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Lipids and Immune Function―
JosephJ. Vitale2and SelwynA. Broitman
Boston University School of Medicine, Mallory Institute of Pathology, Boston, Massachusetts 02118
Abstract
effects on immune function and provide a cogent argument
that altered or depressed immune function may act as a pro
There is in vitro and in vivo evidence to suggest that dietary moter in or is causally related to carcinogenesis. To begin, we
lipids play a role in modulating immune function. A review of must define the terms ‘
‘promoter'
‘
and ‘
‘initiator'
‘
as they relate
the current literature on the interrelationships among dietary to carcinogenesis. Here, the word ‘
‘initiator'
‘
is used to refer to
lipids, blood cholesterol levels, immunosuppression, and any insult(addition or withdrawal of a substance, be it chemical,
tumorigenesis makes for a very strong argument that (a) im
viral, nutrient, etc.) which results in neoplasia, irrespective of
munosuppression may be causally related to lymphoprolifera
time. Nonnutrients or chemicals have been shown to initiate
tive disorders, as well as to tumorigenesis and (b) diets high in cancer. On the other hand, anything that decreases the time at
polyunsaturated
fat,
relative
todietshighinsaturated
fat,
are which tumors appear or that increases numbers of tumors or
more immunosuppressive and are better promotors of tumori
enhances metastases is considered a promoter. There is no
genesis. The effects of dietary fat on immune function seem to evidence that any nutrient, essential or nonessential, fed in
be mediated through its component parts, the unsaturated fatty deficient or excess amounts has ever initiated cancer, although
acids, specifically linoleic, linolenic, and arachidonic. It is not they have been shown to enhance or promote carcinogenesis
clear how these components affect immune function. Several (62). The available evidence also indicates that dietary manip
studies suggest that one effect is mediated by altering the lipid ulations that promote tumorigenesis are immunosuppressive.
component of the cell membrane and thus its fluidity; the more All of this would suggest that immunosuppression may well be
fluid the membrane, the less responsive it is. Thus, fluidity of causally related to neoplasia. For a recent review of this sub
both immune cells and those to be destroyed or protected may ject, see a publication by Posner et a!. (51 ) and others (1 , 2,
be affected. The effects of saturated as well as unsaturated 4—6,8—1
1, 62).
fatty acids may be mediated by modulating serum lipoprotein
It is our opinion that the current data on this subject indicate
levels, prostaglandin metabolism, and cholesterol concentra
that diets high in unsaturated fat have been shown to be good
tions and metabolism.
promoters of chemical carcinogenesis and are also immuno
suppressive
relative
todietshighinsaturated
fat(11,31,32,
Of the several working groups at this Workshop, one deals 37, 38). Before discussing available data on lipid effects on
with the relationship between lipids and the immune system. immune function, a review of some basic immunology, although
There is in vitro and in vivo evidence to suggest that dietary brief, is in order. The immune system is composed of a variety
of cells including T- and B-cells (cellular and humoral immu
lipids play some role in regulating or modulating immune ftinc
tion. This offers the promise that by changing dietary lipids one nity), subsets of these cells, lymphokines, serum factors, com
plement, macrophages, and interactions of these various cell
may be able to modulate
immune function
and thus alter an
individual's susceptibility or resistance to diseases associated types. Subsets of T-cells function either as helper, suppressor,
with altered immune competency; e.g. , immunosuppression or killer cells. Whether the killer cells kill directly, through
interaction with macrophages, or in concert with macrophages
and lymphoproliferative diseases. It is not yet generally ac
which
can also kill or lyse cells is not always clear. B-cells, the
cepted that immunosuppression may be causally related to
solid tumors as well. However, a review of the current literature antibody-producing cells, in some instances require the inter
on the interrelationshipsamong dietary lipids, blood cholesterol action of T-helper cells or in other cases are inhibited by T
levels, immunosuppression, and tumorigenesis makes for a suppressor cell activity, presumably by suppressing T-helper
very strong argument that (a) immunosuppression may also be function. Other B-cells are independent of T-ceII influence; this
depends upon the antigen which determinesT-cell intervention.
