Journal of Gerontology 1976, Vol. 31, No. 3, 271-274
Experimental Allergic Encephalomyelitis in Aged F344 Rats1 Seymour Levine, MD2 and Richard Sowinski, MS2
XPERIMENTAL allergic encephalomyelitis (EAE) is widely used as an animal model for multiple sclerosis (Paterson, 1971; Levine, 1971). A striking feature of the human disease is its predilection for young adults and the rarity of onset in children or after the age of 50 (Kurland, 1952). At the lower end of the age scale, the model matches the human disease, inasmuch as the development of autoimmunity in EAE requires the presence of a mature lymphoid system (Paterson, Drobish, Hanson, & Jacobs, 1970). The present investigation is an attempt to determine whether advanced age protects against EAE in rats as it does against multiple sclerosis in man. MATERIALS AND METHODS
Inbred Fischer 344 (F344) male rats were purchased from Charles River Breeding Laboratories after arrangements through Dr. Don C. Gibson of the National Institute on Aging. These rats had been Caesarian derived, maintained behind a barrier, fed pasteurized feed of standard composition, and monitored for microbial agents. The rats were kept in groups of 4 or 5 in hanging metal cages for 2-6 weeks in our laboratory without barrier precautions before being used. Purina laboratory chow and tap water were offered ad libitum.
'Supported by a grant from the Kroe Foundation. "Pathology Dept., New York Medical College Center for Chronic Disease, Bird S. Coler Hospital, Roosevelt Island, New York 10017.
The antigen was a 40% saline homogenate of previously frozen guinea pig spinal cord or a 0.004% saline solution of purified guinea pig myelin basic protein (for which we are indebted to Dr. R. Gruenewald). The antigen was emulsified, water-in-oil, in an equal volume of Freund's complete adjuvant (85 parts Bayol F mineral oil, 15 parts Arlacel A emulsifying agent, 4 mg/ml killed human tubercle bacilli). The dose of 0.05 ml was injected intradermally into the right hind foot pad with light ether
anesthesia. It contained 10 mg wet weight spinal cord or 1 \x% basic protein. For additional adjuvant effect, 0.1 ml pertussis vaccine concentrate (for which we are indebted to Dr. H. B. Devlin of Parke Davis and Company) was injected into the dorsum of the inoculated foot of some rats. The rats were checked daily for clinical signs of EAE: 3 + paralysis; 2 + weakness; 1 + flaccid tail. They were sacrificed by exsanguination while under anesthesia after paralysis was noted, or 16-21 days after immunization. Entire brain and spinal cord and samples of other organs were fixed in Bouin's fluid, embedded in paraffin, sectioned and stained with hematoxylin-eosin. For passive transfer of EAE, young donor rats were immunized with spinal cord, Freund's adjuvant and pertussis vaccine. Nine days later, when almost every rat was paralyzed, the lymph nodes draining inoculation sites were harvested, pooled, and processed rapidly, in the cold, into 271
Downloaded from http://geronj.oxfordjournals.org/ at Karolinska Institutet on May 23, 2015
Experimental allergic encephalomyelitis (EAE) was produced in 2- to 24-mo.-old F344 rats by active immunization and by passive transfer of lymphoid cells (adoptive immunization) from young rats. With both methods, some 24-mo.-old rats had a reduced, ability to develop this autoimmune disease. However, the immunological deficit was related to incidental serious diseases rather than to old age per se. The aged F344 rat is not a suitable model for comparing EAE to multiple sclerosis in man because the decreased incidence of multiple sclerosis after the age of 50 is not related to other serious illnesses.
LEVINEAND SO WINSKI
272
a cell suspension in Ringer's solution. Cells from 2 donors were injected into the penile vein of each recipient. Recipients were from the same inbred strain, as histocompatibility is essential for passive transfer, but they were of various ages. RESULTS
Table 1. EAE in Rats of Various Ages. Age (Mo.)
