IMMU’tiOLOGY TODAY

hysical exercise has always

been prescribed as a panacea

for illness. Its positive effects

are a result of a complex inter-

action of physiological and psychological

effects, including stress relief, improved

cardiopulmonary function and dietary

changes. However, it is becoming clear that

the immune system responds to increased

physical activity and can be given some of

the credit for exercise-related reduction in

illness and mortality.

As early as 1902, the Boston marathon was

used as an experiment in violent (eccentric)

exercise to demonstrate post-exercise leuko-

cytosis’ and. in more recent years, it has

been shown that elite athletes may become

immune suppressed through overtraining’.

On the other hand, regular recreational ex-

ercise is generally understood to be ben-

eficial to health, whereas total inactivity is

detrimental. So, how much exercise is good

for you and how much is too much? Further-

more, if moderate exercise does boost basal

immune parameters, can it help in situations

of extreme immune requirement, for example

in cancer or following infection with human

immunodeficiency virus (HIV)?

Exercise and immune homeostasis In normal individuals, the numbers and

activity of immune cells increase during a

period of acute exercise, after which they de-

crease to a level below normal for a period of

up to six hours. This is true for lymphocytes,

natural killer (NK) cells and lymphokine-

activated killer (LAK) cells, but not for neu-

trophils, which undergo a sustained neutro-

cytosis (reviewed in Ref. 3). This period of

relative immunosuppression following ex-

ercise has led to the ‘open-window’ theory

of post-exercise susceptibility to infection

(Fig. la; B.K. Pedersen, Copenhagen). One

explanation for the ‘overtraining effect’ seen

in elite athletes is that the window of oppor-

tunity for pathogens is longer, and the degree

of immunosuppression more pronounced,

following extreme acute or prolonged cxcr-

cise. Certainly, incidence of upper respira-

tory tract infection (URTI) in this group is

greater than in individuals who undergo

regular, moderate exercise (L.T. MacKinnon,

Brisbane; E.M. Peters-Futre, Johannesburg).

Setting a current paradigm, D.C. Nicman

(Boone, NC) proposed a ‘J-shaped’ relation-

ship between regular exercise and immunity

to URTI or other infections. Regular, mod-

erate activity is associated with enhanced

resistance, whereas inactivity or extreme

exercise is linked to decreased resistance

(Fig. lb).

Neutrophils: a last line of defence?

One of the more pronounced features of

physical activity on immune parameters is

the prolonged neutrocytosis following acute

exercise. Since neutrophils comprise nearly

60% of circulating white blood cells and are

an important component of innate immune

responses, what are the implications for

neutrophil function? Overall, human neutro-

phi1 activity as measured by chemilumi-

nescence can be increased by as much as

100% in highly conditioned individuals

(J.A. Smith, Belconnen, Australia; E. Ortega,

Bajadoz, Spain). However, during periods

of exercise, a general pattern is observed in

trained and untrained subjects. Although

not all studies concur, the general view is

that moderate exercise boosts neutrophil

functions, including chcmotaxis, phago-

cytosis and the oxidative burst. During ex-

treme exercise, the picture is quite different:

these functions are chronically suppressed,

with the exception of chemotaxis, which is

not affected.

It is attractive to speculate that, during

the period of immunosuppression of other

immmie components, neutrophils are being

mobilized to compensate for the resulting

deficiencies. The removal of this back-up

system following extreme activity would bc

compatible with the propensity of over-

trained individuals to develop URTI.

Exercise, senescence and immune function The incidence of cancer and respiratory

pathogens both show age-related increases.

Is this a function of immune impairment

and is it avoidable? Nieman studied the

basic mitogenic responses of phytohemag-

glutinin (PHA)-stimulated T cells (these rc-

sponscs are decreased in the aged) in 12

elderly women (average age 73 years) who

were in regular training for long-distance

running events. These ‘elite’ elderly subjects

showed, on average, a T-cell PHA response

that was enhanced by more than 600, as

well as a 64% increase in NK-cell activity

compared with sedentary controls. Sur-

prisingly, however, a 12-week training pro-

gramme of 30 previously sedentary women

resulted in no significant increase in T-cell

or NK-cell function, dcspitc an impressive

13% increase in cardiorespiratory capacity.

A separate analysis in aged men (average

age : $3 years) showed tk?!. in general, they

I-& it .wer circulating numbers ot CD3 and CD8 + r cells compared with younger (average

age 2-1.6 years) men (S. Shinkai, Ehime,

Jnpa~~) T-cell mitogenesis ill Icjponse to

PHA or pokeweed mitogcn (PWM), and in

mixed lymphocyte responses (MLRs), were

also significantly reduced, as was the pro-

duction of interleukin 2 (IL-2). However,

closer analysis suggested that CD45RO

‘memory’ cells and activated CD3’ cells

were elevated as a relative proportion of the

The 2nd Symposium of the International Society of Exercise and Immunology: ‘Practical Applications’ was held at Brussels, Belgium, on 17-18 November 1995.

