytopenias have also
occurred. Lymphocyte numbers have been shown
to increase in peripheral blood during physical ex-
ercise of less than 15 minutes duration (De Lanne
et al. 1960; Edwards et al. 1984; Hedfors et al. 1976;
Nguyen et al. 1984; Robertson et al. 1979; Soppi
et al. 1982; Steel et al. 1964) and also after long
term exercise (Moorthy & Zimmerman 1978; Ngu-
yen et at. 1984). There have also been reports in-
dicating that after some long term exercise sched-
ules, in particular after marathon running, little or
no lymphocytosis was present at the end of the race
(Eskola et al. 1976; Moorthy & Zimmerman 1978).
The changes that have been recorded in the total
lymphocyte pool as a result of physical exercise
Exercise and the Immune Response
have also been explored at their subpopulation lev-
els. Although some workers have found no differ-
ences in the relative proportions of T and B
lymphocytes before and after exercise (Bongers &
Bertrams 1984; Hanson & Flaherty 1981; Kanon-
choff et al. 1984; Soppi et al. 1982), others have
reported significant changes in the B cell/T cell ra-
tio (Edwards et al. 1984; Hedfors et al. 1976, 1983;
Landmann et al. 1984; Robertson et al. 1979; Se-
neczko & Rzetelski 1985; Steel et al. 1964; Tomasi
et al. 1982). There has been some evidence that
while the total population of circulating T lympho-
cytes may be depressed after exercise, some sub-
populations of the T cell, which are characterised
by their cytotoxic properties, may become elevated
(Edwards et al. 1984). It has been suggested that
these variations are influenced by hormonal
changes known to occur during exercise (Fauci
1975, 1976; Galbo 1983; Tharp 1975).
More recently research workers have been able
to use monoclonal antibodies to further discrimi-
nate changes in the subsets of the T lymphocyte
compartment (Bongers & Bertrams 1984). Some
workers have been unable to detect any significant
changes in the T 4/T g ratio (Kanonchoff et al. 1984)
following physical exercise. However, at least 6
other studies have found a reduction in the helper
to cytotoxic/suppressor ratio following exercise
(Berk et al. 1985; Cameron et al. 1987; Edwards et
al. 1984; Hedfors et al. 1983; Landmann et al. 1984;
Nguyen et al. 1984). The work of Cameron et al.
(1987) was designed to test selectively each of the
3 main energy systems used in physical exercise
and the results indicated that while a significant
reduction in the T 4/Tg ratio occurred it was not
specifically related to anyone particular energy
system.
Both T4 (helper) and Tg (suppressor/cytotoxic)
lymphocytes play crucial regulatory roles in the
immune response and a reduction of this ratio has
been associated with immunosuppression (Hans-
brough et al. 1984) in circumstances where a sus-
ceptibility to minor infections might also exist.
Another group of lymphocyte-like cells that are
becoming of increasing importance in terms of im-
munosurveillance of the body, in particular for
257
malignant cells and cells carrying and/or possibly
expressing infection induced and related surface
markers (Keast 1980), lack the majority oflympho-
cyte markers, and as a group are known as null
cells. The current consensus is that the numbers of
null cells is increased in circulation as a result of
physical exercise (Cameron et al. 1987; Edwards et
al. 1984; Hanson & Flaherty 1981; Hirsen & Mal-
ham 1983; Nguyen et al. 1984; Targan et al. 1981;
Tomasi et al. 1982). There may also be an en-
hancement of their functions (Hedfors et al. 1976,
1983; Hirsen & Malham 1983; Targan et al. 1981).
Several workers have found the proportion of
neutrophils to be raised in circulation following
physical exercise (De Lanne et al. 1960; Eskola et
al. 1978; Lewicki et al. 1987; Moorthy & Zimmer-
man 1978). An increase in neutrophils has been
correlated with an increase in plasma cortisol
(Moorthy & Zimmerman 1978) while corticoste-
roids are known to be capable of inducing a neu-
trophilia (Bishop & Athens 1968; Cream 1968; Dale
et al. 1975). It has been suggested that plasma cor-
tisol concentration decreases at workloads below
50% of maximal oxygen uptake and only increases
at workloads of greater than 60% of the maximal
oxygen uptake (Comil 1965; Davies & Few 1973;
Few 1974). This may explain some of the varia-
bility that has been recorded following exercise.