causally related to tumorigenesis, as well as to lymphoprolif
In recent years, another cell type has been described which
erative disorders and (b) diets high in polyunsaturated fat,
is
capable of lysing hemopoietic and tumor cell lines in vitro.
relative to diets high in saturated fat, are both immunosuppres
sive and promoters of tumorigenesis. However, since neither These cells, which are called NK cells,3 are neither T-cells, nor
the nutritionist nor the immunologist is certain as to what macrophages, nor B-cells. These cells have been categorized
causes cancer or what cell types in the immune system or as M-cells or marrow-dependent cells and may simply repre
sent one subset of the M-ceIl series. The NK cell seems to be
within the nonimmune host defense system protect the individ
ual from malignancy, this aspect will not be discussed in detail. responsible for the rejection of hemopoietic allografts, genetic
It is our aim, however, to discuss briefly the subject of lipid resistance against certain oncogenic and nononcogenic vi
ruses, and resistance against certain intracellular bacteria (33).
For an excellent review of basic immunology, the reader is
referred to a recent publication by Kumar (33) and a text by
Bethesda, Md. Supported in part by grants-in-aid from the National Large Bowel
Cancer Project; Grant CAl 6750 of the National Cancer Institute, NIH; The
Roitt (54).
1 Presented
at
the
Workshop
on
Fat
and
Cancer,
December
1 0
to
1 2,
1979,
American Egg Board, Park Ridge, Ill.; and The General Foods Fund, Inc., White
Plains, N. Y.
2 To
whom
requests
for
reprints
should
be
addressed,
at
Mallory
Pathology, 784 Massachusetts Avenue, Boston, Mass. 02118.
3706
Institute
of
3 The
abbreviations
used
are:
NK
cells,
natural
killer
cells;
PUFA,
polyunsat
urated fatty acids; LDL, low-density lipoproteins; HDL, high-density proteins.
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Lipids and Immunology
A test commonly used to assess immune function in a number
of research laboratories is the determination of lymphocyte
blast transformation. One can measure the response of lym
phocytes to certain mitogens. The subsequent synthesis of
DNA can be followed
by incubating
isolated
lymphocytes
with
tritiated thymidine. Two mitogens commonly used for assessing
T-cell responsiveness are concanavalin A and phytohemagglu
tinin, whereas lipopolysaccharide is used to assess B-cell
responsiveness. The amount of tritiated thymidine taken up
provides some assessment of the immune system. The T-cell
responding in the in vitro system is predominantly a T-helper
cell.
Dietary Fat and Immune Responses
Using similar techniques, a number of laboratories have
demonstrated that diets relatively high in polyunsaturated fat
inhibit T- but not B-cell responsiveness to mitogen stimulation
(1 1, 37, 41 —43,45). Optimal blast transformation requires the
presence and cooperation of macrophages for processing and
presentation of antigen to the lymphocyte. Therefore, decrease
in lymphocyte blast transformation as a result of some nutri
tional alteration or insult may not be due to T- or B-cell defects
but to aberrations within the macrophage.
Several studies have shown that an increased concentration
of cholesterol within the macrophage inhibits its phagocytic
process (7, 24, 25) and therefore its ability to process and kill
effectively or optimally.
Other studies have shown that diets high in polyunsaturated
fat or the administration of PUFA result in the loss of an animal's
ability to reject skin allografts (41 , 52, 60). Also, PUFA have
been used as adjuvants to immunosuppression in renal trans
plant patients (37, 39, 40, 61) who are at high risk for neopla
sia. Whether these effects of PUFA are mediated through
metabolic or structural aberrations in T-, B-, or M-cells, in
macrophages, or in other cell types (production of complement)
is not clear. Thus, the changes in immune function that occur
with changes in dietary fat (unsaturated versus saturated) may
be mediated by changes in serum or cell cholesterol levels.
