ANIMAL MODEL OF HUMAN DISEASE

Alimentary Toxic Aleukia (Septic Angina, EndemicPanmyelotoxicosis, Alimentary Hemorrhagic Aleukia)

T-2 Toxin-Induced Intoxication of Cats

I. I. LUTSKY, MS, VMD, and N. MOR, DVM, PhD From the Department of Comparative Medicine, HebrewUniversity-Hadassah Medical School, Jerusalem, Israel

Biologic Features

Alimentary toxic aleukia (ATA), a frequently fatalmycotoxicosis, follows the ingestion of overwinteredgrain or grain by-products infested with fungi, andprimarily affects poor rural families in the USSR.1 2ATA in man is characterized by leukopenia, agranu-locytosis, necrotic angina, a hemorrhagic rash, sep-sis, exhaustion of the bone marrow, bleeding fromthe nose, throat, and gums, and fever.34 The toxicmetabolites of fusarial species have been intensivelystudied in efforts to establish the specific etiology ofATA.5-15 Studies with rats, mice, guinea pigs, rab-bits, dogs, swine, sheep, poultry, cattle, and horseswere unsuccessful in the search for an animal model.4The syndrome of ATA has been induced in cats by

administration of the sesquiterpene T-2 toxin (3a-hydroxy4p, 15-diacetoxy-8a-[3-methylbutyroloxy]12, 13-epoxytrichothec-9-ene), a naturally occurringtrichothecene isolated from Fusarium sporotrichi-oides.12"3 T-2 toxin in gelatin capsules, administeredevery 48 hours per os to healthy cats (dosage: 0.08mg/kg body weight), regularly resulted in a fataldisease (average survival time: 3 weeks) with symp-toms of generalized lassitude, weakness, bloody feces,hind-leg ataxia, conjunctivitis, and vomiting. In theterminal stages, anorexia, dyspnea and paralysis werenoted, while dehydration and weight loss (average22%) were more severe.

Gross postmortem findings included severeemaciation, enlarged and hemorrhagic lymph nodes,hemorrhages of the gastric and intestinal mucosa,

lung congestion, petechiae and ecchymoses of themyocardium, and subcutaneous hemorrhages.

Microscopic observations of the alimentary tractshowed erosion of the gastric epithelium, frequentlywith bacterial invasion and cryptitis (Figure 1); ne-crosis of intestinal villi and deep glandular epitheli-um; erythrocytic aggregations in capillaries of thevilli. Additional histologic findings included: hyper-emia of the subcapsular and medullary sinuses of alllymph nodes: hemosiderosis in the spleen, lung, andlymph nodes; and pulmonary congestion and edemaof the lungs. In the spleen depletion of lymphocytesfrom the germinal centers was evident; desquamationof the sinus epithelium was pronounced (Figure 2);and marked erythrophagocytosis reflected the irrita-tion of the reticuloendothelium. Bone sections, reflect-ing severe damage to hematopoiesis, showed hemor-rhagic marrow, hypocellularity, numerous multinu-cleated giant cells throughout the stroma (Figure 3),fibrinoid material in the sinusoids, and large vacuolesreflecting fatty changes.A generalized decrease in circulating blood cells

with anemia, leukopenia, and thrombocytopenia wasa constant hematologic finding in all cats intoxicatedwith T-2 toxin. A slight initial leukocytosis was fol-lowed by a severe progressive leukopenia. Neutro-

Accepted for publication December 8, 1980.Address reprint requests to Irving Lutsky, VMD, Depart-

ment of Comparative Medicine, The Hebrew University-Hadassah Medical School, P.O. Box 1172, Jerusalem, Israel.

0002-9440/81/0807-0189$00.65 © American Association of Pathologists

189

190 LUTSKY AND MOR

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Figure 1-Gastric epithelium (fundus) of cat, after 14 doses of T-2toxin, showing surface erosion, ulcerative cryptitis, and invasion ofthe mucosa by bacterial colonies. (H&E, x 100)

phils were enlarged and showed bizarre nuclear pat-terns and blue foamy cytoplasm; erythrocyte changesincluded anisocytosis, macrocytosis, and poly-chromatism; and thrombocytes showed unusualforms, eg, giant platelets. During intoxication,packed cell volume and hemoglobin concentrationwere reduced, while the erythrocyte sedimentationrate was greatly elevated. Prolonged bleeding timeand whole blood coagulation time reflected defectivehemostasis.

