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The Medical Implications of Nuclear War, Institute of Medicine. ~ 1986 by the National Academy of Sciences. National Academy Press, Washington, D.C. The Immunological Impact of Nuclear Warfare DAVID S. GOFER, M.D., md LA~NCE S. MEN Brown University Program in Medicine, Providlence, Rhode Islandt Medical interest in nuclear warfare initially was focused on the im- mediate effects in human populations of blast, heat, and radiation and the futility of civil defense measures. Recently, the concept of nuclear winter has called attention to intermediate and long-term outcomes. The biolog- ical impact of a major exchange of nuclear weapons has been addressed in general terms, but little attention has been given to the specific elements of potential biological injury. With this paper, we hope to carry biomedical interest in nuclear warfare to another level of detail and specificity by postulating, from a review of relevant literature, that there would be major immunological damage to surviving human populations. We also speculate on the likelihood of additive or synergistic deleterious effects that would arise from exposure to multiple toxic agents. BACKGROUND Human lymphocytes are classified on the basis of differing develop- mental pathways as B lymphocytes and T lymphocytes, which display different immunological functions. B lymphocytes are precursors of an- tibody-secreting cells. T lymphocytes control cellular immune responses and are the effecters of cell-mediated immune reactions; they protect against certain bacterial infections and many veal and fungal infections, and they provide resistance to malignant tumors. There are several distinct functional T lymphocyte subpopulations (Ta- ble 11. Effector T lymphocytes respond specifically to target antigens in 317

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318 HEALTH CONSEQUENCES OF NUCLEAR WAR TABLE 1 Functional Subpopulations of Lymphocytes I. T lymphocytes A. Regulatory T lymphocytes 1. Helper lymphocytes 2. Suppressor lymphocytes B. Effector T lymphocytes 1. Delayed-type hypersensitivity (DTH) 2. Mixed lymphocyte reactivity 3. Cytotoxic T lymphocyte (CTL or killer cells) II. B lymphocytes A. Precursors of antibody-forming cells B. Memory cells C. Regulatory B lymphocytes cell-mediated immune responses, such as the rejection of foreign tumors and the elimination of virus-infected cells. Helper T lymphocytes stimulate the differentiation of B lymphocytes into mature antibody-secreting plasma cells and regulate the activation of effecter T lymphocytes. Suppressor T lymphocytes actively suppress the initiation of specific immune responses by preventing the activation of helper T lymphocytes, hindering helper T lymphocyte interactions with B lymphocytes and directly inhibiting B lymphocyte differentiation. IONIZING RADIATION Numerous studies in animals have demonstrated that ionizing radiation produces significant impairment of the immune system. Whole-body x irradiation with 400 reds in albino rabbits completely eliminates antibody response to an antigen presented 48 hours after exposure. ~ Mice exposed to 450 reds of total body x irradiation exhibit suppressed intracellular digestion of foreign erythrocytes.2 Sublethal x irradiation in mice results in an increased incidence of neoplastic diseases.3 There is much clinical evidence of immunosuppression by x irradiation in humans. Patients receiving extensive radiotherapy for Hodgkin's disease experience an increased incidence of viral infections (herpes zoster and varicella-zoster virus).4 The antibody response to pneumococcal vaccine is profoundly impaired in patients receiving total lymphatic irradiation. The ability of these patients to respond to immunization may not return to normal for as long as four years following therapy.5 Impaired T lym- phocyte-mediated immunity has been noted in Japanese atom bomb sur- vivors 30 years after exposure.6 Studies of human radiation injuries resulting from laboratory accidents, the Pacific Testing Ground accidents, and medical whole-body radiation therapy and in Hiroshima and Nagaski victims reveal an almost 100 percent

