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Acute exercise effects on the immune system

ROWBOTTOM, DAVID G.; GREEN, KATHERINE J.

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Medicine & Science in Sports & Exercise: July 2000 - Volume 32 - Issue 7 - p S396-S405
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Abstract

It is well recognized that exercise causes perturbations to the immune system. Over the past 20 years, the effects of exercise on the circulating numbers and the function of many immune system components have been well described and regularly reviewed (38,56,57,67,87). The aim of this article is not simply to review again this material but to appraise the methodology employed to date and critically evaluate the available data as to whether genuine or artefactual alterations in immune function are being reported. This has widespread implications for the way in which we view acute exercise, and its potential role in affecting individuals’ susceptibility to infection.

There is an increasing awareness in the health professions, as well as the general community, of the benefits of physical activity and exercise for improving and maintaining health. Although epidemiological evidence has suggested that intensive exercise, training and competition in athletes may increase susceptibility to infection (4,23,63,74), this may not be the case with more moderate exercise. When exercise has been prescribed within the American College of Sports Medicine (ACSM) guidelines, reduced rates of infectious episodes in physically active groups by comparison to their sedentary counterparts have been reported (35,60). Almost paradoxically though, observations of apparent decreases in immune cell function after acute exercise are widespread in the literature. The question remains as to whether these observed changes have clinical significance and are able to increase, even for a short period of time, the individual’s susceptibility to infection. These are not simply questions of academic interest but have a very real impact on our reluctance or otherwise to prescribe exercise to those in already immunocompromised states. The “open-window” hypothesis (67) remains popular as an explanation of the effects of exercise on the immune system, but to what extent does acute exercise really leave the window open, or even for that matter ajar?

Circulating Numbers of Immune Cells

Any attempt to summarize the “exercise effect” on immune function is clouded by the variety of experimental protocols employed. All manner of permutations and combinations of exercise intensity, duration, and mode have been reported, using subjects with a wide variety of fitness levels and training histories. In general though, during and immediately after exercise, the total number of white blood cells (leukocytes) in circulation increases. This leukocytosis is roughly in proportion to the intensity and duration of the exercise performed (46) and may be greater in higher ambient temperatures (80). During the postexercise period, there is a characteristic decline in numbers of circulating lymphocytes and monocytes to below resting levels (12,52,66), whereas circulating numbers of neutrophils continue to increase, peaking several hours postexercise (10,46). This phenomenon is widely reported in the literature and has become known as the biphasic response (Fig. 1). There have been observations that suggest the lymphocytopenia characteristic in the period after exercise may begin to become evident even before a particularly prolonged bout of vigorous exercise has been completed (87). Although short-duration or moderate-intensity exercise may only cause perturbations to circulating cell numbers for around 60 min after exercise, homeostasis may not be restored for several hours after particularly long-duration or high-intensity exercise (11,13,20,47). In addition to the many endurance exercise studies, resistance training has been reported to elicit changes of a similar nature and magnitude during and after exercise (49,62,92,93).

Figure 1
Figure 1:
The pattern of change in peripheral blood leukocyte, lymphocyte, and neutrophil counts during and after 45 min of high-intensity (80%JOURNAL/mespex/04.02/00005768-200007001-00004/ENTITY_OV0312/v/2017-07-20T222740Z/r/image-pngO2max) exercise. Data from Nieman et al. (64).

The precise mechanisms responsible for this leukocytosis during and after exercise have not been fully elucidated. Leukocytes are thought to be “flushed” out of marginal pools in regions such as the lungs and spleen, although splenectomy appears to have no effect in reducing leukocyte mobilization during exercise (1). There is substantial evidence to implicate both catecholamines and cortisol as mediators of this process. Studies have used infusion of either epinephrine (32,97) or norepinephrine (31) to replicate catecholamine concentrations observed during exercise. This series of studies was able to partially mimic the exercise-induced changes in leukocyte concentration, including the rapid decline in lymphocyte numbers and the persistent elevation of neutrophils 2 h after infusion (31). Rehman et al. (77) attributed exercise-induced leukocytosis to catecholamine-mediated shedding of adhesion molecules (ICAM-1) from the surface of lymphocytes. Conversely, β- adrenergic antagonists were able to attenuate both leukocytosis and ICAM-1 shedding after exercise (77). A number of studies have observed a correlation between elevated cortisol concentrations during exercise and a parallel elevation in leukocyte number (12,59). Cortisol may also exert a delayed effect during the recovery period after exercise (46).