Moderate Severe exercise exercise

‘Open window/;, /

Time

Above

average

i= 5 5 Average Y 2 eL:

Below average

sedentary Moderate Very high ( Amount and intensity of exercise

I

overall T-cell number. Furthermore, NK-cell

activity and production of IL-lp, interferon y

(IFN-y) or IL-4 were not impaired.

A cohort of 17 elderly men, all of whom

had regularly engaged in running for one

hour each day over the past 17.5 years, was

used as an ‘exercise-conditioned’ experimen-

tal group. However, although PWM and

PHA responses, as well as IL-2 production,

were enhanced in the conditioned group

relative to elderly sedentary subjects, all other

parameters were unchanged. These results

contrast slightly with the elite women

studied by Nieman and suggest that, al-

though age-related decline in some aspects

of immune function can be retarded, the

greatest effects will be seen only in very

highly conditioned subjects.

K cells and the role of

macrophages

Despite anecdotal and epidemiological data

correlating increased physical activity with

lower prevalence and mortality rates for

various site-specific cancers, evidence re-

garding exercise effects on tumour immun-

ity is still preliminary. Treadmill exercise of

C3H/He mice increased NK-cell cytotoxic

activity in these animals, relative to seden-

tary controls, and also caused a decrease in

lung retention of the CIRAS-1 tumour cell

line (L. Hoffman-Goetz, Waterloo). However,

in animals treated with anti-asialo GM, anti-

bodies, which should deplete NK cells, the

latter effect was still observed in response to

exercise. This finding was supported in a

rat model, in which clearance of YAC-1

lymphoma cells from the lungs was only

partially inhibited by anti-asialo GM, treat-

ment (1.H. Jonsdottir, Gothenberg). Further-

more, although C3H/He mice with the

‘beige’ mutation, which causes NK-cell de-

ficiency, retained more CIRAS-1 cells than

their normal counterparts following exer-

cise, they had less tumour load than seden-

tary controls. Clearly, this suggests that NK

cells are responsible for only some of the

antitumour activity.

What mediates the remainder of exercise-

induced tumour-cell resistance? J.M. Davis

(Columbia) argued that macrophages have

a role to play. Three-day acute exercise of

C3H/HeN mice, before inoculation with

mammary adenocarcinoma cells, resulted in

an increase in the number and tumoricidal

activity of peritoneal macrophages compared

with those of sedentary animals. However,

the tumour load in the lungs did not differ

between the two groups. A decrease in

lung tumour foci of a different tumour line

(B16/BL6 melanoma cells) could be seen,

but only when animals were exercised to

exhaustion. Furthermore, an increase was

observed in the irl zrifro cytotoxic activity of

alveolar macrophages from these animals,

suggesting, at least circumstantially, a role

for macrophages in antitumour activity.

Overall, it should be stressed that the

protective effects of exercise may be mani-

fest only at early stages of tumour growth

or metastasis. Localization and growth of

more-aggressive tumour cell lines, Such as

CIRAS-3 or the MMT 66 mammary tumour

cell, was not affected by exercise (Hoffman-

Goetz).

xercise e

Aside from the psychological eftccts of physi-

cal activity, can HIV- individuals benefit

from increased immune function if they

exercise? In a study of eight asymptomatic

HIV- subjects, H. Lllum (Copenhagen)

showed that, although neutrophil and NK-

cell numbers were noi impaired and did in-

crease during acute exercise (cycle ride for

one hour at 75% of VC$max; wrhere VO,max

is a measure of aerobic ability that is used in

the assessment of phvsical fitlless), these cells

did not mobilize as well as in age- and

sex-matched HIV controls. Furthermore,

although NK cells in bcropositive and sero-

negative subjects sholvcd increased levels of

unstimulated and cytoE Ine-induced cytotoxic

activity during acute t -tercise, this increase c

was less pronounced in rhe HIV- subjects.

In a larger study, HIV- subjects at vari-

ous stages of disease undertook a 12-week

training programme, comprising 45 min

exercise per day at 7U-80% predicted maxi-

mum heart rate, three times per week

(A. Laperriere, Miami, FL). The number of

CD4+ T cells in the exercised group in-

creased relative to sedentary controls, as is

the case for uninfected subjects. However, it

is clear that exercise did not appear to stabi-

lize or rel’crse CD4- T-cell counts (which can

be used as a marker of disease) as disease

progresses. Thus, any beneficial immune

effects of exercise in HIV- subjects are likely

to occur early after infection byhen CD-I

counts are not greatly compromised. At later

stages, a small, relative increase in an alread!

diminished pool of CD4 _ T cells mav not be

of great value.