Both eosinophilia and eosinopenia (Cameron et
al. 1987) have been recorded as a result of physical
exercise. These variable observations may again be
related to cortisol levels in the blood (Anderson &
Bro-Rasmussen 1969; De Lanne et al. 1960; Fauci
et al. 1976; Kellgreen & Janus 1951; Moorthy &
Zimmerman 1978; Weber 1971).
The effects of exercise on monocyte dynamics
is by no means clear. The number of circulating
monocytes has been reported to both increase
(Cameron et al. 1987; De Lanne et al. 1960; Ed-
wards et al. 1984; Lewicki et al. 1987) and decrease
(Moorthy & Zimmerman 1978) during and as a
result of exercise. The variations in results may
again be related to cortisol concentrations, al-
though Thompson et al. (1980) found no correla-
tion between endogenous cortisol levels and mon-
ocyte numbers during a 24-hour study.
Exercise and the Immune Response
5.2 Effects of Exercise on
Lymphocyte Function
While the number of lymphocytes in the blood
may be elevated by physical exercise, there is some
evidence to suggest that their function on occa-
sions is also temporarily impaired. The assessment
of lymphocyte function following exercise has usu-
ally involved the in vitro responses of peripheral
blood leucocytes to plant lectins. Phytohaemaglu-
tinin and concanavalin are polyclonal T-Iympho-
cyte mitogens. Pokeweed mitogen and purified
bacterial proteins such as purified protein deriva-
tive are B-cell mitogens and which nonspecifically
stimulate DNA synthesis, blast transformation and
proliferation in lymphocytes (Bellanti 1985; Eskola
et al. 1978; Fauci 1982; Hedfors et al. 1976; Hells-
tedt 1975; Roosnek et al. 1985; Sasaki & Norman
1966). In vitro impairment of responses to these
mitogens has been associated with a variety of im-
mune deficiencies in vivo (Bellanti 1985; Levy &
Kaplan 1974; Lopez-Bortet et al. 1982; Oppenheim
et al. 1970).
Studies to date have not produced a total agree-
ment on the importance or otherwise of some of
the in vitro mitogen reactions oflymphocytes from
trained athletes. Green et al. (1981) found that the
leucocytes of 20 marathon runners responded nor-
mally to phytohaemaglutinin and pokeweed mi-
togen in vitro, while Soppi et al. (1982) found that
a slight increase in lymphocyte responsiveness to
mitogens developed in subjects who underwent a
6-week training programme. However, there is a
large body of information that indicates that im-
mediately after a single bout of exercise, lympho-
cyte transformation in vitro in the presence of mi-
togens can be suppressed. This suppression of
lymphatic activity has occurred over a wide range
of exercise stress. Eskola et al. (1978) reported that
responses of peripheral blood leucocytes to phy-
tohaemaglutinin, concanavalin and purified pro-
tein derivative in vitro were depressed in 8 subjects
30 minutes after completing a marathon, but had
recovered within 24 hours. Suppression oflympho-
cyte function has also been demonstrated following
15 minutes of mild bicycle exercise (Hedfors et al.