Onset* (Days)
Signs' (Score)
1: Cord, CFA, Pert
2 6 12 18 24
8888 8 9 9 10 9999 11 11 12 14 11 13 16 —
3333 3333 3333 3332 33 1 -
2: Cord, CFA
6 24
12 13 13 -
22 1 --
3: BP, CFA, Pert
6 24
13 13 13 14 15
33333
Immunization'
4: BP, CFA
b
15 15 16 18
3321
24 "Guinea pig spinal cord or basic protein (BP) emulsified in complete Freund's adjuvant (CFA), with or without simultaneous injection of pertussis vaccine concentrate (Pert). 'Day of onset and maximum score of severity of clinical signs for individual rats, recorded in the same order. A hyphen represents absence of signs during entire experiment, in the First experiment, half of each group of rats were orchidectomized; this procedure did not influence the results.
0.86 to 2.55 gm (0.23 to 0.71% of body weight)
not including the leukemic rat, compared to 0.25 to 0.75gm (0.10 to 0.29%) for 6-mo.-old rats. Many of the old rats also had chronic kidney disease, scarred liver, peripheral neuropathy, neuroaxonal dystrophy of the gracile and cuneate nuclei of the brain, and small nodules in the adenohypophysis. Thymuses were very atrophic. The heart was not studied. Despite this impressive array of coincidental diseases, histologic examination of the inoculated feet and the draining popliteal lymph node did not reveal any deficiency in processing of the antigenic inoculum. This raised the question whether the deficiency in old rats resided in the process of immunization or in the interaction of immunized cells with the neural target. To help elucidate this problem, we produced EAE by passive transfer of fully immunized lymph node cells from 2- to 3-mo.-old donors to immunologically naive recipient rats of various ages. In each of two trials, the cells were given to pairs of rats aged 2, 6,12,18, and 24 mo. After 6-8 days, all recipients 2, 6, 12, and 18 mo. old developed mild clinical signs of EAE (flaccid tail), confirmed histologically. Necropsy of these younger rats revealed only mild splenic hemosiderosis and early testicular tumors. The results in the 24-mo.-old rats differed between the two trials. In the first trial, (experiment 5, Table 2), the 2 old rats developed clinical signs and histologic lesions equal to the younger animals. Necropsies revealed only mild spenomegaly, testicular tumors and mild chronic pyelonephritis. One old rat had carcinoma of the colon which was localized and nonobstructive. In the second trial (experiment 6, Table 2), 2
Downloaded from http://geronj.oxfordjournals.org/ at Karolinska Institutet on May 23, 2015
In response to intense immunization with spinal cord antigen, Freund's adjuvant and pertussis vaccine, rats aged 2, 6, and 12 mo. developed EAE with almost uniform speed and severity. A lesser response in 18- and 24-mo.old rats was indicated by a somewhat protracted incubation period in all, and milder or absent signs in a few (Table 1). Less intense immunization (without pertussis vaccine or with 1 \xg of myelin basic protein) lengthened the incubation period, but almost every 6-mo.-old rat developed clinical signs. In contrast, not a single 24-mo.-old rat developed clinical EAE under these conditions (Table 1). Although these data clearly indicated an agerelated decline in susceptibility to EAE, the interpretation was clouded by the array of pathologic lesions revealed by necropsies of the old rats (confirming observations of Sass, Rabstein, Madison, Nims, Peters, & Kelloff, 1975). Every 24-mo.- and an occasional 18-mo.-old rat had large interstitial cell tumors of both testes, but this particular lesion was proved to be unimportant by the first experiment recorded in Table 1. In this experiment, half of the rats in each group had been bilaterally orchidectomized 1 week before immunization.
The removal of the normal testes (2- to 18-mo.old rats) or tumor-bearing testes (24-mo.-old rats) had no effect on the onset or severity of clinical EAE. Other lesions were probably much more significant. The 1 24-mo.-old rat that was completely refractory to EAE in the first experiment had chronic myelogenous leukemia involving spleen (weight 4.4gm), marrow, and liver. The rat in the same group with a protracted incubation period had a very extensive mesothelioma involving all peritoneal surfaces. All of the 24-mo.-old rats had extramedullary hematopoiesis, hemosiderosis, and passive congestion of the spleen. Spleens weighed from
ALLERGIC ENCEPHALOMYELITIS IN A GED RA TS
Table 2. Necropsy Findings in 24-Mo.-Old Rats. Exp.