Changes or reductions rather than absolute levels of serum or
cell cholesterol may play the major role in modulating not only
immune function but the rate, induction, or latency period of
chemically induced carcinogenesis. In almost every animal
study, diets high in PUFA are better promoters of tumors than
are diets high in saturated fat (1 1, 15—1
7). Dietary regimens
used to lower serum cholesterol level, such as diets high in
unsaturated fat, appear to place the host at greater risk of
cancer, an observation supported by some recent findings in
humans (22, 50).
In addition to other regulating mechanisms, there is evidence
that fatty acids also influence cholesterol synthesis and catab
olism and thereby affect total body cholesterol pools. Further,
there is general agreement that the lowering of serum choles
terol associated with polyunsaturated fat is attributed to the
essential unsaturated fatty acids linoleic, linolenic, and arach
idonic acids, the same acids which when fed or ingested have
been shown to be immunosuppressive(30, 38, 41 , 45, 49), to
result in defects in the rejection of skin allografts (41 , 44, 52,
60), and to be useful as adjuvants in the immunosuppression
regimen of renal transplanted patients (37, 39, 40, 61).
The point to be made is that the quantity of unsaturated fatty
SEPTEMBER
acids fed and not serum cholesterol levels per se, although
they will be affected by the quality of fat, appear to correlate
best with most of the observed effects on immune function, in
the promotion of carcinogenesis in animal feeding experiments,
and in human clinical trials (17, 50, 51). For example, Kos et
a!. (32) found no effect of hypercholesterolemia on the re
sponse of T- or B-cells to mitogen, no effect on the tumoricidal
activity of peritoneal macrophages, and no effect on the survival
of mice inoculated with cells of a syngeneic methylcholan
threne-induced fibrosarcoma or the Lewis lung carcinoma. In
addition, Kos et aI. (32) calculated the ratio of the number of
regressions of tumor to the number of mice challenged and
found 0/1 0 and 1/1 0 for the normocholesterolemic and hy
percholesterolemic mice, respectively. The study by Kos et a!.
(32) was poor in terms of nutritional design since one group of
control mice was fed a commercial chow, which not only varies
in composition from batch to batch but was, unfortunately,
different in the content of fat, cholesterol, cholic acid, protein,
vitamins, etc., from the quasipurified diet fed the experimental
mice that had been made hypercholesterolemic. Nonetheless,
Kos eta!. (32) did demonstrate that hypercholesterolemic mice
were more susceptible to infectious disease which was asso
ciated with a decreased antibody response to sheep erythro
cytes in vivo. As in the case of the T-ceII, the B-cell response
to mitogen was not affected by hypercholesterolemia, sug
gesting that macrophages may have been affected rather than
B-cells per Se. This observation is supported by several other
studies suggesting that hyperlipidemia adversely affects mac
rophage function (7, 24, 32). In any case, 2 observations
should be noted in the study of Kos et a!. and from another
similar in design (34, 35): (a) the fat fed was lard, a relatively
highly saturated animal fat which was not immunosuppressive
for T-cells and macrophages; and (b) hypercholesterolemia
per se was not the major determinant in the immunosuppres
sion seen in studies dealing with lipids and immune function.
In most studies, marked hypercholesterolemia is induced by
feeding diets high in fat with added and varying amounts of
cholesterol and cholic acid, the hypercholesterolemic diet.
When such diets are fed, regardless of the quality of dietary
fat, hypercholesterolemia is produced (1 1). Rats, in which
serum cholesterol levels are normally in the 90- to 100-mg/
100 ml range on most commercial chows, develop serum
cholesterol levels of 350 to 500 mg/i 00 ml when fed diets
containing cholesterol and cholic acid. However, depending on
the quality of fat and as Broitman et a!. (1 1) demonstrated, T
cell responsiveness to mitogen may be significantly depressed
by a factor of 10 or more in hypercholesterolemic rats fed
unsaturated fat compared to equally hypercholesterolemic rats
fed saturated fat. Omitting dietary cholesterol and cholic acid
from the diet decreased the serum cholesterol levels to ap
proximately 100 mg/i 00 ml in groups of rats fed either satu
rated (20% coconut oil) or unsaturated fat (20% safflower oil),
but the marked difference in T-ceII responsiveness was main
tamed between the 2 dietary fat-fed groups (1 1).