Increases in circulating cellular components of the immune system are not all of the same magnitude during and immediately after an exercise challenge. It has been suggested that some cell types are more susceptible to hormonal influences than others. Natural killer (NK) cells increase in number to a greater extent than T- and B-lymphocytes, although T-suppressor cells increase to a greater extent than T-helper cells (12,26). As a result of these differential responses, the relative proportions of cell types within the lymphocyte pool are altered (11,12,14). A typical pattern of cellular redistribution within the lymphocyte pool during and immediately after exercise is a decrease in the proportion of T-helper cells, with a corresponding increase in the proportion of NK cells (11,26,59,61,66). The proportions of B-lymphocytes and T-suppressor cells may be less affected (Fig. 2). Notably, the ratio of T-helper:T-suppressor cells, which is thought to have clinical importance (28), is reduced by as much as 50% (9,22,88).

Figure 2
Figure 2:
The pattern of changes in the proportions of lymphocyte subsets within the total lymphocyte pool during and after 45 min of high-intensity (80%JOURNAL/mespex/04.02/00005768-200007001-00004/ENTITY_OV0312/v/2017-07-20T222740Z/r/image-pngO2max) exercise. Data from Nieman et al. (64).

A number of important areas of discussion arise from the shifts in the number of circulating cells during and immediately after exercise. First, recent reviews have acknowledged that changes in blood volume during exercise may partially explain the observed changes (46,87). Consequently, some investigators have corrected cell numbers for blood volume shifts after acute exercise (61,88), whereas others have not, on the basis that these had little bearing on the increase in cell numbers (10,18). Kargotich et al. (33) reported that blood volume shifts were maximally a 4% decrease, or hemoconcentration, during exercise and a 3% increase, or hemodilution, in the hour after high-intensity (95% O2max) interval training in swimmers. When cell numbers were corrected for these blood volume shifts, the authors were only able to account for 8% of the immediate postexercise lymphocytosis and 4% of the lymphocytopenia during recovery. Although it may be prudent to correct for blood volume shifts, the changes in cell numbers are relatively large by comparison, suggesting that genuine cell movements into and out of the peripheral circulation are taking place (33).

Second, because the blood compartment is the only one freely accessible in human investigation, our understanding is considerably limited in this regard (89). Much has been made of the clinical significance of changes in circulating cell numbers. It is not clear, though, whether an increase in circulating cell numbers is a positive response in terms of increased availability of cells to become involved in immune reactions, or a negative response if these cells have been drawn from sites where they were already involved in immune reactions. Most immune reactions occur at sites of infection or inflammation; therefore, changes in circulating immune cell numbers may not be a true reflection of changes in other immune tissues (100).

Finally, an analysis of the number of circulating cells only tells half the story, because the function of those cells is an equally important consideration. Unfortunately, we need to consider the impact of the increased number of circulating cells, as well as the changes in cellular proportions on the functional assays that are commonly employed in the literature. There are a number of issues that potentially confound these analyses and affect the conclusions we reach. The immune cells in circulation at rest are being complemented during exercise with other cells flushed from marginal pools. We therefore need to be careful in drawing wholesale conclusions about changes in immune cell function.

A decrease or increase in the function of the cellular pool during exercise has usually been interpreted as an effect of exercise on the function of all the cells in circulation. It needs to be considered that the cells being flushed into circulation may have different characteristics to those normally in circulation at rest. Studies that have reported an increase in the number and density of adhesion markers (2,15,37) or activation markers (10,30,33) during exercise, may simply be a reflection of a higher expression of these receptors on cells normally in the marginal pools. Likewise, if the function of demarginalized cells is significantly lower or higher than circulating cells, by virtue of their relative immaturity or activation status, the addition of these cells to the circulating pool will have the effect of “diluting” or “magnifying” the function of the circulating cells. This may give the artefactual impression of a reduced or increased function of the immune system. It is possible that the function of individual cells is unaffected by exercise and that many of the observed changes in function in many different cell types are merely a reflection of an exercise-induced change in the pool of cells being sampled in the blood compartment. Our current methodological practices do not allow us to distinguish between previously circulating cells and those flushed into circulation by exercise, and so all data should be treated with some caution in this regard.