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THE IMMUNOLOGICAL IMPACT OF NUCLEAR WAR 319 fatality rate in individuals exposed to 500-600 reds or more of whole- body irradiation.7 At the other extreme, recovery and survival is virtually certain in whole-body exposures of less than 100 reds in healthy humans. Infections are prominent among individuals exposed to 200-450 reds. Although there may be some increase in infections 2 to 4 weeks after human exposure in the 100-200 red range, there are usually no serious long-term clinical consequences.7 However, hematopoietic suppression is observed in the 150-200 red range.8 Various studies suggest, therefore, that the vulnerability of the human immune system begins at levels of about 150-200 reds of x irradiation. Rotblat's studies9 suggest that under wartime conditions these levels of vulnerability may be lowered by other deleterious factors, e.g., malnutrition, stress, and exposure. Much of our knowledge of radioimmunology in humans comes from clinical experience with total lymphoid irradiation (TLI) therapy, in which suppression of undesirable immune reactions is attempted by delivering ionizing radiation in multiple doses to lymphoid tissue over a period of weeks. it TLI produces marked and prolonged humoral and cell-mediated immunosuppressive effects in humans. TLI in patients with Hodgkin's disease results in a decrease of helper T lymphocytes for up to 12 months, while the fraction of suppressor T lymphocytes remains constant. Similar effects have been observed in rheumatoid arthritis patients treated with TLI.~2 TLI induces potent nonspecific suppressor lymphocytes which in- hibit the cytotoxic T lymphocyte response.~ In a variety of clinical sit- uations, TLI produces lasting reductions in the ratio of helper to suppressor T lymphocytes. The mechanism of immune suppression by x irradiation appears to be a reduction in T lymphocyte function associated with a reduced ratio of helper to suppressor T lymphocytes. The calculations of Harwell,~3 Ehrlich et al.,~4 Daugherty,is and others indicate that millions of people in the Northern Hemisphere would be exposed to sublethal x irradiation in this range in a 5,000-10,000 megaton (Mt) nuclear exchange. They would be susceptible, therefore, to a wide range of immunodeficiency diseases. ULTRAVIOLET RADIATION Studies in animals have confirmed that ultraviolet-B (UV-B) exposure results in a state of T lymphocyte-mediated immune suppression attrib- utable to a predominance of suppressor T lymphocyte. In mice, for example, UV-B irradiation results in an impairment of antigen-presenting cell functional and a relative excess of suppressor T lymphocytes. The suppressor T lymphocytes generated following exposure to UV-B inhibit the antitumor response. UV-irradiated mice are unable to reject UV-B-induced tumors.'9 This inability to reject tumors is mediated by

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320 HEALTH CONSEQUENCES OF NUCLEAR WAR suppressor cell activity, which persists in UV-B-exposed animals long after termination of UV-B exposure.20 2~ UV-irradiated mice are more susceptible to leukemias and lymphomas22 and to tumors induced by chemical carcinogens.23 UV-induced suppressor lymphocytes appear to be the agents that predispose the host to the premature development of cancer. In studies of the effect of UV irradiation on humans, it has been noted that helper T lymphocytes are more sensitive to UV than are B lympho- cytes.24 Normal human subjects exposed to UV irradiation, both In com- mercial solar and in natural sunlight, exhibit increases in suppressor T lymphocyte