Symposium: History of Nutritional

Dietary and Immune Function1 PATRICIA A. MAKI AND PAUL M. NEWBERNE*2

University of Pennsyluania School of Medicine, Diuision of Oncology Research, Philadelphia, PA and *Boston university School of Medicine, Department of Pathology, Boston, MA 02118

general, animals fed higher levels of polyunsaturated ABSTRACT The influence of dietary lipids on immune fatty acids have reduced immunocompetence. function has come under serious study only within the past two decades. It is clear from whole-animal studies that obesity and consumption of diets high in fat, par ticularly unsaturated fat, depress immunocompetence and enhance risk for serious infectious disease and INFLUENCE OF OBESITY ON . In vitro systems, cell cultures and the tools of IMMUNE RESPONSE Downloaded from molecular biology are moving and immunology closer together with promise of significant benefits. J. Nutr. 122: 610-614, 1992. Overnutrition and obesity can adversely affect the response to . Both quantity and quality of di INDEXING KEY WORDS: etary fat are important determinants of immunologie

competence (6, 7). High-fat diets consistently depress jn.nutrition.org •nutrition •immunology •lipids unsaturated host resistance to tuberculosis and malaria in rats and fats •cholesterol to pneumococcal in chickens (8). We dem onstrated that obese dogs have a decreased capacity to

resist Salmonella infection and canine distempter vi by guest on February 9, 2012 rus (4). The obese beagles had shortened average sur The nutritional status of an individual can have an vival time after distemper infection and the incidence appreciable effect on response to infectious disease and of paralytic encephalitis was significantly increased other aspects of homeostasis under control of the im (Table 1) (9). mune system. The relationship of lipids to the immune In longitudinal studies the incidence of lower re response is complex, multifactorial and poorly under spiratory tract infections was significantly higher in stood. Selected aspects of these interactions will be obese infants than in nonobese infants (10). Adverse presented here. effects on the or decreased ventilatory Manipulation of quality and quantity of fats to capacity due to obesity were suggested as possible evaluate immunocompetence has been under serious mechanisms. More recently, Chandra (6)reported that scrutiny for little more than a decade. The most com about one-third of groups of obese children, adoles prehensive monograph by Scrimshaw et al. (1) did not cents and adults exhibited variable impairment of cell- even list lipids as nutrients reported to influence re mediated immune responses in vivo and in vitro as sponse to infectious agents. Lipids are particularly im well as a reduction of intracellular bacterial killing by portant in providing tissue concentrations of poly- polymorphonuclear leukocytes. Chandra and his unsaturated fats, including linoleic acid, which cannot group have also used genetically obese mice for studies be synthesized in the body and which is required by lymphocytes for optimal function. Recommendations ' Presented as part of a symposium: History of Nutritional Im munology, given at the 75th Annual Meeting of the Federation of to reduce the level of saturated fats and increase the American Societies for Experimental Biology, Atlanta, GA, April level of unsaturated fats in the diet, as is now wide 23,1991. The symposium was sponsored by the American Institute spread in the literature, may have important effects of Nutrition and the American Association of Immunologists, and on the immune system and its response to carcinogen- was coordinated by Patricia B. Swan (Iowa State University). Guest induced tumors (2), experimental allergic encephalo- editor for this symposium was W. R. Beisel, Department of Im munology and Infectious Diseases, The Johns Hopkins University, myelitis (3), a number of infectious by microbial or Baltimore, MD. ganisms (4) and the immune response to both thymic- 2To whom correspondence should be addressed: Boston Uni dependent and thymic-independent antigens (5, 6). In versity School of Medicine, Dept. of Pathology, Boston, MA 02118.

0022-3166/92 $3.00 ©1992American Institute of Nutrition. 610 SYMPOSIUM: HISTORY OF NUTRITIONAL IMMUNOLOGY 611

TABLE 1 Effects of overnutritioa in dogs to resistance to infection with distemper virus1

Average body wt Incidence of encephalitis Average Treatment Initial At infection1 survival3 No. Percent