No. 1
2 3
5 6
0.86 0.86 1.03 4.42 1.09 1.18 0.98 1.04 1.23 1.78 2.55 1.00 1.01 1.06 1.24 0.98 1.13 2.84 10.35
Other Lesions' T,N,L,K T.N.L, K T, N, K, mesothelioma T, N, K, leukemia T,N T.N.L.K T, N, fibrosarcoma (skin) T, N, sebaceous adenoma T,N, epidermal cyst T,N T,N,L T,N, K T,N T, N, mammary fibroma T.N.L.K T, N, K, carcinoma of colon T,N, K T, N, L, K, leukemia, pheochromocytoma T, N, L, K. leukemia
"Splenomegaly was due to cxtramedullary hematopoiesis, hemosiderosis, and passive congestion except where leukemia is stated. T - testicular tumors, N = neuropathy, L = liver disease, K = kidney disease.
24-mo.-old rats did not develop signs or lesions of EAE. Necropsy revealed that both of them had leukemia with severe splenomegaly and infiltrates in liver, as well as pylonephritis. DISCUSSION
The failure of 2 out of 4 old passive transfer recipients to develop EAE, despite the infusion of potent encephalitogenic cells from young donors, indicates a deficit in the recipient's environment and probably in the nonspecific components of the inflammatory response in the target organ. The discrepancy between the two trials, however, suggests that the deficit in these 2 old rats is more readily correlated with specific disease states, especially leukemia, than with old age, per se. Although we have no direct evidence for this interpretation, it is supported by the extensive leukemic infiltration of lymphoid organs which might have immunosuppressed the recipients as much as treatment with cytotoxic drugs (Levine & Hoenig, 1971). The numbers of old rats are small, but our interpretation is supported by the results of active immunization. In experiment 1 (Table 1), the intensive immunization was partially or completely ineffective only in the old rats that had leukemia or a very extensive mesothelioma. In experiments 2, 3, and 4, where the immunization was less intense, EAE was inhibited in old rats even in the absence of leukemia.
However, none of these rats was free of disease (Table 2). Chronic kidney and liver disease and peripheral neuropathy may inhibit immune processes directly or by activation of the adrenal cortex, or they may indicate the presence of a nutritional deficiency. The occurrence of extramedullary hematopoiesis and hemosiderosis in the spleen may indicate a chronic hemolytic state or other hematologic abnormality: although some splenic changes were noted in rats as young as 6 mo., the hematologic abnormality may have greater immunosuppressive effects in old age. The development of EAE is dependent on an intact lymphoid system. It is well known that the lymphoid system undergoes atrophy and has decreased ability to mount T-cell immune responses with advancing age (Walford, 1969, Roberts-Thomson, Whittingham, Youngchaiyud, & Mackay, 1974). Therefore, the results in any individual rat probably depend on a balance between the intensity of the immunizing regimen, the "normal" atrophy of lymphoid tissues, and the immunosuppressive effects of specific disease states. Onset of multiple sclerosis in man is rare after the age of 50, during the period of life when the passage of time has left an obvious imprint but no major systemic illness is likely to be present. The 24-mo.-old F344 rat is not a good model for this presenile period of human life because of the multiplicity of specific illnesses (Sass et al., 1975). The 18-mo.- old F344 rat may be a better model, but even these animals had splenic changes and peripheral neuropathy. Probably a strain with a longer life-span would be a better model for studying the immunopathology of the presenile period. Some specific diseases associated with advanced age in rats were strongly inhibitory to development of EAE (leukemia), while others were inconsequential (interstitial cell tumors of testes) and others have not been evaluated. Our work emphasizes the needs for better models of aging in rodents (Gibson, 1972) and for complete necropsies to insure proper and critical evaluation of the data. REFERENCES
Gibson, D. C. (Ed.) Development of the rodent as a model system of aging. Publication No. 72-121, NIH, Bethesda, 1972. Kurland, L. T. Epidemiologic characteristics of multiple sclerosis. American Journal of Medicine, 1952,12, 561571.