activity sufficient to impair defense against tumors.25~26 The pathophysiologic mechanism appears to differ for UV-A and UV-B ex- posure, but relative predominance of suppressor T lymphocytes results in both instances.27 Clinical data on the effect of UV irradiation on humans also are available from studies of long-term psoralen plus UV-A (PUVA) radiation therapy for psoriasis. PUVA photochemotherapy causes a reduction in helper T lymphocytes and a reduction in the lymphocytic response to the mitogen phytohemagglutinin.28 The abnormally low response to mitogens is as- sociated with a decrease in the percentage of helper lymphocytes.29 If the predominant nuclear winter scenarios prove accurate, the in- creased UV-B exposure of human populations can be expected to impair immune function in a manner similar to the effects of ionizing radiation; i.e., it would result in a reduction of the helper-to-suppressor T lymphocyte ratios in many survivors. Crutzen and Birks30 estimate a 37-70 percent average ozone reduction in a nuclear exchange ranging from 5,000 to 10,000 Mt and predict that a 10,000-Mt nuclear war would result in increases in UV-B radiation by a factor greater than 5 throughout most of the Northern Hemisphere. Turco et al.3~ and Ehrlich et alto estimate UV-B doses of roughly twice the normal level in the Northern Hemisphere after a 5,000-Mt exchange and an increase by a factor of 4 following a 10, 000-Mt exchange. Such increases in UV radiation exposure would be in the range expected to affect T lymphocyte populations in the survivors. Based on the assumption that skin cancer incidence is proportional to lifetime UV radiation dose, a National Academy of Sciences committee has estimated that a 50 percent reduction in global ozone would cause an increase in skin cancer of approximately 10 percent that would be main- tained for 40 years.32 BURNS AND TRAUMA Severe immunosuppression occurs after major burns and traumatic in- juries. Burn patients often show altered cellular immune responses, such

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THE IMMUNOLOGICAL IMPACT OF NUCr:FAR WAR 321 as impaired skin test reactivity to antigens and delayed graft rejection. Burns and wounds in the skin also serve as portals of entry for infection. The resultant increase in the incidence and severity of infection in trauma and burn patients is well known. Gram-negative bacilli are the most com- mon wound pathogens, and sepsis is the most common cause of death in survivors of the shock phase of thermal injury.33 34 Several recent studies support the concept that reduced T lymphocyte activity is largely responsible for burn-induced immunosuppression.35 36 Clinical evidence suggests that depressed T lymphocyte function is caused by a shift in the balance of suppressor and helper T lymphocyte subpop- ulations following thermal injuries. Sepsis is most likely to occur when suppressor cell populations are at a maximum, 7 to 14 days after the injury.37 A high suppressor-to-helper T lymphocyte ratio has been noted in patients soon after burn injuries of greater than 30 percent of body surface area, and high levels of postburn suppressor T lymphocyte activity accurately predict the incidence of mortality from sepsis.38 T lymphocyte function is significantly depressed in burn injuries covering more than 25 percent of the body surface area,36 accompanied by a reduction in helper and an increase in suppressor T lymphocytes.39 Reduced helper-to-sup- pressor ratios are a predictor of mortality from sepsis. Thus, blast and burn injuries in nuclear war survivors can be expected to reduce immune competence in a manner similar to the effect of ionizing and ultraviolet radiation. The T lymphocytes would primarily be affected, and, specifically, a decrease in the ratio of helper-to-suppressor T lym- phocytes would be anticipated. PSYCHOLOGICAL FACTORS: STRESS, DEPRESSION, AND