[CANCER RESEARCH 41, 3706-371 0, September 1981)0008-5472/81 /0041-0000$02.00

Lipids and Immune Function―

JosephJ. Vitale2andSelwynA. BroitmanBoston University School of Medicine, Mallory Institute of Pathology, Boston, Massachusetts 02118

Abstract

There is in vitro and in vivo evidence to suggest that dietarylipids play a role in modulating immune function. A review ofthe current literature on the interrelationships among dietarylipids, blood cholesterol levels, immunosuppression, andtumorigenesis makes for a very strong argument that (a) immunosuppression may be causally related to lymphoproliferative disorders, as well as to tumorigenesis and (b) diets high inpolyunsaturatedfat,relativetodietshighinsaturatedfat,aremore immunosuppressive and are better promotors of tumorigenesis. The effects of dietary fat on immune function seem tobe mediated through its component parts, the unsaturated fattyacids, specifically linoleic, linolenic, and arachidonic. It is notclear how these components affect immune function. Severalstudies suggest that one effect is mediated by altering the lipidcomponent of the cell membrane and thus its fluidity; the morefluid the membrane, the less responsive it is. Thus, fluidity ofboth immune cells and those to be destroyed or protected maybe affected. The effects of saturated as well as unsaturatedfatty acids may be mediated by modulating serum lipoproteinlevels, prostaglandin metabolism, and cholesterol concentrations and metabolism.

Of the several working groups at this Workshop, one dealswith the relationship between lipids and the immune system.There is in vitro and in vivo evidence to suggest that dietarylipids play some role in regulating or modulating immune ftinction. This offers the promise that by changing dietary lipids onemay be able to modulate immune function and thus alter an

individual's susceptibility or resistance to diseases associatedwith altered immune competency; e.g. , immunosuppressionand lymphoproliferative diseases. It is not yet generally accepted that immunosuppression may be causally related tosolid tumors as well. However, a review of the current literatureon the interrelationshipsamong dietary lipids, blood cholesterollevels, immunosuppression, and tumorigenesis makes for avery strong argument that (a) immunosuppression may also becausally related to tumorigenesis, as well as to lymphoproliferative disorders and (b) diets high in polyunsaturated fat,relative to diets high in saturated fat, are both immunosuppressive and promoters of tumorigenesis. However, since neitherthe nutritionist nor the immunologist is certain as to whatcauses cancer or what cell types in the immune system orwithin the nonimmune host defense system protect the individual from malignancy, this aspect will not be discussed in detail.It is our aim, however, to discuss briefly the subject of lipid

1 Presented at the Workshop on Fat and Cancer, December 1 0 to 1 2, 1979,

Bethesda, Md. Supported in part by grants-in-aid from the National Large BowelCancer Project; Grant CAl 6750 of the National Cancer Institute, NIH; TheAmerican Egg Board, Park Ridge, Ill.; and The General Foods Fund, Inc., WhitePlains, N. Y.

2 To whom requests for reprints should be addressed, at Mallory Institute of

Pathology, 784 Massachusetts Avenue, Boston, Mass. 02118.

effects on immune function and provide a cogent argumentthat altered or depressed immune function may act as a promoter in or is causally related to carcinogenesis. To begin, wemust define the terms ‘‘promoter'‘and ‘‘initiator'‘as they relateto carcinogenesis. Here, the word ‘‘initiator'‘is used to refer toany insult(addition or withdrawal of a substance, be it chemical,viral, nutrient, etc.) which results in neoplasia, irrespective oftime. Nonnutrients or chemicals have been shown to initiatecancer. On the other hand, anything that decreases the time atwhich tumors appear or that increases numbers of tumors orenhances metastases is considered a promoter. There is noevidence that any nutrient, essential or nonessential, fed indeficient or excess amounts has ever initiated cancer, althoughthey have been shown to enhance or promote carcinogenesis(62). The available evidence also indicates that dietary manipulations that promote tumorigenesis are immunosuppressive.All of this would suggest that immunosuppression may well becausally related to neoplasia. For a recent review of this subject, see a publication by Posner et a!. (51) and others (1, 2,4—6,8—11, 62).