Downloaded from http://geronj.oxfordjournals.org/ at Karolinska Institutet on May 23, 2015
4
Spleen (Grams)"
273
274
LEVINEAND SO WINSKI
experimental correlates. In M. Samter (Ed.), ImmunoLevine, S. Relationship of experimental allergic encephalological diseases, 2nded. Little, Brown, Boston, 1971. myelitis to human disease. Research Publications of Association for Research in Nervous & Mental Diseases, Roberts-Thomson, I. C , Whittingham, S., Youngchaiyud, U., & Mackay, I. R. Aging, immune response, and mor1971,49, 33-49. tality. Lancet, 1974, //, 368-370. Levine, S., & Hoenig, E. M. A new form of localized allergic encephalomyelitis featuring polymorphonuclear Sass, B., Rabstein, L.S., Madison, R., Nims, R.M., Peters, R. L., & Kelloff, G. J. Incidence of spontaneous neoneutrophilic leukocytes. American Journal of plasms in F344 rats throughout the natural life-span. Pathology, 1971,64, 13-30. Journal of National Cancer Institute, 1975, 54, 1449Paterson, P. Y., Drobish, D. G., Hanson, M. A., & 1456. Jacobs, A. F. Induction of experimental allergic encephalomyelitis in Lewis rats. International Archives of Walford, R. L. The immunologic theory of aging. Williams & Wilkins, Baltimore, 1969. Allergy & Applied Immunology, 1970,37, 26-40. Paterson, P. Y. The demyelinating diseases: Clinical and
Patricia C. MacKeen was the recipient of the award for the outstanding student paper presented at the Gerontological Society's 1975 scientific meeting in Louisville. Her paper, Cytophotometric Determination of Cytoplasmic Azure B RNA Levels Throughout the Life-Span of Tokophrya lemnariwn, was cowritten with Dr. Robert B. Mitchell at the Pennsylvania State University, where Ms MacKeen is a doctoral candidate in physiology.
Downloaded from http://geronj.oxfordjournals.org/ at Karolinska Institutet on May 23, 2015
1975 Biological Sciences Section Student Award
Experimental Allergic Encephalomyelitis in Aged F344 Rats1 Seymour Levine, MD2 and Richard Sowinski, MS2
XPERIMENTAL allergic encephalomyelitis (EAE) is widely used as an animal model for multiple sclerosis (Paterson, 1971; Levine, 1971). A striking feature of the human disease is its predilection for young adults and the rarity of onset in children or after the age of 50 (Kurland, 1952). At the lower end of the age scale, the model matches the human disease, inasmuch as the development of autoimmunity in EAE requires the presence of a mature lymphoid system (Paterson, Drobish, Hanson, & Jacobs, 1970). The present investigation is an attempt to determine whether advanced age protects against EAE in rats as it does against multiple sclerosis in man. MATERIALS AND METHODS
Inbred Fischer 344 (F344) male rats were purchased from Charles River Breeding Laboratories after arrangements through Dr. Don C. Gibson of the National Institute on Aging. These rats had been Caesarian derived, maintained behind a barrier, fed pasteurized feed of standard composition, and monitored for microbial agents. The rats were kept in groups of 4 or 5 in hanging metal cages for 2-6 weeks in our laboratory without barrier precautions before being used. Purina laboratory chow and tap water were offered ad libitum.
'Supported by a grant from the Kroe Foundation. "Pathology Dept., New York Medical College Center for Chronic Disease, Bird S. Coler Hospital, Roosevelt Island, New York 10017.