Controlenergy)Low diet (313 kj energy)Highdiet (209.2 kj diet (418.4 kj energy)9.29.39.69.28.113.01014811/155/1620/23743187 1Adapted from Newberne (9). 1 Fed respective diets for 6 wk before infection. 3 Time to onset of paralytic encephalitis. Downloaded from on immune function. Obese mice in general do not pared with that of mice fed lower concentrations. Rel perform as well in terms of immunocompetence as atively severe challenging infections masked the di nonobese mice, but these results are often variable and etary effects of fat in avian tuberculosis. However, may relate in part to the numerous documented nu with less severe infections low dietary fat prolonged tritional, metabolic and endocrine alterations observed the median survival time of chickens and led to re jn.nutrition.org in these inbred animals (6). duced numbers of tubercles per tissue section of the spleen (12). Monkeys fed diets rich in polyunsaturated fatty acids developed severe diarrhea; examination of the feces revealed high concentrations of Endomoeba

EFFECTS OF QUALITY AND QUANTITY OF by guest on February 9, 2012 DIETARY FAT ON THE IMMUNE SYSTEM histolytica (1). Fiser et al. (13) observed that feeding dogs diets high Based on literature reports, before the 1970s there in fat considerably increased the severity of infectious was very little interest in the influence of dietary fat viral canine hepatitis, similar to our findings with dis on immunocompetence. In the early 1960s there were temper virus (9). This was associated with decreased a few significant papers, and selected data from some capacity of the white blood cell series to perform nor of them are included. For example, effects of dietary mally. Monkeys were also affected by hypercholester- fat on mice injected with viable and nonviable tuber olemia. culosis vaccines (11) and chickens with avian tubercle In studies examining effects of quality of dietary bacilli have been investigated (12). The addition of fat on induced liver cancer and immune function, we fatty acid mixtures to equal 5% of a synthetic diet (14, 15) found that corn oil increases the incidence regularly increased the survival time of mice as com and frequency of liver tumors compared with beef fat

TABLEZ Dietary fat, liver tumors and lymphocyte stimulation after exposure to aftatoxin «,'

Dietary fat content Rats with liver tumors

Beef fat Corn oil Aflatoxin B! No. Percent Phytohemagglutinin stimulation index2

280280230230+ 32/60+ ±4218.4 60/600/300/30531000074.5 ±1281. 6±5321.4 + 16 1Adapted from Newberne et al. (14, 15). 2 Stimulation index = ratio between mean cpm stimulated cultures divided by mean cpm unstimulated. 612 MAKI AND NEWBERNE

(Table 2). Further, corn oil markedly decreased re ficient diet displayed a significant depression of re sponse of lymphocytes to phytohemaglutin A (PHA), sponse to EFA (0.5%). In this case the diet was deficient a plant-derived mitogen that stimulates cells to syn in linoleic acid, contained in oil extracted from plant thesize DNA and undergo cell divisions. sources (21). As the level of fat in the diet increased, We have published data on the effects of quality or the blastogenic response to alloantigen approached the quantity of dietary fat on the immune system with levels observed with lymphocytes from EFA-deficient some interesting results (16). Weanling male Sprague- animals (23). Marshall and Johnston (24) and Cathcart Dawley rats (Charles River Breeding Laboratories, et al. (25), among others, in general found that unsat- Wilmington, MA) were randomly assigned to dietary urated fats depress T cell function. In recent years groups and fed one of four purified diets containing considerable interest in the physiological effect on ¡n mixed fat at a 5% level (control diet) or a specific fat - 3) versus (n - 6) fatty acids has developed and con at a 24% level, to include saturated (beef tallow), poly- flicting results have been reported with no clear and unsaturated (Mazólacorn oil, Corn Products Inter consistent effect on (n - 3) fatty acids, (25, 26). national, Englewood Cliffs, NJ) or partially saturated An influence of dietary fat on T cell function has (Crisco, Proctor &. Gamble, Cincinnati, OH) fat at also been reported. Several groups reported effects of 24%. The rats were maintained on the various dietary content and saturation of dietary fat on the delayed- regimens either 2.5 or 5 mo. After 2.5 mo of dietary type hypersensitivity (DTH) response. DeWille and treatment, high-fat groups exhibited splenic hyperpla- coworkers (27) reported that increasing the corn-oil sia; there were no consistent morphologic changes seen content of mouse diets resulted in an increase in DTH Downloaded from in the mesenteric lymph nodes, however. Splenocytes response (Table 3). In contrast, Thomas and Erickson from rats fed the 24% polyunsaturated fat diet were (28) observed a decrease in DTH response when the cultured in fetal bovine serum. They exhibited a de level of dietary fat was increased from 0.5 to 20%. pressed lymphocyte transformation response which