It is our opinion that the current data on this subject indicatethat diets high in unsaturated fat have been shown to be goodpromoters of chemical carcinogenesis and are also immunosuppressiverelativetodietshighinsaturatedfat(11,31,32,37, 38). Before discussing available data on lipid effects onimmune function, a review of some basic immunology, althoughbrief, is in order. The immune system is composed of a varietyof cells including T- and B-cells (cellular and humoral immunity), subsets of these cells, lymphokines, serum factors, complement, macrophages, and interactions of these various celltypes. Subsets of T-cells function either as helper, suppressor,or killer cells. Whether the killer cells kill directly, throughinteraction with macrophages, or in concert with macrophageswhich can also kill or lyse cells is not always clear. B-cells, theantibody-producing cells, in some instances require the interaction of T-helper cells or in other cases are inhibited by Tsuppressor cell activity, presumably by suppressing T-helperfunction. Other B-cells are independent of T-ceII influence; thisdepends upon the antigen which determinesT-cell intervention.

In recent years, another cell type has been described whichis capable of lysing hemopoietic and tumor cell lines in vitro.These cells, which are called NK cells,3 are neither T-cells, normacrophages, nor B-cells. These cells have been categorizedas M-cells or marrow-dependent cells and may simply represent one subset of the M-ceIl series. The NK cell seems to beresponsible for the rejection of hemopoietic allografts, geneticresistance against certain oncogenic and nononcogenic viruses, and resistance against certain intracellular bacteria (33).For an excellent review of basic immunology, the reader isreferred to a recent publication by Kumar (33) and a text byRoitt (54).

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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A test commonly used to assess immune function in a numberof research laboratories is the determination of lymphocyteblast transformation. One can measure the response of lymphocytes to certain mitogens. The subsequent synthesis ofDNA can be followed by incubating isolated lymphocytes with

tritiated thymidine. Two mitogens commonly used for assessingT-cell responsiveness are concanavalin A and phytohemagglutinin, whereas lipopolysaccharide is used to assess B-cellresponsiveness. The amount of tritiated thymidine taken upprovides some assessment of the immune system. The T-cellresponding in the in vitro system is predominantly a T-helpercell.

Dietary Fat and Immune Responses

Using similar techniques, a number of laboratories havedemonstrated that diets relatively high in polyunsaturated fatinhibit T- but not B-cell responsiveness to mitogen stimulation(11, 37, 41 —43,45). Optimal blast transformation requires thepresence and cooperation of macrophages for processing andpresentation of antigen to the lymphocyte. Therefore, decreasein lymphocyte blast transformation as a result of some nutritional alteration or insult may not be due to T- or B-cell defectsbut to aberrations within the macrophage.

Several studies have shown that an increased concentrationof cholesterol within the macrophage inhibits its phagocyticprocess (7, 24, 25) and therefore its ability to process and killeffectively or optimally.

Other studies have shown that diets high in polyunsaturatedfat or the administration of PUFA result in the loss of an animal'sability to reject skin allografts (41 , 52, 60). Also, PUFA havebeen used as adjuvants to immunosuppression in renal transplant patients (37, 39, 40, 61) who are at high risk for neoplasia. Whether these effects of PUFA are mediated throughmetabolic or structural aberrations in T-, B-, or M-cells, inmacrophages, or in other cell types (production of complement)is not clear. Thus, the changes in immune function that occurwith changes in dietary fat (unsaturated versus saturated) maybe mediated by changes in serum or cell cholesterol levels.Changes or reductions rather than absolute levels of serum orcell cholesterol may play the major role in modulating not onlyimmune function but the rate, induction, or latency period ofchemically induced carcinogenesis. In almost every animalstudy, diets high in PUFA are better promoters of tumors thanare diets high in saturated fat (11, 15—17). Dietary regimensused to lower serum cholesterol level, such as diets high inunsaturated fat, appear to place the host at greater risk ofcancer, an observation supported by some recent findings inhumans (22, 50).

In addition to other regulating mechanisms, there is evidencethat fatty acids also influence cholesterol synthesis and catabolism and thereby affect total body cholesterol pools. Further,there is general agreement that the lowering of serum cholesterol associated with polyunsaturated fat is attributed to theessential unsaturated fatty acids linoleic, linolenic, and arachidonic acids, the same acids which when fed or ingested havebeen shown to be immunosuppressive(30, 38, 41 , 45, 49), toresult in defects in the rejection of skin allografts (41 , 44, 52,60), and to be useful as adjuvants in the immunosuppressionregimen of renal transplanted patients (37, 39, 40, 61).