BEREAVEMENT Chazov and Vartanian40 have estimated that at least one-third of the population surviving a nuclear war would suffer from severe emotional and behavioral disturbances. Stress, depression, and bereavement have all been reported to alter the immune system and increase the risk of infection. Studies in animals under stress have shown an increased susceptibility to infection by coxsackie B. polio, herpes, and vesicular stomatitis vi- ruses.4~ Rats given a graded series of stressors manifest progressive suppression of lymphocyte function.42 Clinical studies suggest that psychological variables influence suscep- tibility to infection and delay recovery from upper respiratory diseases, influenza, herpes simplex lesions, and tuberculosis.43 These psychologi- cally induced altered immune states are probably mediated by changes in lymphocytes. T lymphocyte function is significantly depressed in bereaved

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322 HEALTH CONSEQUENCES OF NUCLEAR WAR spouses.44 Marked decreases in lymphocyte mitogenic activity have been noted among patients with primary depressive illness.45 46 Suppression of mitogen-induced lymphocyte stimulation in widowers has been associated with bereavement.47 Clinically depressed patients have been shown to have an increased mortality rate, cancer rate, and incidence of certain viral infections.46 48 The mechanisms by which stress influences the immune system are largely unknown. Neuroendocrine mediation has been suggested. Once again, T lymphocytes appear to mediate the abnormal immunological state. MALNUTRITION It has long been recognized that nuclear war would have a major impact on agriculture and world food supplies. More recently, Harwell~3 has written that nuclear winter could result in termination of agricultural pro- duction and distribution systems and that widespread starvation might ensue. Specifically, he predicted that surviving populations would be deprived of vitamins A, Bit, and C; riboflavin; and iron. Each of these nutrients is important in maintaining a healthy immune response. Studies in rats and mice indicate that vitamin B ~2 may be highly important to T lymphocyte immune reactions.49 Riboflavin-deficient an- imals are more susceptible to infection.S Vitamin A deficiency in animals leads to depleted numbers of T lymphocytes; depressed lymphocyte re- sponse to certain mitogens; and an increased frequency and severity of bacterial, viral, and protozoan infections.S Iron deficiency is also accom- panied by impaired in vitro lymphocyte responsiveness to mitogenic stim- ulation.S Abnormalities of T lymphocyte function have also been noted in pyridoxine and zinc deficiency.S~ Based on epidemiologic observations, the World Health Organization report on interactions between nutrition and infectionS2 noted that severe ascorbic acid (vitamin C) deficiency tends regularly to lower resistance to most infectious diseases. There is epidemiological and clinical evidence that the cell-mediated immune response is defective in protein-calorie malnutrition.S3 Individuals with protein-calorie malnutrition have a high incidence of infection, par- ticularly by mycobactena, viruses, and fungi; and they develop lympho- penia with decreased cutaneous hypersensitivity to several antigens.s4 In communities where protein-calorie malnutrition is prevalent, there is a high mortality from infections which cause only minor illnesses in well- nourished individuals.55 The diminished cellular immunity of protein-calorie malnutrition is as- sociated with a marked decrease in the number of T lymphocytes.S6 Almost every conceivable alteration of the T lymphocyte subpopulation and its