Function of Circulating Immune Cells

T-lymphocytes.

T-lymphocytes are largely responsible for coordinating the response of many components of cell-mediated immunity via their activity and their release of soluble factors such as cytokines. T-lymphocytes proliferate in vivo in response to specific antigens, and it is this consistent, reproducible cellular behavior that has been the basis of assessing in vitro T-lymphocyte function. Proliferation can be induced in vitro by polyclonal mitogens such as phytohemagglutinin (PHA) and concanavalin-A (Con-A), although more specific mitogens have been recently evaluated (44).

There is a general consensus among authors that T-lymphocyte proliferative responses are reduced during and after exercise. Although the magnitude and duration of the effect may differ, this observation is consistently reported during and after exercise of both high and moderate intensity as well as long and short duration. A number of studies have reported a significant (30–60%) reduction in T-lymphocyte proliferation immediately after repeated (15–25) maximal (120% O2max) or near-maximal (90–95% O2max) 60-s sprints (9,10,26). Others have reported a similar effect after prolonged running at 75–80% O2max for 45 min (64) and up to 150 min (68). Moderate-intensity (50–60% O2max) cycling (79,88) and walking (54,64) of 45- to 60-min duration has been reported to reduce T-lymphocyte function by 30–50%. In summary, exercise of the intensity (50–85% O2max) recommended by the American College of Sports Medicine (ACSM) has been shown to elicit temporary decreases in T-lymphocyte function. Questions remain though, as to the interpretation of these observations.

The main argument for caution in the interpretation of these observations stems from the exercise-induced alterations in the proportions of lymphocyte subsets. T-lymphocyte proliferation assays use a constant number of cells, both pre- and post-exercise. The large increase in the proportion of NK cells within the total lymphocyte pool, and the corresponding decline in the proportion of T-lymphocytes, results in fewer cells capable of responding to mitogenic stimulation in assays completed postexercise (26). It is therefore not surprising that lower proliferative responses have consistently been observed during and after exercise. In addition, the relative proportions of T-helper and T-suppressor cells are known to be altered by exercise (12,26), and recent studies suggest that the two cell types may be differentially sensitive to mitogen, particularly PHA (Green et al., unpublished observations).

A number of authors have noted a parallelism between T-lymphocyte proliferation and the proportion of T-lymphocytes in the total lymphocyte pool (26,88). Frisina et al. (9) reported that proliferation responses immediately after exercise were also negatively correlated with the increased proportion of NK cells. An approach to accommodate this confounding factor has been to express the observed T-lymphocyte proliferation responses on a per T-cell basis. When expressed in this manner, moderate intensity exercise (50–60% O2max), high-intensity exercise of a short duration, and resistance training to fatigue do not affect T-lymphocyte function (62,64,65). On the other hand, high-intensity exercise (75–80% O2max) of a longer duration (45–150 min) still results in a reduced mitogen response (10–21%), even when results are expressed on a per T-cell basis, although the magnitude of the effect is substantially reduced (51,64).

A simple mathematical correction may not be sufficient to ameliorate the changes in the complex interactions of cell types that inevitably occur with a change in lymphocyte proportions during exercise. Two other approaches have been attempted to date. Tvede et al. (98) used a flow cytometric sorting of cells after 3 d of culture with PHA and reported mitogen responses per 1000 T-helper cells. Using this technique, they reported that 60 min of cycle ergometer exercise (75% O2max) did not affect T-lymphocyte proliferative responses. Hinton et al. (26) used a magnetic separation technique (50) to isolate T-lymphocytes by positive selection before assessment of functional status. Although a mitogen proliferation assay conducted on the total lymphocyte pool produced an expected reduction in response immediately after 15, 1-min running intervals at 95% O2max, the function of the isolated T-lymphocytes was not affected (Fig. 3). Techniques are now available to separate “untouched” T-lymphocytes by positive depletion and the application of these methodologies to longer duration bouts of exercise remain to be evaluated. The main criticism of this type of methodology has been the disruption of the lymphocyte pool that is caused, and the removal of any synergistic activities of the cell types that may occur in the proliferation response.