There appears to be a consensus among some of our col
leagues in immunology that the NK cell is of prime importance
in immunosurveillance and neoplasia, although the complexi
ties of the immune surveillance system would suggest that
other cell types may be involved. In any case, there is no
evidence that either saturated fat, unsaturated fat, or hyper
cholesterolemia affect NK cells. In our laboratory, NK cell
1981
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3707
J. J. Vitale and S. A. Broitman
a
In
a
a
a
30
20@
1@.../
a
10@
U
5.
2;
‘Diet II (Polyunsaturated
Diet I (Polyunsaturated
Fat)
Fat
& Cholesterol)
:---:----@@
.
30
20@
10•
5
2
Diet IV (Saturated Fat
& Cholesterol)
Diet III (Saturated Fat)
3.1 12.5
50
200
3.1 12.5 50
200
log e/t
Chart 1. Effect of dietary saturated and unsaturated fat, with and with
out added cholesterol (1%) and cholic acid (0.3%), NK cell activity. Data are
presented as log percentage of specific release [(lysis in presence of effector
cells —lysis in the absence of effector cells)/(total possible lysis —lysis
in the absence of effector cells)) plotted against log of the effector cell/target
cell ratio (e/t).
activity in rats fed diets containing either 20% coconut oil or
20% safflower oil, with or without added cholesterol and cholic
acid, was the same (Chart 1)•4
In addition, similarly treated
animals do not lose their abilityto reject syngeneic or allogeneic
bone marrow transplants,5 a function presently attributed to M
cells or NK cells (33).
There are nutritional manipulations which appear to affect M
cells or NK cells such as iron deficiency which abrogates
resistance to the growth of syngeneic bone marrow transplants
(53) and which also suppresses T-ceIl function and promotes
chemically induced carcinogenesis (65). Here, we would again
remind the reader that every nutritional insult that promotes
cancer has been shown to suppress some component of cell
mediated immunity (62, 63).
Dietary fat, like dietary protein, derives its biological value
from its component parts. It seems reasonable and perhaps
safe at this juncture to suggest that the effects of dietary fat on
immune function are mediated through its component parts,
the unsaturated fatty acids, specifically linoleic, linolenic, and
arachidonic. One line of evidence suggests that cholesterol
and unsaturated fatty acids exert their effect on immune cells
by altering the lipid component of the cell membrane (i 8, 20,
38, 47, 56, 57). When lymphocytes are exposed to mitogen,
there are marked alterations in the membrane phospholipid,
fatty acid, and cholesterol composition (27—29,38, 57). The
addition of substrates which inhibit cholesterol synthesis to in
vitro systems results in a decreased response of T-Iymphocytes
to mitogens (26, 38) and to decreased activity of cytolytic
(killer) T-cells (26). Linoleic and arachidonic acids, as well as
prostaglandins, inhibit T-celI responses to mitogen as does 25hydroxycholesterol(7, 38), the latter being a potent inhibitor of
cholesterol synthesis. The addition of cholesterol to these in
4 L.
J.
Kraus,
R.
M.
Williams,
and
S.
A.
Broitman.
Relationship
of
dietary
fat
and cholesterol to T-cell mitogenesis and natural killer cell activity in rats given
1,2-dimethylhydrazine, manuscript in preparation.