The antigen was a 40% saline homogenate of previously frozen guinea pig spinal cord or a 0.004% saline solution of purified guinea pig myelin basic protein (for which we are indebted to Dr. R. Gruenewald). The antigen was emulsified, water-in-oil, in an equal volume of Freund's complete adjuvant (85 parts Bayol F mineral oil, 15 parts Arlacel A emulsifying agent, 4 mg/ml killed human tubercle bacilli). The dose of 0.05 ml was injected intradermally into the right hind foot pad with light ether
anesthesia. It contained 10 mg wet weight spinal cord or 1 \x% basic protein. For additional adjuvant effect, 0.1 ml pertussis vaccine concentrate (for which we are indebted to Dr. H. B. Devlin of Parke Davis and Company) was injected into the dorsum of the inoculated foot of some rats. The rats were checked daily for clinical signs of EAE: 3 + paralysis; 2 + weakness; 1 + flaccid tail. They were sacrificed by exsanguination while under anesthesia after paralysis was noted, or 16-21 days after immunization. Entire brain and spinal cord and samples of other organs were fixed in Bouin's fluid, embedded in paraffin, sectioned and stained with hematoxylin-eosin. For passive transfer of EAE, young donor rats were immunized with spinal cord, Freund's adjuvant and pertussis vaccine. Nine days later, when almost every rat was paralyzed, the lymph nodes draining inoculation sites were harvested, pooled, and processed rapidly, in the cold, into 271
Downloaded from http://geronj.oxfordjournals.org/ at Karolinska Institutet on May 23, 2015
Experimental allergic encephalomyelitis (EAE) was produced in 2- to 24-mo.-old F344 rats by active immunization and by passive transfer of lymphoid cells (adoptive immunization) from young rats. With both methods, some 24-mo.-old rats had a reduced, ability to develop this autoimmune disease. However, the immunological deficit was related to incidental serious diseases rather than to old age per se. The aged F344 rat is not a suitable model for comparing EAE to multiple sclerosis in man because the decreased incidence of multiple sclerosis after the age of 50 is not related to other serious illnesses.
LEVINEAND SO WINSKI
272
a cell suspension in Ringer's solution. Cells from 2 donors were injected into the penile vein of each recipient. Recipients were from the same inbred strain, as histocompatibility is essential for passive transfer, but they were of various ages. RESULTS
Table 1. EAE in Rats of Various Ages. Age (Mo.)
Onset* (Days)
Signs' (Score)
1: Cord, CFA, Pert
2 6 12 18 24
8888 8 9 9 10 9999 11 11 12 14 11 13 16 —
3333 3333 3333 3332 33 1 -
2: Cord, CFA
6 24
12 13 13 -
22 1 --
3: BP, CFA, Pert
6 24
13 13 13 14 15
33333
Immunization'
4: BP, CFA
b
15 15 16 18
3321
24 "Guinea pig spinal cord or basic protein (BP) emulsified in complete Freund's adjuvant (CFA), with or without simultaneous injection of pertussis vaccine concentrate (Pert). 'Day of onset and maximum score of severity of clinical signs for individual rats, recorded in the same order. A hyphen represents absence of signs during entire experiment, in the First experiment, half of each group of rats were orchidectomized; this procedure did not influence the results.
0.86 to 2.55 gm (0.23 to 0.71% of body weight)
not including the leukemic rat, compared to 0.25 to 0.75gm (0.10 to 0.29%) for 6-mo.-old rats. Many of the old rats also had chronic kidney disease, scarred liver, peripheral neuropathy, neuroaxonal dystrophy of the gracile and cuneate nuclei of the brain, and small nodules in the adenohypophysis. Thymuses were very atrophic. The heart was not studied. Despite this impressive array of coincidental diseases, histologic examination of the inoculated feet and the draining popliteal lymph node did not reveal any deficiency in processing of the antigenic inoculum. This raised the question whether the deficiency in old rats resided in the process of immunization or in the interaction of immunized cells with the neural target. To help elucidate this problem, we produced EAE by passive transfer of fully immunized lymph node cells from 2- to 3-mo.-old donors to immunologically naive recipient rats of various ages. In each of two trials, the cells were given to pairs of rats aged 2, 6,12,18, and 24 mo. After 6-8 days, all recipients 2, 6, 12, and 18 mo. old developed mild clinical signs of EAE (flaccid tail), confirmed histologically. Necropsy of these younger rats revealed only mild splenic hemosiderosis and early testicular tumors. The results in the 24-mo.-old rats differed between the two trials. In the first trial, (experiment 5, Table 2), the 2 old rats developed clinical signs and histologic lesions equal to the younger animals. Necropsies revealed only mild spenomegaly, testicular tumors and mild chronic pyelonephritis. One old rat had carcinoma of the colon which was localized and nonobstructive. In the second trial (experiment 6, Table 2), 2