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THE IMMUNOLOGICAL IMPACT OF NUCLEAR WAR 323 function (as well as the B lymphocyte population and its function) can be evoked through nutritional, protein, or caloric manipulation.57 In severe protein-calorie deprivation, the entire lymphocyte population and T lym- phocyte immunity can virtually be eliminated. The cellular immune def- icits associated with protein-calorie maInu~ition correlate with the frequency and severity of infections with Car~ida albicans, measles, and tubercu- losis, all of which are T lymphocyte-mediated infections. DISCUSSION Sublethal injuries in combination can prove lethal. Since the five major Injurious agents associated with nuclear warfare attack the same compo- nent of the immune system, the T lymphocyte, and generally do so in a similar manner by decreasing the helper-to-suppressor T lymphocyte ratio, additive influences can be anticipated. Impairment of immunity to a variety of infectious diseases and tumors is likely. Infections associated clinically with depressed cell-mediated immunity have been those with intracellular pathogens like tuberculosis, leprosy, and histoplasmosis;57 DNA-type vi- rus infections (e.g., varicella-zoster virus, cytomegalovirus); and a variety of rarer pathogens (e.g., Legionella, Pneumocystis, and Toxoplasma). Abrams and Von Kaenel33 have suggested that in the post-nuclear-war world, surviving populations would be particularly susceptible to tuber- culosis. A striking similarity exists between acquired immunodeficiency syn- drome (AIDS) and the anticipated immunosuppressed condition of sur- vivors of a nuclear war: both are characterized by absolute depression of the helper T lymphocyte population, reduced helper-to-suppressor T lym- phocyte ratios, reduced lymphocytic response to mitogens and antigens, and reduced to absent antibody response following immunization. In AIDS, the T lymphocyte abnormalities appear to be induced by infection with the human T lymphocyte virus type III (HTLV-III), which kills helper T lymphocytes. The resulting profound immunosuppression apparently pro- duces enhanced susceptibility to other infections. These are listed in Table 2. Patients with AIDS also experience increased incidences of malignan- cies, especially Kaposi's sarcoma, which is thought to be caused by the cytomegalovirus. AIDS patients frequently develop non-Hodgkins lym- phomas, oral squamous cell carcinoma, and cloacogenic carcinomas. Since large numbers of the survivors of nuclear war can be expected to have immunologic deficits like those in individuals with AIDS, an increase in the incidence of AIDS-related diseases should be anticipated. The data of von Hippel~s and others suggest an immediate at-risk popu

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324 HEALTH CONSEQUENCES OF NUCLEAR WAR TABLE 2 Principal Agents of Infection in Patients with Acquired Immunodeficiency Syndrome (AIDS) Viruses Herpesvirus (types 1 and 2) Cytomegalovirus Varicella-zoster Adenovirus Epstein-Barr Re~ovirus (HTLV-I, -III) F. ungl Candida albicar~s Cryptococcus neoforrnans Nocardia Protozoa Pneumocystis carinii Toxoplasma gondii Isospora sp. Cryptosporidium Giardia iamblia Entameeba histolytica Mycobactena Mycobacterium tuberculosis Mycobacterium avium- intracellulare Mycobacterium kansasii Legionella sp. Spirochetes Treponema sp. (including Treponema pallidum) Bactena Campylobacter sp. Neisseria sp. (including Neisseria gonorrhoeae) Shigella sp. Salr~wnella sp. Chlamydia SOURCE: Ammann (1984: Table 22-10).58 Reproduced with permus- sion, from Shtes, D.P., et al. (editors): Basic and Clinical Immunology, 5th ed. @) 1984 by Lange Medical Publications, Los Altos, California. ration of at least 10 million Americans in an attack directed at strategic targets only. Exposure to UV radiation, malnutrition, and stress could increase this in the months and years following an attack. SUMMARY AND CONCLUSIONS Survivors of a nuclear attack would suffer from injuries caused by ionizing and UV radiation, physical trauma, burns, malnutrition, and psychosocial stress. Several