5 P. Rodday
3708
and
J. J. Vitale,
unpublished
observations.
vitro systems reverses the effect of 25-hydroxycholesterol(26)
and enhances the response of T-cells to mitogen (29). The
effects of 25-hydroxycholesterol, unsaturated fatty acids or
prostaglandins do not appear to be the result of toxicity to the
lymphocyte (45). However, the exact mechanism by which
these substrates affect T-ceII function is not clear, and several
possibilities for the observed effects that have been discussed
(12, i 4, 20, 21 , 27, 38) are: (a) an alteration in the fluidity of
the membrane which may alter the configuration of receptor
sites on the lymphocyte rendering it less competent or respon
sive; (b) alterations in cyclic adenosine 3':5'-monophosphate
concentrations or activation affecting antigen-lymphocyte in
teraction; (c) decreased macrophage function which would
also affect antigen-lymphocyte interaction; and (d) decreased
cholesterol synthesis within the cell which appears to be a
prerequisite for DNA synthesis and subsequent blastogenesis
(i9).
When the fluidity of lymphocyte membranes is decreased in
the presence of cholesterol, enhanced responses of T-cells to
mitogen (29, 38) and increased cytolytic (killer) T-cell activity
(26) occur. Membranes
having a lower ratio of polyunsaturated
to saturated fatty acids are generally less fluid than those
having a higher ratio (38), ratios which can be affected by the
quality
offatfed.
There appears to be a dichotomy. On the one hand, in in
vitro studies, the addition of liposomai cholesterolto the media
enhances T-cell responsiveness and overcomes the depress
ing effect of 7-ketocholesterol(29) and 25-hydroxycholesterol
(26),
both of which
block
cholesterol
synthesis.
Chen
et a!.
(19) have demonstrated that cholesterol synthesis, which must
and does precede DNA synthesis, is required for the generation
of new membranes during blastogenesis. However, the addition
of cholesterol liposomes would be expected to turn off choles
terol synthesis within the cell, according to feedback mecha
nisms outlined by Brown and Goldstein (i 3, i 4), and therefore
decrease T-cell responsiveness, which it does not in vitro.
Obviously, membrane fluidity alone is not the controlling factor
in blastogenesis nor are serum cholesterol levels or cholesterol
synthesisperse. Rather, the gradients between medium, mem
brane, and intracellular cholesterol content (and synthesis)
appear to be important determinants for optimal blastogenesis
as suggested by several studies (26, 29, 38, 59). Since the
quality of fat influences serum and cellular cholesterol levels,
the effects of fatty acid on immune function and on oncogenesis
may be mediated through changes in cholesterol metabolism
or vis a vis prostoglandins.
Recently, Meade and Mertin (38) published an excellent
review in which they concluded, ‘
‘We
have described the
effects of fatty acids on immune cells in vitro and in vivo, but it
is clear we are still largely at the stage of describing phenomena
rather than understanding them. We may summarize by saying
that a wide variety of fatty acids produce effects on both the
lymphoid and the reticuloendothelialsystems, the actual effects
produced depending on the method of administration as well
as the chemical nature of the fatty acid. With regard to fatty
acids, diet, and disease, we consider it too early yet to say
whether a role for fatty acids in the biochemistry of immune
cells, or effects of fatty acids in vivo, have any relevance to
human disease.―
We disagree with this conclusion. Most certainly dietary fat,
and therefore fatty acids, plays some role in at least 2 major
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Lipids and Immunology
diseases, cancer and atherosclerosis. It may not be clear as to
how fatty acids exert their effects on immune function or to
what extent one can transfer in vitro data to in vivo happenings.
One cannot, however, completely ignore the overwhelming
data, both experimental and epidemiological, that equate (a)
dietary unsaturated fats with immunosuppression and promo
tion of various cancers, (b) increased dietary fat intake with an
increased incidence of colon cancer and perhaps cancer at
other sites, and (c) hypercholesterolemia and highly saturated
fat dietswith cardiovasculardisease and atherosclerosis. Some
readers may well ask about the intrusion of cardiovascular
disease in this discussion on lipids and immunology. Several
studies suggest an immune component in the pathogenesis of
atherosclerosis(3, 27, 28). Alving et a!. (3) have demonstrated
that human complement can be activated in the presence of
high concentrations of membrane cholesterol resulting in mem
brane change. These observations may have important impli
cations clinically as well as in our understanding of the patho
genesis of atherosclerosis.