Figure 3
Figure 3:
T-lymphocyte proliferation responses during and after intense interval training, using a total lymphocyte preparation (•) and a sample of purified T-lymphocytes (○). From Hinton et al. (26) with permission.

Recently developed flow cytometric analysis of the early expression of activation markers on T-lymphocytes has been proposed as an alternative approach to traditional proliferation assays (5,45). The application of this technique to study the effects of exercise has the advantage of allowing the expression of these markers to be assessed on individual T-helper and T-suppressor cells. In this way, the lymphocyte pool can be undisturbed, while still allowing the activation on a per cell basis to be directly evaluated. Our preliminary results (Green et al., unpublished observations) and those of others (84) suggest that even long-duration (60 min), high-intensity (75–80% O2max) exercise is unable to alter the responsiveness of T-helper and T-suppressor cells to mitogen. Taken together, these data indicate that at least some of the reported decreases in T-lymphocyte function after exercise are an artefact of the reported changes in lymphocyte proportions. Recent advances in methodology are beginning to call into question the assumption that exercise causes a decrease in the function of T-lymphocytes.

B-lymphocytes and immunoglobulin.

The effects of acute exercise on the function of B-lymphocytes have attracted much less attention than T-lymphocytes but may be equally important. There is, however, a partial interdependence of T- and B-lymphocyte function, with the latter being partially coordinated by an interaction with T-helper cells. The B-lymphocyte response is a combination of cellular proliferation and differentiation as well as the production of immunoglobulin (Ig) capable of binding to specific antigens. Consequently, the function of B-lymphocytes has been investigated using a number of different approaches.

Mitogen-stimulated proliferation, using pokeweed mitogen (PWM), has been used to assess both the proliferative response, and also the in vitro synthesis of Ig by B-lymphocytes during and after acute exercise. Mackinnon et al. (39) observed no change in the in vitro IgA and IgG production immediately after 120 min of high-intensity (70–80% O2max) exercise in trained cyclist. Other studies have reported a decrease in the in vitro IgA, IgG, and IgM production after short duration (15 min) moderate-intensity exercise (24) and 120 min of high-intensity (80% O2max) exercise (96). Although the proportion of B-lymphocytes in cell culture may not be overtly affected by exercise (12,26), their response to PWM is dependent on their interaction with T-helper cells, the proportion of which is known to be altered considerably as previously discussed. Consequently, whether the observed changes can be attributed to changes in T-helper number, T-helper function, B-lymphocyte proliferation, or Ig synthesis is difficult to state with any certainty. It is possible that the reduced function of B-lymphocytes assessed in this way may be subject to similar artefactual influences as T-lymphocyte proliferation. Conversely, it has been observed that in vitro Ig synthesis may still be suppressed 2 h after exercise at a time when the proportion of T-helper cells has been restored (96). The authors suggested that these results indicated a potential role for activated monocytes in down-regulating B-lymphocyte function through the production of prostaglandins.

The production of Ig by B-lymphocytes in vivo has been assessed by measuring the circulating concentrations of specific Ig both before and after exercise. It has been suggested that Ig has an important role in host defense, and therefore low levels may be indicative of an increased risk of infection. However, there is very little evidence of serum Ig changes during or after exercise. A number of authors have failed to find a change in the serum concentrations of IgA, IgE, IgG, or IgM, even after high-intensity exercise (70–80% O2max) of 20- to 120-min duration (6,21,39). Even in those studies where changes have been observed, they are predominantly increases of a moderate magnitude (<20%) and have been variously attributed to plasma volume changes, diurnal variation and an influx of Ig from extravascular pools during exercise (55,69).