independent lines of research have indicated that these separate agents converge on the T lymphocyte component of the immune system, generally causing a reduction in T lymphocytes and a decrease in the ratio of helper-to-suppressor T lymphocytes. T lymphocyte defects are associated with some of the most disabling immunodef~ciencies. T lymphocytes are essential in the defense against a variety of bacterial diseases and are vital in resistance to many viral and fungal diseases. Patients with AIDS show depression of T lymphocyte populations and reduced helper-to-suppressor T lymphocyte ratios similar to those anticipated in millions of nuclear war survivors. There is con- siderable experimental evidence that T lymphocytes provide immune sur

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THE IMMUNOLOGICAL IMPACT OF NUCLEAR WAR 325 veillance against cancer. T lymphocyte functional abnormalities may explain some of the susceptibility to malignancy which is clinically associated with exposure to ionizing and UV radiation. Multiple factors converging on a single element of We immune system, the T lymphocyte, can be expected to be additive. The possibility of synergy has been raised by several observers,33 59 and this could magnify Me impact. Severe immunodeficiencies of the T lymphocyte variety are to be anticipated after exposure of human populations to nuclear war. Epidemics of diseases in which T lymphocytes mediate the immune re- sponse would be likely in Me months and years following a nuclear attack. NOTES ~Dixon, F. J., D. W. Galmage, and P.H. Mauren. 1952. Radiosensitive and radioresistant phases in the antibody response. J. Immunol. 68:693-700. Donaldson, D. M., S. Marcus, K. K. Gyi, and E. H. Perkins. 1956. The influence of immunization and total body x-irradiation on intracellular digestion by peritoneal phago- cytes. J. Immunol. 76:192-199. 3Peter, C. P., E. H. Perkins, W. J. Peterson, H. E. Walburg, and T. Makinodan. 1975. The late effects of selected immunosuppressants on immunocompetence, disease incidence, and mean life expectancy. Mechanisms of Ageing and Development 4:251-261. 4Reboul, F., C. Donaldson, and H. Kaplan. 1978. Herpes zoster and varicella infections in children with Hodgkin's disease. Cancer 41:95-99. 5Siber, G. R., S. A. Weitzman, A. C. Aisenberg, H. J. Weinstein, and G. Schiffman. 1978. Impaired antibody response to pneumococcal vaccine after treatment for Hodgkin's disease. N. Eng. J. Med. 299:442-448. 6Akiyama, M., M. Yamakido, K. Kobuke, D. S. Dock, H. B. Hamilton, A. A. Awa, and H. Kato. 1983. Peripheral lymphocyte response to PHA and T cell population among atomic bomb survivors. Radiat. Res. 93:572-580. 7Bond, V., T. Fliedner, and J. Archambeua. 1965. Mammalian Radiation Lethality. New York: Academic Press. ~Cronkite, E. P. 1981. The effects of dose, dose rate, and depth dose upon radiation mortality. Proceedings from a Symposium of the National Council of Radiation and Pro- tection Measurements, Reston, Va., April 27-29. The Control of Exposure of the Public to Ionizing Radiation in the Event of Accident War Attack. Bethesda, Md.: National Council of Radiation and Protection Measurements. 9Rotblat, J. 1986. Acute Radiation Mortality in a Nuclear War. This volume. ~Strober, S. 1984. Managing the immune system with total lymphoid irradiation. Pp. 369-378 in The Biology of Immunologic Diseases, F. J. Dixon and D. W. Fisher, eds. Sunderland, Mass.: Sinauer Associates. Posher, M., E. Reinherz, H. Lane, P. Mauch, S. Hellman, and S. F. Schlossman. 1983. Circulating lymphocyte populations in Hodgkin's disease after mantle and paraaortic irradiation. Blood 64:705-708. Afield, E. H., E. G. Engelman, C. P. Terrell, and S. Strober. 1984. Reduced in vitro immune responses of purified human leu-3 (helper/inducer phenotype) cells after lymphoid irradiation. J. Immunol. 132: 1031- 1035. 3Harwell, M. A. 1984. Nuclear Winter. New York: Springer-Verlag. ~4Ehrlich, P., et al. 1983. Long-term biological consequences of nuclear war. Science. 222:1293-1300.