The point to be made is that the quantity of unsaturated fatty

acids fed and not serum cholesterol levels per se, althoughthey will be affected by the quality of fat, appear to correlatebest with most of the observed effects on immune function, inthe promotion of carcinogenesis in animal feeding experiments,and in human clinical trials (17, 50, 51). For example, Kos eta!. (32) found no effect of hypercholesterolemia on the response of T- or B-cells to mitogen, no effect on the tumoricidalactivity of peritoneal macrophages, and no effect on the survivalof mice inoculated with cells of a syngeneic methylcholanthrene-induced fibrosarcoma or the Lewis lung carcinoma. Inaddition, Kos et aI. (32) calculated the ratio of the number ofregressions of tumor to the number of mice challenged andfound 0/1 0 and 1/1 0 for the normocholesterolemic and hypercholesterolemic mice, respectively. The study by Kos et a!.(32) was poor in terms of nutritional design since one group ofcontrol mice was fed a commercial chow, which not only variesin 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 experimentalmice that had been made hypercholesterolemic. Nonetheless,Kos eta!. (32) did demonstrate that hypercholesterolemic micewere more susceptible to infectious disease which was associated with a decreased antibody response to sheep erythrocytes in vivo. As in the case of the T-ceII, the B-cell responseto mitogen was not affected by hypercholesterolemia, suggesting that macrophages may have been affected rather thanB-cells per Se. This observation is supported by several otherstudies suggesting that hyperlipidemia adversely affects macrophage function (7, 24, 32). In any case, 2 observationsshould be noted in the study of Kos et a!. and from anothersimilar in design (34, 35): (a) the fat fed was lard, a relativelyhighly saturated animal fat which was not immunosuppressivefor T-cells and macrophages; and (b) hypercholesterolemiaper se was not the major determinant in the immunosuppression seen in studies dealing with lipids and immune function.

In most studies, marked hypercholesterolemia is induced byfeeding diets high in fat with added and varying amounts ofcholesterol and cholic acid, the hypercholesterolemic diet.

When such diets are fed, regardless of the quality of dietaryfat, hypercholesterolemia is produced (11). Rats, in whichserum cholesterol levels are normally in the 90- to 100-mg/100 ml range on most commercial chows, develop serumcholesterol levels of 350 to 500 mg/i 00 ml when fed dietscontaining cholesterol and cholic acid. However, depending onthe quality of fat and as Broitman et a!. (11) demonstrated, Tcell responsiveness to mitogen may be significantly depressedby a factor of 10 or more in hypercholesterolemic rats fedunsaturated fat compared to equally hypercholesterolemic ratsfed saturated fat. Omitting dietary cholesterol and cholic acidfrom the diet decreased the serum cholesterol levels to approximately 100 mg/i 00 ml in groups of rats fed either saturated (20% coconut oil) or unsaturated fat (20% safflower oil),but the marked difference in T-ceII responsiveness was maintamed between the 2 dietary fat-fed groups (11).

There appears to be a consensus among some of our colleagues in immunology that the NK cell is of prime importancein immunosurveillance and neoplasia, although the complexities of the immune surveillance system would suggest thatother cell types may be involved. In any case, there is noevidence that either saturated fat, unsaturated fat, or hypercholesterolemia affect NK cells. In our laboratory, NK cell

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Diet I (PolyunsaturatedFat)

vitro systems reverses the effect of 25-hydroxycholesterol(26)and enhances the response of T-cells to mitogen (29). Theeffects of 25-hydroxycholesterol, unsaturated fatty acids orprostaglandins do not appear to be the result of toxicity to thelymphocyte (45). However, the exact mechanism by whichthese substrates affect T-ceII function is not clear, and severalpossibilities for the observed effects that have been discussed(12, i 4, 20, 21 , 27, 38) are: (a) an alteration in the fluidity ofthe membrane which may alter the configuration of receptorsites on the lymphocyte rendering it less competent or responsive; (b) alterations in cyclic adenosine 3':5'-monophosphateconcentrations or activation affecting antigen-lymphocyte interaction; (c) decreased macrophage function which wouldalso affect antigen-lymphocyte interaction; and (d) decreasedcholesterol synthesis within the cell which appears to be aprerequisite for DNA synthesis and subsequent blastogenesis(i9).