Downloaded from http://geronj.oxfordjournals.org/ at Karolinska Institutet on May 23, 2015
In response to intense immunization with spinal cord antigen, Freund's adjuvant and pertussis vaccine, rats aged 2, 6, and 12 mo. developed EAE with almost uniform speed and severity. A lesser response in 18- and 24-mo.old rats was indicated by a somewhat protracted incubation period in all, and milder or absent signs in a few (Table 1). Less intense immunization (without pertussis vaccine or with 1 \xg of myelin basic protein) lengthened the incubation period, but almost every 6-mo.-old rat developed clinical signs. In contrast, not a single 24-mo.-old rat developed clinical EAE under these conditions (Table 1). Although these data clearly indicated an agerelated decline in susceptibility to EAE, the interpretation was clouded by the array of pathologic lesions revealed by necropsies of the old rats (confirming observations of Sass, Rabstein, Madison, Nims, Peters, & Kelloff, 1975). Every 24-mo.- and an occasional 18-mo.-old rat had large interstitial cell tumors of both testes, but this particular lesion was proved to be unimportant by the first experiment recorded in Table 1. In this experiment, half of the rats in each group had been bilaterally orchidectomized 1 week before immunization.
The removal of the normal testes (2- to 18-mo.old rats) or tumor-bearing testes (24-mo.-old rats) had no effect on the onset or severity of clinical EAE. Other lesions were probably much more significant. The 1 24-mo.-old rat that was completely refractory to EAE in the first experiment had chronic myelogenous leukemia involving spleen (weight 4.4gm), marrow, and liver. The rat in the same group with a protracted incubation period had a very extensive mesothelioma involving all peritoneal surfaces. All of the 24-mo.-old rats had extramedullary hematopoiesis, hemosiderosis, and passive congestion of the spleen. Spleens weighed from
ALLERGIC ENCEPHALOMYELITIS IN A GED RA TS
Table 2. Necropsy Findings in 24-Mo.-Old Rats. Exp.
No. 1
2 3
5 6
0.86 0.86 1.03 4.42 1.09 1.18 0.98 1.04 1.23 1.78 2.55 1.00 1.01 1.06 1.24 0.98 1.13 2.84 10.35
Other Lesions' T,N,L,K T.N.L, K T, N, K, mesothelioma T, N, K, leukemia T,N T.N.L.K T, N, fibrosarcoma (skin) T, N, sebaceous adenoma T,N, epidermal cyst T,N T,N,L T,N, K T,N T, N, mammary fibroma T.N.L.K T, N, K, carcinoma of colon T,N, K T, N, L, K, leukemia, pheochromocytoma T, N, L, K. leukemia
"Splenomegaly was due to cxtramedullary hematopoiesis, hemosiderosis, and passive congestion except where leukemia is stated. T - testicular tumors, N = neuropathy, L = liver disease, K = kidney disease.
24-mo.-old rats did not develop signs or lesions of EAE. Necropsy revealed that both of them had leukemia with severe splenomegaly and infiltrates in liver, as well as pylonephritis. DISCUSSION
The failure of 2 out of 4 old passive transfer recipients to develop EAE, despite the infusion of potent encephalitogenic cells from young donors, indicates a deficit in the recipient's environment and probably in the nonspecific components of the inflammatory response in the target organ. The discrepancy between the two trials, however, suggests that the deficit in these 2 old rats is more readily correlated with specific disease states, especially leukemia, than with old age, per se. Although we have no direct evidence for this interpretation, it is supported by the extensive leukemic infiltration of lymphoid organs which might have immunosuppressed the recipients as much as treatment with cytotoxic drugs (Levine & Hoenig, 1971). The numbers of old rats are small, but our interpretation is supported by the results of active immunization. In experiment 1 (Table 1), the intensive immunization was partially or completely ineffective only in the old rats that had leukemia or a very extensive mesothelioma. In experiments 2, 3, and 4, where the immunization was less intense, EAE was inhibited in old rats even in the absence of leukemia.