258
1976). In this study the pokeweed mitogen re-
sponses were depressed despite the fact that there
was an increased proportion of B cells in the leu-
cocyte samples. Hedfors et al. (I983) have devel-
oped the notion that the suppression of T cell re-
sponses to mitogens and the suppression that is
found in the allogenic mixed lymphocyte reaction
in postexercise peripheral blood samples could be
due to a decreased proportion of T -helper lympho-
cytes. The reduction in T 4fT8-lymphocyte ratios
that have been shown to occur after exercise can
be interpreted to support these views. It has also
been shown that when the T 4fT8 ratio of T -helper
lymphocytes to T-suppressor lymphocytes falls
below 1.5 then DNA synthetic responses of
lymphocytes to polyclonal T-cell mitogens be-
comes decreased (Chailleux et al. 1985; Filipovich
et al. 1982). However, once again some workers
have not been able to support these results (Ed-
wards et al. 1984). Recently, Cameron et al. (1987)
have shown that individuals can vary widely in
their responses to both T - and B-polyclonal
lymphocyte mitogens in vitro. The variations seen
were not consistent within an individual who might
on one day produce peripheral blood lymphocytes
postexercise that exhibited a depressed response to
the mitogens and on another day produce lympho-
cytes with a heightened response. However, taking
the results overall, there was a greater number of
tests showing suppression of responsiveness to the
mitogens than there were showing heightened ac-
tivity. There was no evidence of in vitro prosta-
glandin synthesis being responsible for the vari-
ations seen and the sera of the athletes failed to
modify any in vitro responses. In a second set of
trials where the T 4fT8 ratios were determined it
was shown that these were severely reduced im-
mediately postexercise, but there was no consistent
relationship between this reduction and respon-
siveness of the subjects' lymphocytes to polyclonal
DNA mitogens (Cameron et al. 1987). There was
significant suppression of polyclonal lymphocyte
responses postexercise, when all the treatments were
analysed together under the heading of'nonspecific
exercise stress'. However, none of the 3 exercise
protocols alone produced consistent results. These
Exercise and the Immune Response
protocols had been designed to place the major en-
ergy stress onto 1 of the 3 energy systems used in
sports activities and for which individuals can be
trained.
While the results when viewed from the T 4fT 8
ratio viewpoint might be variable, it may well be
that the ratio is in part hiding a critical real number
threshold for. suppression in mitogen activity in
vitro, which at this time could reside in either the
T-helper lymphocytes (T 4) or the T-suppressor
lymphocytes (T 8) [Berk et al. 1985].
The reduced response to T- and B-cell mitogens
and the lowered T 4fT 8 ratio may reflect a tempor-
ary immune suppression of cell-mediated immu-
nity sufficient to allow micro-organisms and in
particular viruses time to evade early immunolog-
ical recognition and thus establish on-going infec-
tions in the athlete.
5.3 Effects of Exercise on Antibody Synthesis
In humans, normal levels of IgG, IgA and IgM
have been recorded in marathon runners (Green et
al. 1981) and marathon runners who were immun-
ised immediately after a race with antitetanus tox-
oid antigen showed no impairment of their abili-
ties to produce antibody (Eskola et al. 1978), even
though this is the time when in vitro immune
suppression of antibody synthesis has been shown
to occur (Hedfors et al. 1983). On the other hand,
Tomasi et al. (1982) sampled cross-country skiers
for salivary IgA immunoglobulin levels before and
after a race and found them to be suppressed after
the race. It was then suggested that the breathing
of cold air had influenced salivary antibody secre-
tion. Petrova et al. (1983) have produced evidence
for a reduction of both serum and secretory im-
munoglobulins which is related to increasing in-
tensity of exercise work load. In animal studies,
antibody production in response to a primary anti-
gen inoculation in exercised rats and mice was not
significantly different to that of non-exercised ani-
mals (Carmack 1984; Cross 1985). Earlier studies
by Douglas (1974) showed that while primary re-
sponses to an antigen were not altered by daily ex-
ercising of mice, secondary responses could be en-
259
hanced. There have been few other studies that
provide any further information on whether or not
humoral antibody production can be influenced
significantly by physical exercise. The rudimentary
information available suggests at this time that in
vivo humoral responses may not be modified to
any great extent by exercise, although the role of
overtraining in this area might be usefully inves-
tigated.
5.4 Effects on the Phagocytic Cells
Several research.groups have shown that both
the number of circulating monocytes and their
functions can be modified by physical exercise and
that over a physical training period the number of
insulin receptors increase significantly on the mon-
ocytes of the trainees, suggesting a substantial in-
crease in the potential for energy metabolism to
occur and hence an increase in the phagocytic ac-
tivity of the cells (Bieger et al. 1980; Koivisto et
al. 1979, 1980; Pedersen et al. 1980; Soman et al.
1978, 1979).
A bidirectional effect has been shown for the
affinity binding of insulin to its receptors on mon-
ocytes (Michel et al. 1984). Exhaustive exercise de-
creased the binding efficiency of insulin to mon-
ocyte receptors while moderate exercise increased
its binding affinity; these results could be repro-
duced in vitro.