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326 HEALTH CONSEQUENCES OF NUCLEI We Daugherty, W., B. Levi, and F. van Hippel. 1986. Casualties due to the blast, heat, and radioactive fallout from various hypothetical nuclear attacks on the United States. This volume. Charm, W. 1980. Biological Effects of Ultraviolet Radiation. Cambridge: Cambridge University Press. i7Greene, M., M. I. Greene, M. S. Sy, M. Kripke, and B. Benacerraf. 1979. Impairment of antigen-presenting cell function by ultraviolet radiation. Proc. Natl. Acad. Sci. USA 76:6591-6595. i8Elmets, C. A., et al., 1983. In viva low dose UVB irradiation induces suppressor cells to contact sensitizing agents. Pp. 317-336 in The Effect of Ultraviolet Radiation on the Immune System, J. A. Parrish, ed. Johnson & Johnson Baby Products Co., Skillman, N.J. i9Kripke, M. L., and M. S. Fisher. 1976. Immunologic parameters of ultraviolet car- cinogenesis. J. Natl. Cancer Inst. 57:211-215. 20Spellman, C. W., and R. A. Daynes. 1977. Modification of immunological potential by ultraviolet radiation. Transplantation 24:120-126. Parrish, J. A. 1983. P. 213 in The Effect of Ultraviolet Radiation on the Immune System. Johnson & Johnson Baby Products Co., Skillman, N.J. 22Ebbesen, P. 1981. Enhanced lymphoma incidence in BALB/c mice after ultraviolet light treatment. J. Natl. Cancer Inst. 67:1077. 23Roberts, L. K., and R. A. Daynes. 1980. Modification of the immunogenic properties of chemically induced tumors arising in hosts treated concomitantly with ultraviolet light. J. Immunol. 125:438-447. 24Cripps, D., S. Horowitz, and R. Hong. 1974. Selective T cell killing of human lym- phocytes of ultraviolet radiation. Cell. Immunol. 14:80-86. 2sHersey, P., et al. 1983. Alteration of T cell subsets and induction of suppressor T cell activity in normal subjects after exposure to sunlight. J. Immunol. 31 (1):171-174. 26Hersey, P., et al. 1983. Immunological effects of solarium exposure. Lancet i:545- 548. 27Sober, A., and T. Fitzpatrick. 1984. Yearbook of Dermatology. Chicago, Ill: Year Book Medical Publishers. 28Moscicki, R. A., M. L. Morison, J. A. Parrish, K. J. Bloch, and R. B. Colvin. 1982. Reduction in the fraction of circulating helper: inducer T cells identified by monoclonal antibodies in psoriatic patients treated with psoralen/ultraviolet A radiation (PUVA). J. Invest. Dermatol. 79:205-208. 29Morison, W. L., et al. 1981. Abnormal lymphocyte function following long-term PUVA therapy for psoriasis. J. Invest. Dermatol. 76:303. 30Crutzen, P. J., and J. W. Birks. 1982. The atmosphere after a nuclear war: Twilight at noon. Ambio 11:114-125. 3~Turco, R. P., O. B. Toon, T. P. Ackerman, J. B. Pollack, and C. Sagan. 1983. Nuclear winter: Global consequences of multiple nuclear explosions. Science 222(4630): 1283-1292. 32National Academy of Sciences. 1975. Long Term Worldwide Effects of Multiple Nu- clear Weapons Detonations. National Research Council. Publication 2418. Washington, D.C.: National Academy of Sciences. 33Abrams, H., and W. Von Kaenel. 1981. Medical problems of survivors in nuclear war. N. Eng. J. Med. 305:1226-1232. 34Gelfand, J. A. 1984. Infections in burn patients: A paradigm for cutaneous infection in the patient at risk. Am J. Med. 76:158-165. 3sMckvine, A. J., J. H. N. Wolfe, K. Collins, and J. A. Mannick. 1983. Fatal injections in mice after injections of immunosuppressive serum factors from surgical patients. Br. J. Surg. 70:558-561.