persisted after 5 mo of dietary treatment. Mesenteric jn.nutrition.org node lymphocytes from rats fed the 24% partially sat urated diet for 2.5 mo had an enhanced response to TABLES concanavalin A; at 5 mo the response was elevated in Dietary fat influence on DTH response1

the groups fed saturated as well as partially saturated by guest on February 9, 2012 fat diets. Thus the modulating effect of fat on the im DTH index**3 mune system depended on the duration of feeding, and the type of fat consumed and the lymphatic organ ex DietEFA Erickson31.46±0.06'1.88 etal.11.73 amined. (0%)0.5%deficient cornoil8% oil)8%PUFA (safflower ±0.091.84 FATS, FATTY ACIDS AND oil)13%SFA (coconut ±0.041.73 ±0.132.51 cornoil20% +0.071.50 LYMPHOCYTES SUBSETS PUFA20% SFA50% ±0.10*1.51 Plasma lipoproteins, comprised of a variety of sub corn oilThomas ±0.20t2. sets differing in both structure and biological activity, ±0.05*DeWille serve in transport and bioregulatory functions. Eding- 33 ±0.13t ton and Curtiss (17) and Harmony and Hui (18) de scribed these phenomena more than a decade ago and 1Compiled from Thomas and Erickson (28) and DeWille et al. concluded that dietary content influenced con (27). PUFA = polyunsaturated fatty acids, SFA = saturated fatty acids. centration and composition of plasma lipoproteins. 1 DTH response to dinitrofluorobenzene (DNFB). Mice were Saturable surface receptors for specific inhibitory low sensitized by spreading 50 pL of a 2% solution of DNFB on shaved density lipoproteins were identified on lymphocytes areas of back. Five days later, 10 pL of a 1% DNFB solution was and it was shown that different types of lipoproteins applied to the right ear. Ten hours after the second administration have different receptors. Cholesterol and its oxidation of DNFB, mice were injected with 74 kBq of '"I-iododeoxyuridine. products have also been shown to suppress immuno- Twenty-six hours after the second administration of DNFB mice were killed and both ears were removed and counted in a gamma competence (19, 20). counter. DTH index calculated from the cpm (test ear) - cpm (back- The observation of Erickson and coworkers (21- ground)/cpm (control ear) - cpm (background). 23) that high levels of dietary fat, in particular poly 3 DTH response to B16 melanoma cells injected intradermally unsaturated fat, suppressed the response of lympho into the left ear of allogeneic BALB/c mice previously maintained cytes to T cell mitogens stimulated interest in exam on experimental diets and treated with cyclophosphamide. DTH index calculated from the ear swelling of the experimental/control ining the effect of fat content and saturation on other subject. aspects of immune function. Lymphocytes from ani * Significantly different from 0.5% corn oil. mals maintained on an essential fatty acid (EFA)-de- t Significantly different from 0% corn oil. SYMPOSIUM: HISTORY OF NUTRITIONAL IMMUNOLOGY 613

This effect was observed whether the source of dietary fat was safflower oil or coconut oil. TABLE 4 The immune system is thought to play a key role Lymphoproliferation in MRL-lpr mice? in defense against tumor formation; dietary influences node cells cells on immune function may also serve to regulate this (XlCT7)90 (X10-7)81 process and the influence of dietary fat content on car- GenderMaleFemaleDietSafflower cinogenesis has been well established (2, 29, 30). A oilMenhaden ±859 ±947 decrease in tumor latency and a decreased ability of oilNonpurified ±12*75 ±10*69 spleen and peritoneal exúdatecells from mice fed high dietSafflower ±1690 ±971 oilMenhaden +2426 ±945 fat diets to lyse B16 melanoma cells in vitro has been oilNonpurified ±6*44 ±14*50 reported. dietLymph ± 6Spleen ± 5 1Adapted from Kelley et al. (31). n = 10/group. Numbers are lymphocytic cells (x ±SD)X 10~7/group. 2Menhaden oil values differed significantly from those of the EFFECT OF DIETARY FAT ON MODELS OF other diets: P < 0.05 (Mann-Whitney U test). SYSTEMIC LÜPISERYTHROMATOSIS (SLE)