When the fluidity of lymphocyte membranes is decreased inthe presence of cholesterol, enhanced responses of T-cells tomitogen (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 thosehaving a higher ratio (38), ratios which can be affected by thequalityoffatfed.

There appears to be a dichotomy. On the one hand, in invitro studies, the addition of liposomai cholesterolto the mediaenhances T-cell responsiveness and overcomes the depressing 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 mustand does precede DNA synthesis, is required for the generationof new membranes during blastogenesis. However, the additionof cholesterol liposomes would be expected to turn off cholesterol synthesis within the cell, according to feedback mechanisms outlined by Brown and Goldstein (i 3, i 4), and thereforedecrease T-cell responsiveness, which it does not in vitro.Obviously, membrane fluidity alone is not the controlling factorin blastogenesis nor are serum cholesterol levels or cholesterolsynthesisperse. Rather, the gradients between medium, membrane, and intracellular cholesterol content (and synthesis)appear to be important determinants for optimal blastogenesisas suggested by several studies (26, 29, 38, 59). Since thequality of fat influences serum and cellular cholesterol levels,the effects of fatty acid on immune function and on oncogenesismay be mediated through changes in cholesterol metabolismor vis a vis prostoglandins.

Recently, Meade and Mertin (38) published an excellentreview in which they concluded, ‘‘Wehave described theeffects of fatty acids on immune cells in vitro and in vivo, but itis clear we are still largely at the stage of describing phenomenarather than understanding them. We may summarize by sayingthat a wide variety of fatty acids produce effects on both thelymphoid and the reticuloendothelialsystems, the actual effectsproduced depending on the method of administration as wellas the chemical nature of the fatty acid. With regard to fattyacids, diet, and disease, we consider it too early yet to saywhether a role for fatty acids in the biochemistry of immunecells, or effects of fatty acids in vivo, have any relevance tohuman disease.―

We disagree with this conclusion. Most certainly dietary fat,and therefore fatty acids, plays some role in at least 2 major

a

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Diet IV (Saturated Fat& Cholesterol)

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Chart 1. Effect of dietary saturated and unsaturated fat, with and without added cholesterol (1%) and cholic acid (0.3%), NK cell activity. Data arepresented as log percentage of specific release [(lysis in presence of effectorcells —lysis in the absence of effector cells)/(total possible lysis —lysisin the absence of effector cells)) plotted against log of the effector cell/targetcell ratio (e/t).

activity in rats fed diets containing either 20% coconut oil or20% safflower oil, with or without added cholesterol and cholicacid, was the same (Chart 1)•4In addition, similarly treatedanimals do not lose their abilityto reject syngeneic or allogeneicbone marrow transplants,5 a function presently attributed to Mcells or NK cells (33).

There are nutritional manipulations which appear to affect Mcells or NK cells such as iron deficiency which abrogatesresistance to the growth of syngeneic bone marrow transplants(53) and which also suppresses T-ceIl function and promoteschemically induced carcinogenesis (65). Here, we would againremind the reader that every nutritional insult that promotescancer has been shown to suppress some component of cellmediated immunity (62, 63).

Dietary fat, like dietary protein, derives its biological valuefrom its component parts. It seems reasonable and perhapssafe at this juncture to suggest that the effects of dietary fat onimmune function are mediated through its component parts,the unsaturated fatty acids, specifically linoleic, linolenic, andarachidonic. One line of evidence suggests that cholesteroland unsaturated fatty acids exert their effect on immune cellsby 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). Theaddition of substrates which inhibit cholesterol synthesis to invitro systems results in a decreased response of T-Iymphocytesto mitogens (26, 38) and to decreased activity of cytolytic(killer) T-cells (26). Linoleic and arachidonic acids, as well asprostaglandins, inhibit T-celI responses to mitogen as does 25-hydroxycholesterol(7, 38), the latter being a potent inhibitor ofcholesterol 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 given1,2-dimethylhydrazine, manuscript in preparation.