Immunoglobulin is not solely synthesised by circulating B-lymphocytes but also, and importantly, by plasma cells within the mucosal lymphoid tissue. Mucosal IgA secretion in saliva is regarded by many as a first line of defense against many pathogens. A variety of studies in athletes have observed a decrease in salivary IgA after high-intensity exercise (70–80% O2max) for 120 min or more (39,95) and after intense interval training (41). However, studies that have investigated exercise of the intensity (50–80% O2max) and duration (20–45 min) recommended by ACSM have invariably reported no significant change in salivary IgA (27,42,48). It has been suggested that correcting IgA concentration for total protein concentration would account for the exercise effects on altered salivary flow rates (42).

Natural killer cells.

Natural killer (NK) cells are recognized as a first line of defense against many tumor and virus-infected cells, as they have the ability to initiate cytotoxic killing without prior sensitization. The most common assay for NK cell cytotoxic function has been incubation with a target cell-line, with the degree of cytotoxic killing measured by the release of radio-labeled chromium from the target cells as they are lysed (8).

The effects of acute exercise on NK cell function measured in this manner are fairly consistent. During, or immediately after, exercise, an intensity-dependent increase in NK cell function has been widely reported. Moderate-intensity (50% O2max) running for 45 min has been reported to increase NK cytotoxic killing by 50% (65), whereas higher-intensity (70–80% O2max) running and cycling may result in up to 100% increases in NK cell function (65,72,73,86,97). During the recovery period after exercise, a 10–60% suppression in NK cell function has been observed that may last for a number of hours (40,65,72,73,86). In general, this suppression in function for a period of time after acute exercise is only reported after longer-duration (60–180 min) exercise.

At face value, these data appear to indicate an augmented NK cell function during exercise of the nature recommended by ACSM. Once again, a cautious approach to their interpretation is warranted when the nature of the current methodology is examined. The NK cell assay system traditionally uses a fixed number of lymphocytes, in the same way as the T-lymphocyte proliferation assay, and is therefore exposed to the same methodological concerns. It has already been observed that acute exercise causes a significant increase in the number of circulating NK cells (11,26,59,61,66) by as much as 400%. Furthermore, since circulating NK cell numbers increase to a greater extent than other lymphocyte subsets, the proportion of NK cells within the total lymphocyte pool also increases from around 15% to as much as 30% (32,53,65,71). As a consequence, there will be more NK cells available in the assay system for cytotoxic killing after exercise, and the observed changes may, at least in part, be an artefact of this redistribution of lymphocyte subsets.

By expressing NK cell function on a per NK cell basis, a number of authors have attempted to delineate the effects of changes in cell numbers and changes in individual cell function. When this simple mathematical correction is applied, NK cell function has been reported to remain unchanged after both 45 min of running at 50% O2max (65) and 150 min of running at 75% O2max (58). On the other hand, 120 min of cycling (40) and 45 min of running (65) at 80% O2max have both been reported to increase NK cytotoxicity per NK cell in the period after exercise (Fig. 4). Expression of NK cell activity per NK cell has raised a further concern with regard to the quantification of NK cells in a number of studies (87). Current international agreement defines an NK cell as CD3CD16+CD56+ (25), whereas many early studies used only a single surface marker (CD16+ or CD56+) to identify NK cells. In some cases, this technical inability to determine all three markers simultaneously may have lead to an overestimation of NK cell numbers, although the differences may be slight (87).

Figure 4
Figure 4:
Natural killer cell activity (NKCA) during and after 45 min of high-intensity (80%JOURNAL/mespex/04.02/00005768-200007001-00004/ENTITY_OV0312/v/2017-07-20T222740Z/r/image-pngO2max) exercise expressed as both the total NKCA (•) and the NKCA per NK cell (○). Data from Nieman et al. (65).

Technology now exists for the effective separation of lymphocyte subsets using monoclonal antibodies and either magnetic separation methods or flow cytometric techniques (50). It is perhaps surprising that the published literature does not contain any reports of purified NK cell fractions being used to examine the effects of exercise on NK cell function. However, taken together, the available data would suggest that changes observed in NK cell function even after prolonged, intense exercise are more a reflection of changes in circulating cell numbers than any dramatic changes in the cytotoxic function of individual cells.