In recent years there has been increasing interest in tools of molecular biology are helping to bring Downloaded from therapeutic manipulation of dietary fatty acids for the the fields of nutrition and immunology closer treatment of diseases with an autoimmune compo together. nent. By far the most studied is SLE, perhaps because of the existence of convenient rodent models of this disease. Massive lymphoproliferation is characteristic of the LITERATURE CITED jn.nutrition.org progression of the SLEdisease in MRL-1pr mice. Lym- 1. Scrimshaw, N. S., Taylor, C. E. & Gordon, J. E. (1968) Inter phoadenopathy of the spleen and lymph nodes was actions of Nutrition and Infection, Monograph No. 57, World prevalent in mice treated with nonpurified diet or saf- Health Organization, Geneva, Switzerland. flower-oil diets but was greatly reduced in mice fed 2. Nauss, K. M., Locniskar, M. & Newberne, P. M. (1983) Effect by guest on February 9, 2012 fish-oil diets (31) (Table 4). Moreover, the onset of of alterations in the quality and quantity of dietary fat on 1,2- serum DNA antinuclear antibodies was delayed from dimethylhydrazine-induced colon tumorigenesis in rats. Cancer 4 to 8 mo in animals fed EFA-deficient diets (32). Res. 43: 4083-4090. 3. Alexander, J. W., Saito, H., Ogle, C. K. & Trocki, O. (1986) The In reviewing the data over the past 25 y or more importance of lipid type in the diet after burn injury. Ann. Surg. years, it is clear that the weight of evidence points to 204: 1-8. a profound influence of dietary fat on the properties 4. Newberne, P. M. & Williams, G. (1970) Nutritional influences of the subsets of immune cell populations and the ca on the course of infection. In: Resistance to Infectious Disease. Dunlop, R. H., and Moon, H. W., (eds.) Saskatoon Press, V. pacity of these cells to respond to challenges. Immune Saskatchewan, Canada. responses can be enhanced or depressed by dietary lip- 5. Newberne, P.M. &Thurman,G. B. (1981) Working group IV. ids, depending upon both the concentration and extent Lipids and the immune system. Report and recommendations. of unsaturation of fatty acids. Lipoproteins with reg Cancer Res. 41: 3803-3804. 6. Chandra, R. K. (1981) Immune response in overnutrition. ulatory roles, delayed hypersensitivity, autoimmune Cancer Res. 41: 3795-3796. diseases, cancer and other types of disease all appear 7. Meade, C. J. & Merlin, J. (1976) The Mechanism of immu- to respond to alterations in dietary fat but in different noinhibition by arachidonic and linoleic acid. Int. Arch. ways and to different degrees. Dietary fat clearly plays Appi. Immunol. 51: 2-24. a role of considerable importance in recognizing self 8. Beisel, W. R. & Fiser, R. H. (1970) Lipid metabolism during and nonself tissues. infectious illness. Am. J. Clin. Nutr. 23: 1069-1079. 9. Newberne, P. M. (1966) Overnutrition and resistance of dogs Overnutrition and obesity are not in our favor with to distemper virus. Fed. Proc. 25: 1701-1712. respect to immunocompetence. Obesity and in fact 10. Hutchinson-Smith, B. (1970) The relationship between the high fat diets, depress host resistance to infectious weight of an infant and lower respiratory infections. Med. Off. disease and apparently influence susceptibility to some 123: 257-262. 11. Hedgecock, L.W. (1958) The effect of diet on the inducement forms of cancer. of acquired resistance by viable and non-viable vaccines in ex We are now in a position to learn more about the perimental tuberculosis. Am. Rev. Tuberc. Pulm. Dis. 77: 93- role of lipids in regulating the immune system. The 98. trend to examine effects of blends of fats instead of 12. Solotorovsky, M., Squibb, R. L. & Wogan, G. N. (1961) The one fat only is to be encouraged because it is realistic effect of dietary fat and vitamin A on avian TB. Am. Rev. Respir. and conforms more to the human situation. In vitro Dis. 84: 226-232. 13. Fiser,R. H., Denniston, J.C., McGann, V. G., Kaplan,J.,Alder, tests and models are important and useful but must W. H., Kastello, M. D. & Beisel, W. R. (1973) Altered immune be equated with whole-animal or human evalua function in hypercholesterdemic monkeys. Infect. Immun. 8: tions if they are to be of significant use. The new 105-109. 614 MAKI AND NEWBERNE