UNE 1996

liiMUN&tiGY TODAY

Overall, HIV* individuals show both im-

paired natural and acquired immunity.

Even though a proportional boost in im-

munity occurs during and after exercise,

any long-term significance of this finding is

a topic of considerable debate. An analysis

of the combined psychological, physical

and immune effects of exercise during HIV

disease is needed to characterize this issue

further.

Concluding remarks Recent work has clearly shown that various

types of exercise may have potentially consid-

erable effects, both positive and negative, on

immune parameters. In order to profit from

the beneficial effects of moderate physical ac-

tivity and to avoid the detrimental effects of

intense exercise, it is important to undersiand

the complex underlying mechanisms. These

certainly involve neuroendocrinological fac-

tors, which are known to have marked effects

on immune cells, and possibly the metabolic

products of muscle exertion.

Studies in the human system have dem-

onstrated that the classical methods of ex-

ercise physiology, in which muscle stress

and cardiorespiratory work-rate act ab a de-

tailed measure of physical capacity, can be

used in the laboratory to generate highly

significant data concerning the interface be-

tween physical activity and immune homeo-

stasis. Furthermore, animal models are now

being developed to provide highly reductive

ifr ivirlo data in support of these fundamental

studies. The critical question is not whether

exercise can influence immune parameters,

but whether these changes can be impressive

clinically.

Rob& Brines is Editor of Immunology Today;

Laurie Hoffman-Goetz (Guetzl.~dcyce~ll.nci.

r7ilz.goz~) is nt the Division of Cnmev Preuentioiz

mrd Cm&o/, Nntionnl Cnrlcer hstifute, Nntioml

Zmtihtes of Health, Bethesda, MD 2089, USA,

otrd nt tk Dept of Hmltk Studies, Llrhcrsify uf

Waterloo, Wnterloo, Chtnrio, Cmndn N2L 3G1;

Bente Klarhd Pedersen is nt fl7e Dcpt of

Illfectiolls Diseases M7722, Riphospitnlet, 20

Tngtwszwj, 2200 Copeulmqerl N, Dcrwwk.

References

1 Larrabee, R.C. (1902) 1. Md. Rm. 7. 76-82 2 Fitzgerald, L. (1988) It~r~r~trr~~~l. %llo!/ 9. 337-339 3 Hoffman-Go&, L. and Pedersen, B.K. (19Y44)

I~ummI. Todq 15, 352-387

urray,

ecrosis is readily de-

tectable in many experi-

mental as well as human

tumors. This is due mainly

to the inability of the vascular supply to

keep up with the nutritional demands of

the rapidly growing tumor (I? Vaupel,

Mainz), as demonstrated by the appearance

of necrosis beyond the diffusion limit of

oxygen. This phenomenon has been ex-

ploited by the development of novel thera-

peutic strategies to treat tumors - collec-

tively known a5 ‘vascular targeting’.

Vascular targeting comprises strategies that

either destroy the pre-existing vasculature

of the tumor or prevent the formation of

new blood vessels, through angiogenesis,

together with the subsequent inhibition

of further tumor growth. In principle,

depriving the tumor parenchyma of nutri-

ents and oxygen will lead to rapid ischemic

necrosis; however, it has become clear that

complete tumor regression is not achieved

50 readily.

The induction of tumor necrosis J. Moore (Manchester) discussed the mecha-

nism of action of photodynamic therapy.

The use of drugs that can be photoactivated

in combination with laser light has shown

great promise in the treatment of canine

prostate cancer, and this therapy is now en-

tering clinical trials. This treatment induces

a rapid hemorrhagic necrosis and its major

target appears to be the endothelium.

However, the effects are more reversible

than tumor necrosis factor (TNF)-induced

necrosis, probably because of the lack of an

immune response.

Many vasoactive chemicals transiently

reduce blood flow in experimental tumors,

without altering the growth of the tumor

(J.C. Murray, Nottingham). Exceptions to

this are flavone-g-acetic acid and 5,6-

dimethylxanthenone acetic acid, which in-

duce a major decrease in blood flow in

experimental tumors, and rapid tumor re-

gression. This activity appears to be retated

to the ability of these agents to induce the

transcription of TNF and interferon y (IFN-y)

in host immune cells. Many conventional

chemotherapeutic agents also induce cyto-

kine production by host cells; in some cases,

this may be due to apoptosis of tumor cells.

Therefore, the initial damaging effect of

*The symposium ‘Tumor Necrosis: Factors and Principles’ was held at Ringberg, Germany, on 29 October-l November 1995.