A final consideration has to be made with regard to acute exercise and NK cell function. Almost without exception, investigations to date have used the chromium release assay for assessing NK cell cytotoxicity. Although this measure of the secretory pathway of lysis is an important component of NK cell activity, it is by no means the only pathway of NK cell-mediated killing of target cells (8). Indeed clinical studies suggest that the secretory pathway may not be the predominant killing mechanism used by NK cells in vivo, with many tumor target cells being eliminated by NK cells using nonsecretory mechanisms of killing (99). Future evaluations of the effects of exercise on NK cell function will need to include a broader array of in vitro assays than has previously been used.

Neutrophils.

Neutrophils represent about 60% of the circulating leukocyte pool, and form part of the innate immune response. They migrate to sites of infection where they bind, ingest and kill pathogens (phagocytosis) by a combination of oxidative and nonoxidative means. Although the number of neutrophils in circulation increases after exercise in proportion to both intensity and duration (10,12,46), it has been the effects of exercise on their function that has attracted recent interest. Neutrophils can be isolated from the total leukocyte pool by gradient centrifugation, often producing a sample of 95–98% purity for investigation (19). A range of assays has been employed to assess the different components of neutrophil function.

The phagocytic function of neutrophils has been investigated by the ability of cells to ingest fluorescently labeled latex beads. Immediately after both moderate-intensity (50–70% O2max) exercise (3) and maximal exercise (19), phagocytic activity of neutrophils has been reported to be increased and may remain elevated for up to 24 h (19). Once ingested, neutrophils may kill pathogens by the release of intracellular granules containing proteolytic enzymes or by a “respiratory burst” of reactive oxygen species (ROS). The effects of acute exercise on each of these nonoxidative and oxidative methods of killing have been investigated.

The release of intracellular granules, or degranulation, is associated with an increased concentration of proteolytic enzymes (e.g., elastase) in plasma, as well as an increased expression of surface antigens (CD11b and CD16) on neutrophils. A number of studies have reported that acute exercise produces an increase in plasma elastase concentration following long duration (60–150 min) moderate-intensity (50–60% O2max) exercise (81,90) and high-intensity exercise (80–100% O2max) to exhaustion (17,81). Gray et al. (17) also reported an increased expression of CD11b and CD16 on circulating neutrophils 6 h and 24 h after maximal exercise.

The effect of acute exercise on in vitro stimulated respiratory burst of neutrophils is less conclusive. A decreased production of ROS has been reported immediately after moderate intensity (50–60% O2max) exercise of both short (40 min) and long (150 min) duration (76,81), and immediately after high-intensity exercise (80–100% O2max) to exhaustion (19,81). This has been termed a “postexercise refractory period” and suggested to represent a time during which neutrophils are potentially less responsive to microbial challenge (75). Conversely, 60–90 min of moderate-intensity exercise (50–70% O2max) has been reported elsewhere to significantly increase ROS production (90,94).

Although these data are somewhat inconclusive, a number of comments need to be made with regard to their interpretation. First, it is open to question whether the activation status of circulating cells are being altered or neutrophils with a different activation status are being added to the circulating pool. Arguments for both points of view have been put forward. A lack of association between ROS production and cellular redistribution after exercise favors the former (17,91), although a significant relationship between increased ROS production and the addition of newly matured neutrophils to circulation favors the latter (94). Second, many authors have highlighted the role that neutrophils play in responding to structural damage in skeletal muscle induced by acute exercise. If this is the major promoter of postexercise changes in neutrophil activation, to what extent can we draw conclusions from these data about the ability of neutrophils to phagocytose bacterial agents after acute exercise? Finally, it is perhaps unfortunate that very few of these studies have investigated shorter-duration, moderate-intensity exercise of the nature recommended by ACSM. In the main, they have established the effects of longer-duration or higher-intensity exercise on neutrophil function.

Other contributory factors.

In the past, many assays to assess the function of the immune system have been conducted on cells isolated from whole blood. This approach can only establish the function of those cells in a standardized in vitro environment. Acute exercise is known to alter the in vivo circulating environment of these cells, with a number of hormonal and other potentially immunomodulatory factors being affected. Many in vitro assays have not, and in some cases still do not, account for these indirect effects on the immune system, and therefore preclude a holistic understanding of the effects of exercise on the immune system in vivo.