While phagocytosis and antigen processing have
been shown to remain unchanged following the
running of a marathon (Green et al. 1981), a large
study involving 91 sportsmen and 30 healthy adults
not active in sport showed a decrease in functional
activity of neutrophils along with a decrease in
serum and secretory immunoglobulins (Petrova et
al. 1983). Recently results obtained from condi-
tioned cyclists support these results and Lewicki et
al. (1987) suggest that nonspecific immunity may
be stressed by maximal physical exertion and con-
tribute to an increased susceptibility of the sports-
person to infection.
Exercise and the Immune Response
5.5 Effects on Natural Killer Cells
Several groups have reported an increased num-
ber of natural killer and related null cells being
mobilised by exercise and that their activities are
enhanced (Cameron et al. 1987; Edwards et al. 1984;
Hanson & Flaherty 1981; Hirsen & Malham 1983;
Nguyen et al. 1984; Targan et al. 1981). This is of
particular interest as there has been the occasional
report that exercise has enhanced the resistance of
experimental animals to tumour growth (Good &
Fernandes 1981). While this can result from an ar-
ray of cellular activity (Keast 1980) a group of null
cells, the natural killer cells, are being projected as
the main group responsible for an immune sur-
veillance role with the activity of recognising and
destroying the first few neoplastic cells that de-
velop and which may have the potential for de-
veloping at some later time into a malignant can-
cer.
5.6 Effects on Platelets
It has been known for some time that platelets
exhibit some bacteriocidal and/or bacteriostatic
properties (Myhre et al. 1974).
There is also recent evidence that platelets may
be involved in other immunological events such as
the lysis of tumour cells (Ibele et al. 1985), schis-
tosomes (Joseph et al. 1983) and cells opsonised
with antibody (Soppi et al. 1982). In addition to
their traditional roles in providing mediators and
matrices for the induction of the clotting of blood,
platelets are also considered to play a role in in-
flammation, both by the release of mediators and
by aggregation which traps leucocytes and induces
venous occlusion (Bellanti 1985). Inflammation can
be the outcome of both overwork and trauma in-
duced by physical exercise. Platelet numbers in
peripheral circulation have been shown to rise after
exercise (Freedman et al. 1977; Peatfield et al.
1985). Platelets can be categorised on their cellular
volumes, and those of the larger volume group can
be mobilised preferentially by physical exercise
(Peatfield et al. 1985). Cameron et al. (1987) have
shown that in exercise designed to stress mainly
260
the glycolytic (lactate) energy cycle in trained ath-
letes, on average there was a 43.5% increase in the
number of platelets in circulation. This increase was
greater than that induced by exercise designed to
stress either the phosphate (31% increase in num-
bers of circulating platelets) or the aerobic (23%
increase in platelet numbers) energy systems. In this
study there was no evidence for a preferential mob-
ilisation of larger platelets than those seen pre-
exercise.
6. Exercise, Hormones and Immunity
It is now well established that during strenuous
physical activity and exercise many metabolic and
hormonal changes take place in the body (Bunt
1986; Galbo 1983). The current state of knowledge
of the mechanisms of action of hormones import-
ant in physical activity has been detailed by Bunt
(1986). Sympathetic nervous activity increases as
a result of exercise and the levels of several hor-
mones, such as adrenaline (epinephrine), nor-
adrenaline (norepinephrine), vasopressin, gluca-
gon, growth hormone, adrenocorticotrophic
hormone, cortisol and thyroid stimulating hor-
mone, have been shown to increase in concentra-
tion in blood. Many of the changes have been con-
sidered to be components of the stress response
(Selye 1976). While the early definitions of stress
have been summarised as 'the nonspecific response
of the body to any demand' (Selye 1976), more re-
cently the term 'stress' has been taken to encom-
pass the activating agent, the reaction to it and the
consequences of that reaction (Stein 1985). Thus a
variety of stimuli, both psychological and physical,
have been shown to be stressors and have included
such psychological stressors as bereavement,
depression and anxiety and such physical stressors
as surgical trauma, electrical shock, thermal stress
and starvation (Selye 1976). Relatively little em-
phasis has been placed on the role of stress, in-
duced by physical exercise, on the immune system,
although it is implicit in all the research under-
taken. Physiological and biochemical stress occur
during exercise and may subsequently influence
immunocompetence by subtle means (Ardawi &
Exercise and the Immune Response
Newsholme 1985). In general, psychological stress
has been shown to be capable of inducing suppres-
sion of the immune system (Gisler et al. 1971; Hin-
kle et al. 1962; Monjan & Collector 1977; Solomon
et al. 1974; Yamanda 1964). However, in some
cases, enhancement of some immune reactions has
been recorded (Gisler et al. 1971; Monjan & Col-
lector 1977)..