However, none of these rats was free of disease (Table 2). Chronic kidney and liver disease and peripheral neuropathy may inhibit immune processes directly or by activation of the adrenal cortex, or they may indicate the presence of a nutritional deficiency. The occurrence of extramedullary hematopoiesis and hemosiderosis in the spleen may indicate a chronic hemolytic state or other hematologic abnormality: although some splenic changes were noted in rats as young as 6 mo., the hematologic abnormality may have greater immunosuppressive effects in old age. The development of EAE is dependent on an intact lymphoid system. It is well known that the lymphoid system undergoes atrophy and has decreased ability to mount T-cell immune responses with advancing age (Walford, 1969, Roberts-Thomson, Whittingham, Youngchaiyud, & Mackay, 1974). Therefore, the results in any individual rat probably depend on a balance between the intensity of the immunizing regimen, the "normal" atrophy of lymphoid tissues, and the immunosuppressive effects of specific disease states. Onset of multiple sclerosis in man is rare after the age of 50, during the period of life when the passage of time has left an obvious imprint but no major systemic illness is likely to be present. The 24-mo.-old F344 rat is not a good model for this presenile period of human life because of the multiplicity of specific illnesses (Sass et al., 1975). The 18-mo.- old F344 rat may be a better model, but even these animals had splenic changes and peripheral neuropathy. Probably a strain with a longer life-span would be a better model for studying the immunopathology of the presenile period. Some specific diseases associated with advanced age in rats were strongly inhibitory to development of EAE (leukemia), while others were inconsequential (interstitial cell tumors of testes) and others have not been evaluated. Our work emphasizes the needs for better models of aging in rodents (Gibson, 1972) and for complete necropsies to insure proper and critical evaluation of the data. REFERENCES
Gibson, D. C. (Ed.) Development of the rodent as a model system of aging. Publication No. 72-121, NIH, Bethesda, 1972. Kurland, L. T. Epidemiologic characteristics of multiple sclerosis. American Journal of Medicine, 1952,12, 561571.
Downloaded from http://geronj.oxfordjournals.org/ at Karolinska Institutet on May 23, 2015
4
Spleen (Grams)"
273
274
LEVINEAND SO WINSKI
experimental correlates. In M. Samter (Ed.), ImmunoLevine, S. Relationship of experimental allergic encephalological diseases, 2nded. Little, Brown, Boston, 1971. myelitis to human disease. Research Publications of Association for Research in Nervous & Mental Diseases, Roberts-Thomson, I. C , Whittingham, S., Youngchaiyud, U., & Mackay, I. R. Aging, immune response, and mor1971,49, 33-49. tality. Lancet, 1974, //, 368-370. Levine, S., & Hoenig, E. M. A new form of localized allergic encephalomyelitis featuring polymorphonuclear Sass, B., Rabstein, L.S., Madison, R., Nims, R.M., Peters, R. L., & Kelloff, G. J. Incidence of spontaneous neoneutrophilic leukocytes. American Journal of plasms in F344 rats throughout the natural life-span. Pathology, 1971,64, 13-30. Journal of National Cancer Institute, 1975, 54, 1449Paterson, P. Y., Drobish, D. G., Hanson, M. A., & 1456. Jacobs, A. F. Induction of experimental allergic encephalomyelitis in Lewis rats. International Archives of Walford, R. L. The immunologic theory of aging. Williams & Wilkins, Baltimore, 1969. Allergy & Applied Immunology, 1970,37, 26-40. Paterson, P. Y. The demyelinating diseases: Clinical and
Patricia C. MacKeen was the recipient of the award for the outstanding student paper presented at the Gerontological Society's 1975 scientific meeting in Louisville. Her paper, Cytophotometric Determination of Cytoplasmic Azure B RNA Levels Throughout the Life-Span of Tokophrya lemnariwn, was cowritten with Dr. Robert B. Mitchell at the Pennsylvania State University, where Ms MacKeen is a doctoral candidate in physiology.
Downloaded from http://geronj.oxfordjournals.org/ at Karolinska Institutet on May 23, 2015
1975 Biological Sciences Section Student Award