Glutamine has attracted increasing attention in the field of exercise immunology, by virtue of its role as a fuel source for the immune system. A number of in vitro studies have reported that a decreased availability of glutamine to the cells of the immune system compromised their function (70,82). Acute exercise studies have observed significant reductions in plasma glutamine concentration after high-intensity (95% O2max) interval training (34,36) and long-duration, moderate-intensity exercise (78). These effects may last for a number of hours after exercise (Fig. 5). Irrespective of the in vitro function of immune cells, there is the potential for these in vivo effects to exert an immunosuppressive effect on the immune system.

Figure 5
Figure 5:
Changes in plasma concentrations of glutamine during and after intense interval training in swimmers. Data from Kargotich et al. (34).

The extent to which postexercise depressions of plasma glutamine have clinical importance for immune function is still open to question (43,83). Rohde et al. (83) have reported that there was no association between plasma glutamine changes and lymphocyte proliferation changes during and after a total of 135 min of exercise completed in three bouts. Although the authors were able to maintain plasma glutamine concentrations during one exercise trial by oral supplementation, in comparison with a placebo condition, the decrease and recovery of lymphocyte proliferation was not different between the two trials. Unfortunately, the authors did not report any attempt to replicate the in vivo glutamine concentrations in the in vitro assays but instead completed the proliferation assays without glutamine. Hence, lymphocytes were apparently separated from their in vivo environment by density centrifugation, and their function was evaluated in a standardized in vitro environment, without consideration for variances in the in vivo glutamine concentration from which they had been removed. Until these not inconsiderable methodological difficulties have been resolved, the extent to which glutamine changes after exercise exert an immunosuppressive effect in vivo remains inconclusive.

It is widely reported in the literature that serum concentrations of cortisol increase during and after acute exercise (64,85), particularly after high-intensity (>70% O2max) exercise. Although cortisol is thought to have a role in the redistribution of circulating cells, as previously discussed, cortisol is also regarded as a potent modulator of immune cell function (7,16,29). Importantly, the adverse effects of cortisol on the immune system have been shown to be a function of biologically available “free” cortisol, and not total cortisol concentration, which is predominantly bound to corticosteroid binding globulin (7,16). Free cortisol concentration may rise disproportionately to previously reported elevations in total cortisol, even reaching 10-fold increases after maximal exercise (85). This powerful immunosuppressive effect is not considered when isolated immune cells are assayed in vitro. The advent of whole blood assays of immune function may effectively account for these and other changes in blood constituents, and are an important advance in methodology. Their limitation may be in their inability to delineate the effects of a number of contributing factors.

Conclusions

There have been many reports of altered immune function after acute exercise, both increased or decreased, depending on the particular immune cell under investigation. Recent careful scrutiny of methods used has highlighted that many functional assays were producing predominantly artefactual changes, brought about by cellular redistribution. In the main, there is little evidence to suggest that the range of exercise intensities and durations recommended by ACSM has a detrimental effect on the function of individual T- and B-lymphocytes, NK cells, and neutrophils. In light of this knowledge, it may be warranted to recommend appropriate exercise interventions to many populations, even those in immunocompromised states, without fear of causing short-term detrimental effects on immune function.

However, many questions remain unanswered, particularly with regard to the process of “flushing out” of previously marginalized cells, and whether this is a positive or negative response. The same is also true of the depletion of circulating cells in the postexercise period. Although individual cells may not be as adversely affected as previously supposed, it is uncertain whether the numerical content of the circulating population is an important consideration. It is also presently unclear whether these brief changes are of sufficient duration to have major clinical implications. It may be prudent to regard the blood compartment only as our region of accessibility but to be cautious, perhaps even agnostic, about the clinical value of these observations.

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Keywords:

LYMPHOCYTE PROLIFERATION; LEUCOCYTOSIS; NATURAL KILLER CELL ACTIVITY; IMMUNOSUPPRESSION; NEUTROPHILS

© 2000 Lippincott Williams & Wilkins, Inc.