Alterations of immune function caused by stress
are usually considered to be mediated mainly by
adrenal hormones (Besedovsky et al. 1985), al-
though in adrenalectomised animals that have been
stressed further immunomodulation is still possi-
ble (Stein 1985). Changes in thyroid hormones,
growth hormones and sex steroids, which have been
induced by stress, as well as direct sympathetic
nervous stimulation of immunocompetent tissues,
have allIed to alterations in immune function (Stein
1985). The importance of eliminating psychologi-
cal stress in research into the immunology of ex-
ercise was illustrated by a study in which the coach
and the coxswain of a college rowing eight exhib-
ited eosinopenic responses comparable with those
of the rowers during a major race, but not during
training sessions (Reynold et al. 1951).
6.1 Catecholamines and the Immune System
in Exercise
One of the most important changes to occur
during physical exercise has been shown to be the
increase in sympathoadrenal activity, which results
in increases in the blood concentrations of the cate-
cholamines adrenaline (epinephrine) and nor-
adrenaline (norepinephrine). Adrenaline is an
adrenal medullary hormone, while noradrenaline
is primarily a sympathetic neurotransmitter which
can also function as a hormone (Galbo 1983).
Raised levels of catecholamines have been found
to increase heart rate, cause vasoconstriction in the
splanchnic region, increase metabolic rates of
working muscle fibres, increase substrate mobilis-
ation and stimulate sweating (Bunt 1986; Galbo
1983). The concentrations of these hormones in
blood are increased exponentially with the inten-
sity and duration of exercise (Bloom et al. 1976;
261
Davies et al. 1974; Galbo et al. 1973,1977), return
to normal levels rapidly after short term heavy ex-
ercise (Hagberg et al. 1979), but have been shown
to remain high for at least 30 minutes after mod-
erate exercise (Galbo et al. 1975, 1976). Adrenaline
levels have been shown to rise as much as 8 times
during prolonged exercise (Galbo et al. 1977) and
therefore, in the light of the mounting evidence that
sympathoadrenal immunoregulation exists (Bese-
dovsky et al. 1985), becomes a potential modulator
of immune reactivity as a result of physical exer-
cise.
Catecholamines have been shown to modify
both the number and function of circulating
lymphocytes. Infusion of adrenaline has caused
leucocytosis (Crary et al. 1983; Eriksson & Hedfors
1977; Gader & Cash 1975; Mishler & Sharp 1976;
Steel et al. 1971) which included both a lympho-
cytosis and a neutrophilia. Some of the effects of
adrenaline on the subpopulations of circulating
leucocytes may well be sequential in nature, with
a predominant and immediate rise in lymphocytes
followed after about 30 minutes by a neutrophilia
(Gader & Cash 1975; Steel et al. 1971). While
Eriksson and Hedfors (1977) found a decrease in
the proportion of T lymphocytes after the admin-
istration of adrenaline this was not confirmed by
Crary et al. (1983), although they did find a re-
duction in the T 4fT 8 ratio. These data tend to agree
with changes in leucocyte populations that occur
as a result of physical exercise (Eskola et al. 1978;
Hedfors et al. 1976, 1983; Nguyen et al. 1984; Steel
et al. 1964) and lend support to the hypothesis that
adrenaline may be directly or indirectly largely re-
sponsible for the changes in leucocyte numbers seen
in the peripheral blood after exercise.