5 P. Rodday and J. J. Vitale, unpublished observations.

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diseases, cancer and atherosclerosis. It may not be clear as tohow fatty acids exert their effects on immune function or towhat extent one can transfer in vitro data to in vivo happenings.One cannot, however, completely ignore the overwhelmingdata, both experimental and epidemiological, that equate (a)dietary unsaturated fats with immunosuppression and promotion of various cancers, (b) increased dietary fat intake with anincreased incidence of colon cancer and perhaps cancer atother sites, and (c) hypercholesterolemia and highly saturatedfat dietswith cardiovasculardisease and atherosclerosis. Somereaders may well ask about the intrusion of cardiovasculardisease in this discussion on lipids and immunology. Severalstudies suggest an immune component in the pathogenesis ofatherosclerosis(3, 27, 28). Alving et a!. (3) have demonstratedthat human complement can be activated in the presence ofhigh concentrations of membrane cholesterol resulting in membrane change. These observations may have important implications clinically as well as in our understanding of the pathogenesis of atherosclerosis.

An association has been made between cardiovascular disease and colon cancer (56). Yet, there is no evidence fromeither experimental animals or from observations in humansthat cardiovascular disease is associated with an increasedrisk of cancer or that the latter is associated with increasedrisk of the former. Both are associated with levels of dietary fat(1 1 ) or perhaps more importantly with the quality and quantityof fatty acids (i 1).

Indeed, all availableexperimentaldata would suggest thatdiets high in saturated fats would favor atherosclerosiswhereasunsaturated fatty acid diets would favor neoplasia (2, i i ) andthat both affect some component(s) of the immune systemwhich in turn probably enhances or promotes the diseaseprocess. If fats or unsaturated fatty acids play a role in oncogenesis and atherosclerosis, perhaps the roles are mediatedthrough changes in or shifts between LDL and HDL. It is nowgenerally accepted that high LDL levels, ratherthan cholesterollevels per se, are associated with an increased risk to atherosclerosis whereas high HDL levels are associated with a decreased risk to cardiovascular disease and that diet, smoking,alcohol, exercise, among other factors, can alter lipoproteinconcentrations (64). What is of interest here is that serumlipoproteins have a regulatory role in immune responses presumably by regulating the expression of specific cell receptors(12, 14, 27, 28). Morse et a!. (46) have demonstrated thatlipoproteins isolated from normal human plasma inhibited theproliferation of lymphocytes stimulated by allogeneic cells orlectins, but to varying degrees. Intermediate LDL was the mostpotent Inhibitor followed by very-low-density lipoprotein, LDL,and HDL. As is known, the binding of normal serum LDL byhuman fibroblast cells and lymphocytes influences the sterolcontent of these cells by modulating the rates of uptake,esterification, and synthesis of cholesterol (23, 27). At thisjuncture, it does not seem unreasonable to believe that lipoproteins play a role not only in the pa@thogenesisof atherosclerosisbut also in at least some forms of cancer (48); that immune orhost defense cells are affected in both diseases and thatcholesterol concentrations per se may be uninformative aboutan individual's risk to c@ancer,atherosclerosis or perhaps toother diseases. After all, cholesterol is an essential componentof every cell, and normally its concentration is regulated tosome degree. Finally, we offer one plausible explanation for

the association between lipids and cancer. If tumor cells ortransformed cells (premalignant) are no longer regulated interms of cholesterol uptake, esterification, and synthesis, ashas been shown (58), then changes in the concentration ofLDL or HDL may enhance either the growth or the transformation of aberrant cells to malignant cells by further deregulating cholesterol metabolism. However, what seems like aâ€â€˜chicken and the egg' ‘situation is not in fact. Since all of the

experimental data suggest that no dietary manipulation in theabsence of a carcinogen initiates cancer, then one can onlyassume that alterations in lipid metabolism influenced by atleast the quality and quantity of dietary fat further perpetuatesthe defect(s) initiated by the carcinogen. Those same factorswhich promote carcinogenesis may in addition suppress thosesystems that normally destroy or keep aberrant cells in check.The tumor cell itself may further perpetuate itself by influencingIipid-cholesterol-regulatingmechanisms of the normal cell. Perhaps it would be trite to state the obvious; more work must bedone. George Mann may indeed be correct in his assessment(36); and possibly a new era is beginning with interest in theinteractions of nutrition-immunology-heart-cancer.

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