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THE IMMUNOLOGICAL IMPACT OF NUCLEAR WAR 327 36Menon, T., T. Sundararaj, S. Subramanian, R. Murugesan, and C. R. Sunderarajan. 1984. Kinetics of peripheral blood T cell numbers and functions in patients with burns. J. Trauma 24:220-223. 37Munster, A. M. 1984. Immunologic response of trauma and burns. Am. J. Med. 143- 145. 38McIrvine, A. J., J. B. O'Mahony, I. Saporoschetz, and J. A. Mannick. 1982. Depressed immune response in burn patients: use of monoclonal antibodies and functional assays to define the role of suppressor cells. Annals of Surgery 196(3):297-304. 39Antonacci, A., R. Good, and S. Gupta. 1982. T-cell subpopulations following thermal injury. Surgery 55: 1-8. 40Chazov, E., and M. Vartanian. 1982. Effects on human behavior. Ambio 11:158-160. 4~Amkraut, A., and G. F. Solomon. 1975. From the symbolic stimulus to the pathophys- iologic response: Immune mechanism. Int. J. Psych. Med. 5(1):541-563. 42Keller, S. E., J. M. Weiss, S. J. Schliefer, N. E. Miller, and M. Stein. 1981. Suppres- sion of immunity by stress: Effect of a graded series of stressors on lymphocyte stimulation in the rat. Science 213:1397-1400. 43Kaplan, H., A. Freedman, and B. Sadock. 1980. Comprehensive Textbook of Psy- chiatry/III. P. 1965. Baltimore: Williams & WiLkins. 44Bartrop, R. W., E. Luckhurst, L. Lazarus, L. G. Kiloh, and R. Penny. 1977. Depressed lymphocyte function after bereavement. Lancet i:834-836. 4sKronfol, Z., J. Silva, J. Greden, S. Dembinski, R. Gardner, and B. Carroll. 1983. Impaired lymphocyte function in depressive illness. Life Sci. 33:241-247. 46Schleifer, S. J., S. E. Keller, A. T. Meyerson, M. J. Raskin, K. L. Davis, and M. Stein. 1984. Lymphocyte function in major depressive disorder. Arch. Gen. Psych. 41:48 486. 47Schleifer, S., S. E. Keller, M. Camerino, J. C. Thornton, and M. Stein. 1983. Suppres- sion of lymphocyte stimulation following bereavement. J. Am. Med. Assoc. 250:373-377. 48Shekelle, R. B., W. J. Raynor, A. M. Ostfeld, D.C. Garron, L. A. Bieliauskas, S. C. Liu, C. Maliza, and O. Paul. 1981. Psychological depression and 17-year risk of death from cancer. Psychosomat. Med. 43:117-125. 49Newberne, P. M. 1977. Effect of folic acid, B~2, choline, and methionine on immu- nocompetence and cell-mediated immunity. Pp. 373-386 in Malnutrition and the Immune Response, R. Suskind, ed. New York: Raven Press. sNeumann, C. G. 1977. Nonspecific host factors and infection in malnutrition A review. Pp. 366 in Malnutrition and the Immune Response, R. Suskind, ed. New York: Raven Press. s~Beisel, W. R. 1981. Single-nutrient effects of immunologic functions. J. Am. Med. Assoc. 245:53-58. s2WHO Monograph Series 1968. Interactions of Nutrition and Infection, Vol. 57; P. 100. Geneva: World Health Organization. 53Edelman, R. 1977. Cell-mediated immune response in protein-calorie malnutrition A review. Pp. 47-75 in Malnutrition and the Immune Response, R. Suskind, ed. New York: Raven Press. 54Levy, J. A. 1984. Nutrition & the Immune System. Pp. 293-298 in Basic and Clinical Immunology, 5th ea., D. P. Stites, J. D. Stobo, H. H. Fudenberg, and J. V. Wells, eds. Los Altos, Calif.: Lange Medical Publications. ssSmith, N. J., S. Khadrovi, V. Lopez, and B. Hamza. 1977. Cellular immune response in Tunisian children with severe infantile malnutrition. Pp. 105-109 in Malnutrition and the Immune Response, R. Suskind, ed. New York: Raven Press. 56Neumann, C. G., E. R. Stiehm, M. Swenseid, A. C. Ferguson, and G. Lawlor. 1977.

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328 HEALTH CONSEQUENCES OF NUCLEAR WAR Cell-mediated immune response in Ghanaian children with protein-calorie malnutrition. Pp. 77-89 in Malnutrition and the Immune Response, R. Suskind, ed. New York: Raven Press. s7Good, R. A. 1977. Biology of the cell-mediated immune response A review. Pp. 29- 46 in Malnutrition and the Immune Response, R. Suskind, ed. New York: Raven Press. s8Ammann, A. J. 1984. Immunodeficiency diseases. In Basic and Clinical Immunology, D. P. Stites, J. D. Stobo, H. H. Fudenberg, and J. V. Wells, eds. Los Altos, Calif.: Lange Medical Publications. s9Chandra, R. M., and Newberne P. M. 1977. Nutrition, Immunity, and Infection. P. 2. New York: Plenum Press.