The site of mobilisation of leucocytes after ad-
renaline infusion or exercise is unclear. It has been
suggested that a lymphocytosis may result from in-
creased emptying of lymph into the blood stream
via the thoracic duct, while neutrophils might be
originating from the bone marrow due to increased
blood flow (Gader & Cash 1975). However, Steel
et al. (1971) were unable, at that time, to show any
increased influx of lymphocytes from the thoracic
duct to the blood stream. Mishler and Sharp (1976)
Exercise and the Immune Response
have also refuted the hypothesis that neutrophils
are mobilised from the bone marrow by adrena-
line, on the basis that these would be expected to
be immature cells. They suggested that the cells
were being mobilised from the lungs and the spleen
and the marginated pool where the cells are known
to adhere to the walls of sma)! venules and capil-
laries (Crary et al. 1983; Mishler & Sharp 1976;
Muir et al. 1984). The changes recorded in the sub-
sets of cells mobilised have been proposed as a re-
sult of differing circulation times between T
lymphocytes and B lymphocytes (Sprent 1973), al-
though it has also been proposed that the various
lymphocyte subsets may vary in their stickiness or
sensitivity to adrenaline or be marginated in dif-
ferent amounts (Crary et al. 1983; Hedfors et al.
1976).
Noradrenaline has also been claimed to increase
the number of circulating leucocytes after its in-
fusion (Gader et al. 1975).
While there have been differences in the timing
and dosage used, it appears that catecholamines can
also affect immunological function. Metabolically,
catecholamines have been shown to increase adenyl
cyclase activity leading to an increase in intracell-
ular cyclic adenosine monophosphate (cAMP)
[Strom et al. 1977], which has been found to in-
hibit both T and B cell responses to mitogens (Estes
et al. 1971; Watson 1976). Adrenaline 100 ~mol
inhibited tritiated thymidine uptake when added
to lymphocyte cultures stimulated with phytohae-
maglutinin, but it was not inhibitory when added
at more physiological concentrations (Hadden et
al. 1970; Keast, unpublished data). Other studies
have shown that the leucocytes from individuals
inoculated with adrenaline do not respond to phy-
tohaemaglutinin, concanavalin or pokeweed
mitogen in vitro (Crary et al. 1983), neither do they
if isoprenaline (isoproterenol), {1-adrenergic com-
pound, is added to cultures at physiological con-
centrations (Goodwin et al. 1978, 1979; Goodwin
& Webb 1980; Hadden et al. 1970).
The proliferation of human lymphocytes stim-
ulated by phytohaemaglutinin has been reported to
both increase (Hadden et al. 1970, 1971) and de-
crease (Goodwin et al. 1979), if noradrenaline was
262
added to cultures at physiological concentrations.
Interestingly, Hadden et al. (1970) also found that
isoprenaline caused a slight enhancement of the
mitogen response, but if it was added with pro-
pranolol, the response was significantly greater,
suggesting that enhancement of lymphocyte trans-
formation was occurring through the a-receptor
mechanism and inhibition through the {1-receptor
mechanism.
6.2 Glucocorticoids and the Immune System
in Exercise
Adrenocorticotrophic hormone originates in the
anterior pituitary gland and increases with exercise
to stimulate the production of the major adrenal
cortical hormone, cortisol (Bunt 1986). Cortisol
enhances both free fatty acid mobilisation and glu-
coneogenesis as its main biochemical functions.
Serum cortisol levels have been shown to rise dur-
ing exercise but the levels may not peak until after
the exercise has been completed (Bunt 1986; Few
1974; Davies & Few 1973; Dessypris et al. 1976;
Gawel et al. 1979; Kuoppasalmi et al. 1980; Sutton
et al. 1969). It has been suggested that an increase
in the level of cortisol in blood over a period of
time may contribute to some of the physiological
adaptations to training (Galbo 1983).
Corticosteroids have been shown to affect the
immune system (Cupps & Fauci 1982) and are gen-
erally considered to be immunosuppressive. Phy-
tohaemaglutinin-, concanavalin- and pokeweed
mitogen-induced transformation in vitro has been
shown to be depressed by the addition of cortico-
steroids (Gillis et al. 1979; Goodwin et al. 1979;
Gordon & Nouri 1981; Neifield & Tormey 1979;
Nowell 1961; Smith et al. 1977; Webel & Ritts
1977). The mixed lymphocyte reaction has also
been depressed by cortisone (Ilfeld et al. 1977; Katz
& Fauci 1979) but there has been some evidence
that Ig synthesis can be further enhanced, in cul-
tures stimulated by pokeweed mitogen, by the ad-
dition oflow levels of cortisone (Cooper et al. 1979).