14. Newberne, P. M., Weigert, J. &.Kula, N. (1979) Effects of di 25. Cathcart, E. S., Leslie, C. A., Meydani, S. N. & Hayes, K. C. etary fat on hepatic mixed function oxidases and liver cancer in (1987) A fish oil diet retards experimental amyloidosis, mod rats. Cancer Res. 39: 3986-3991. ulates lymphocyte function and decreases macrophage arachi- 15. Newberne, P. M. (1981) Dietary fat immunological response donate metabolism in mice. J. Immunol. 139: 1850-1854. and cancer in rats. Cancer Res. 41: 3783-3785. 26. Kelley, D. S., Nelson, G. J., Serrato, C. M., Schmidt, P. C. & 1Õ.Locisker, M., Nauss, K. M. & Newberne, P. M. (1983) The Branch, L. B. (1988) Effects of type of dietary fat on indices of effect of quality and quantity of dietary fat on the immune sys immune status in rabbits. J. Nutr. 118: 1376-1384. tem. J. Nutr. 113:951-961. 27. DeWille, J. W., Fraker, P. J. & Romsos, D. R. (1981) Effects of 17. Edington, T. S. & Curtiss, L. K. (1981) Plasma lipoproteins with dietary fatty acids on delayed-type hypersensitivity in mice. J. regulatory properties with capacity to regulate lymphocyte Nutr. 111:2039-2043. function and the immune response. Cancer Res. 41: 3786-3788. 28. Thomas, I. K. & Erickson, K. L. (1985) Lipid modulation of 18. Harmony, J. A. K. ölHui, D. Y. (1981) Inhibition of membrane mammary tumor cell cytolysis: Direct influence of dietary fat bound LDL of the primary inductive events of mitogen stimu on the effector component of cell-mediated cytotoxicity. J. Nati. lated lymphocyte activation. Cancer Res. 41: 3799-3802. Cancer Inst. 74: 675-680. 19. Humphries, G. M. K. (1981) Differences in ability of compactin 29. Chan, P. C., Ferguson, K. A. & Doa, T. L. (1983) Effects of and oxidized cholesterol to suppress in vitro immune responses. Cancer Res. 41:3789-3791. different dietary fats on mammary carcinogenesis. Cancer Res. 43: 1079-1083. 20. Gross, R. L. & Newberne, P. M. (1980) Role of nutrition in immunologie function. Physiol. Rev. 60: 188-302. 30. Leyton, J., Lee, M. L., Locniskar, M., Belury, M. A., Slaga, T. J., 21. Erickson, K. L. (1986) Dietary fat modulation of immune re Bechtel, D. & Fischer, S. M. (1991) Effects of type of dietary sponse. Int. J. Immunopharmacol. 8: 529-543. fat on phorbol ester-elicited tumor promotion and other events in mouse skin. Cancer Res. 51: 907-915. 22. Erickson, K. L., Adams, D. A. a Scibienski, R. J. (1986) Dietary Downloaded from fatty acid modulation of murine B-cell responsiveness. J. Nutr. 31. Kelley, V. E., Ferretti, A., Izui, S. & Strom, T. B. (1985) A fish 116: 1830-1840. oil diet rich in reduces cyclooxygenase 23. Erickson, K. L., Adams, D. A. & McNeil, C. }. (1983) Dietary metabolites and suppresses in MRL-Ipr mice. J. Immunol. lipid modulation of immune responsiveness. Lipids 18: 468- 134: 1914-1919. 474. 32. Hurd, R. R., Johnston, J. M., Okita, J. R., MacDonald, P. C., Ziff, M. & Gilliam, J. N. (1981) Prevention of glomerulone-

24. Marshall, L. A. &. Johnston, P. V. (1985) The influence of di jn.nutrition.org etary essential fatty acids on rat immunocompetent cell pros- phritis and prolonged survival in New Zealand black/New Zea taglandin synthesis and mitogen-inducedblastogenesis. J. Nutr. land white FI hybrid mice fed on essential fatty acid-deficient 115: 1572-1580. diet. J. Clin. Invest. 67: 476-485. by guest on February 9, 2012