An association has been made between cardiovascular dis
ease and colon cancer (56). Yet, there is no evidence from
either experimental animals or from observations in humans
that cardiovascular disease is associated with an increased
risk of cancer or that the latter is associated with increased
risk of the former. Both are associated with levels of dietary fat
(1 1 ) or perhaps
more importantly
with the quality and quantity
of fatty acids (i 1).
Indeed, all availableexperimentaldata would suggest that
diets high in saturated fats would favor atherosclerosiswhereas
unsaturated fatty acid diets would favor neoplasia (2, i i ) and
that both affect some component(s) of the immune system
which in turn probably enhances or promotes the disease
process. If fats or unsaturated fatty acids play a role in onco
genesis and atherosclerosis, perhaps the roles are mediated
through changes in or shifts between LDL and HDL. It is now
generally accepted that high LDL levels, ratherthan cholesterol
levels per se, are associated with an increased risk to athero
sclerosis whereas high HDL levels are associated with a de
creased risk to cardiovascular disease and that diet, smoking,
alcohol, exercise, among other factors, can alter lipoprotein
concentrations (64). What is of interest here is that serum
lipoproteins have a regulatory role in immune responses pre
sumably by regulating the expression of specific cell receptors
(12, 14, 27, 28). Morse et a!. (46) have demonstrated that
lipoproteins isolated from normal human plasma inhibited the
proliferation of lymphocytes stimulated by allogeneic cells or
lectins, but to varying degrees. Intermediate LDL was the most
potent Inhibitor followed by very-low-density lipoprotein, LDL,
and HDL. As is known, the binding of normal serum LDL by
human fibroblast cells and lymphocytes influences the sterol
content of these cells by modulating the rates of uptake,
esterification, and synthesis of cholesterol (23, 27). At this
juncture, it does not seem unreasonable to believe that lipopro
teins play a role not only in the pa@thogenesis
of atherosclerosis
but also in at least some forms of cancer (48); that immune or
host defense cells are affected in both diseases and that
cholesterol concentrations per se may be uninformative about
an individual's risk to c@ancer,atherosclerosis or perhaps to
other diseases. After all, cholesterol is an essential component
of every cell, and normally its concentration is regulated to
some degree. Finally, we offer one plausible explanation for
SEPTEMBER
the association between lipids and cancer. If tumor cells
transformed cells (premalignant) are no longer regulated
terms of cholesterol uptake, esterification, and synthesis,
has been shown (58), then changes in the concentration
LDL or HDL may enhance
either
the growth
or
in
as
of
or the transfor
mation of aberrant cells to malignant cells by further deregu
lating cholesterol metabolism. However, what seems like a
‘
‘chicken
and
the
egg'
‘situation
is
not
in
fact.
Since
all
of
the
experimental data suggest that no dietary manipulation in the
absence of a carcinogen initiates cancer, then one can only
assume that alterations in lipid metabolism influenced by at
least the quality and quantity of dietary fat further perpetuates
the defect(s) initiated by the carcinogen. Those same factors
which promote carcinogenesis may in addition suppress those
systems that normally destroy or keep aberrant cells in check.
The tumor cell itself may further perpetuate itself by influencing
Iipid-cholesterol-regulatingmechanisms of the normal cell. Per
haps it would be trite to state the obvious; more work must be
done. George Mann may indeed be correct in his assessment
(36); and possibly a new era is beginning with interest in the
interactions of nutrition-immunology-heart-cancer.
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Academic Press, Inc., 1968.
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CANCERRESEARCHVOL. 41
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Lipids and Immune Function
Joseph J. Vitale and Selwyn A. Broitman
Cancer Res 1981;41:3706-3710.
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