In vivo the administration of low doses of cor-
ticosteroids has induced some suppression of im-
mune functions while experimentally abnormal
Exercise and the Immune Response
amounts of cortisol, in particular in the neonate,
has produced sometimes lethal modification to the
immune system (Keast 1968, 1969; Keast and Wal-
ters 1969). Hydrocortisone, dexamethasone and
prednisolone given in vivo have been shown to sig-
nificantly modify the ability of lymphocytes to re-
spond subsequently in vitro to both mitogens and
by Ig production (Fauci 1976; Gillis et al. 1979;
Saxon et al. 1978). While the numbers of circulat-
ing lymphocytes have been shown on occasions to
vary inversely with circadian changes in plasma
cortisol (Tavadia et al. 1975; Thompson et ai. 1980)
their circadian rhythm with respect to phytohae-
maglutinin-induced transformation coincides di-
rectly with changes in plasma cortisol, suggesting
a positive effect of cortisol on lymphocyte function
at physiological levels (Tavadia et al. 1975).
The level of other hormones is also modified as
a result of physical exercise and some of the prop-
erties of insulin with respect to its influence on the
immune system have already been discussed. Al-
dosterone and antidiuretic hormone as well as the
sex hormones may well affect lymphocyte func-
tions through their abilities or otherwise to main-
tain electrolyte balances or the synthesis and ma-
turation of cells within the bone marrow (Bunt
1986). The role of hormonal modification to the
immune system as a result of physical exercise is
an area of research deserving more attention in the
future.
7. Prostaglandins, Exercise and the
Immune System
Although changes in lymphocyte function dur-
ing exercise might be related to hormonal altera-
tions, it is possible that they may be mediated at
the local level. Prostaglandins of the E series, which
can be synthesised by macrophages (Gemsa et al.
1982) have been shown to suppress the lymphocyte
response to T-cell mitogens when added to cultures
in physiological concentrations (Gemsa et al. 1982;
Goodwin et al. 1978; Gordon et al. 1979; Novo-
grodsky et al. 1979). There is also evidence that B
lymphocyte proliferation in Staphylococcus aureus
stimulated cultures is inhibited by PGE 2 (Jelinek
263
et al. 1985; Thompson et al. 1984). Production of
a B-cell proliferation factor was also shown to be
reduced under these culture conditions (Jelinek et
al. 1985). However, there appears to be little re-
search published as yet to indicate whether or not
prostaglandin-mediated changes to immune func-
tion can be modified by physical exercise. The work
of Cameron et al. (1987) suggested, however, that
over a series of exercise protocols, designed to spe-
cifically stress each of the recognised major energy
systems utilised in physical exercise, there was no
effect within the tissue culture systems used that
could be attributable to abnormal variations or
levels of prostaglandin production from the leu-
cocytes under test:
8. Conclusion
The literature for the most part indicates that
exercise protocols with respect to duration and in-
tensity needs to be better controlled in studies de-
signed to explore the role of exercise stress on the
immune system.
Despite limitations in this area research has in-
dicated that physical exercise, possibly in associa-
tion with hormonal changes, can modify the im-
mune system in several ways. Physical exercise
appears to be producing, for the most part, major
fluctuations in both total leucocyte number and the
currently established cellular immunoregulatory
network. However, the difference in acute response
to exercise and the response to chronic exercise and
overtraining needs urgent clarification.
Both specific and polyclonal mitogen responses
of cells of the immune system in vitro, have been
shown to be modified often suggesting that tem-
porary immune suppression may be an outcome of
exercise. The extent to which these changes occur
appear to be related to intensity of exercise, al-
though this is by no means absolute.
Preliminary evidence indicates that variation in
lymphocyte subsets in circulation is also found and
it is tempting to speculate that changes in these
parameters may be indicators of overtraining
(chronic fatigue). If this could be verified, then its
Exercise and the Immune Response
refinement might provide a major contribution to
aid athlete management.
The role of exercise in immunity appears to be
a fertile field for future research.
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Authors' address: Associate Professor Alan R. Morton, Depart-
ment of Human Movement and Recreation Studies, University
of Western Australia, Nedlands, Western Australia 6009 (Aus-
tralia).