Comparison With Human Disease

ATA in man initially includes inflammation of thegastric and intestinal mucosa, a severe progressiveleukopenia, anemia, and an increased erythrocytesedimentation rate. Subsequently petechial hemor-rhages of both the skin and mucosa together with en-larged lymph nodes are seen. Pancytopenic abnor-malities intensify, and blood coagulation is dimin-ished. The pathologic features of the respiratorysystem include bronchopneumonia, pulmonaryhemorrhages, sepsis, and lung abscesses. Vomiting,bloody feces, lassitude, and incoordination are alsoobserved. All of the clinical features, the pancyto-penia, and the gross and microscopic pathologicchanges seen in cats receiving T-2 toxin via the ali-mentary route were strikingly similar to the diseasesyndrome of alimentary toxic aleukia in man. 1,3-5

Usefulness of the Model

This feline model provides for greater insight into

Figure 2-Section of spleen fromcat, after 14 doses of T-2 toxin,showing depletion of lymphocytes,desquamation of the sinus endothe-lium, and marked erythrophagocy-tosis. (H&E, x 500)

AJP * August 1981

Vol. 104 * No. 2 ALIMENTARY TOXIC ALEUKIA 191

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Figure 3-Section of sternal bone ' qv-from cat after 20 doses of T-2 toxi1n,showing hypoplasia of the marrowand many multinucleate giant cellsscattered throughout the stroma;sinusoidal congestion is pro-nounced. (H&E, x 400)

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the pathogenesis, therapy, and immune features'4 ofmycotoxicoses generally, and trichothecene-induceddisease specifically. The model allows for study of theeffects of long-term trichothecene ingestion; providesfor detection of early mycotoxic changes before irre-versible effects occur; can aid in improving tech-niques for identification and measurement of myco-toxins in tissues, body fluids, and excreta; andenables the study of trichothecenes 1) as inhibitors ofprotein synthesis and 2) in carcinogenesis. The cat isa laboratory animal large enough for evaluating thepharmacologic, pathologic, hematologic, biochemi-cal, immunologic, and clinical aspects of alimentarytoxic aleukia and analogous disease.

Availability

T-2 toxin is produced by Makor Chemicals Ltd.,P.O. Box 6570, Jerusalem, Israel. Cats remain readilyavailable laboratory animals, whose general goodhealth and immunity to feline panleukopenia shouldbe established prior to their use in ATA studies.

References

1. Mayer CF: Endemic panmyelotoxicosis in the Russiangrain belt. Military Surgeon, 1953, 113:173-189

2. Forgacs J, Carll WT: Mycotoxicoses. Advances Vet Sci1962, 7:273-382

3. Chilikin VI: Osobennosti i spornye voprosy Kliniki,patogeneze i lecheniia alimentarno-toksicheskoi aleikii.Acta Chkalov Inst Epidemiol Microbiol 1947, 2:145-151

4. Joffe AZ: Alimentary Toxic Aleukia, Microbial Toxins.Edited by S Kadis, A Ciegler, SJ Ajl. New York, Aca-demic Press, 1971, pp 139-189

5. Sarkisov AC: Mikotokochsikozi. State PublishingHouse for Agriculture Literature, Moscow, 1954

6. Joffe AZ: Toxicity and antibiotic properties of someFusaria. Bull Res Counc Israel 1960, 8D:81-95

7. Bamburg JR, Strong FM, Smalley EB: Toxins frommoldy cereals. J Agr Food Chem 1969, 17:443-450

8. Ueno Y, Sato N, Ishii K, Enomoto M: Toxicologicalapproaches to the metabolites of Fusaria. Jpn J ExpMed 1972, 42:461-472

9. Yagen B, Joffe AZ: Screening of toxic isolates of Fusa-rium poae and Fusarium sporotrichioides involved incausing alimentary toxic aleukia. Appl Environ Micro-biol 1976, 32:423-427

10. Yagen B, Joffe AZ, Horn P, Mor N, Lutsky II: Toxinsfrom a strain involved in ATA, Mycotoxins in Humanand Animal Health. Edited by JV Rodricks, CW Hes-seltine, MA Mehlman. Park Forest, IL, Pathatox, 1977pp 329-336

11. WHO Task Group on Environmental Health Criteriafor Mycotoxins: Mycotoxins. Environmental HealthCriteria II, World Health Organization, Geneva, 1979

12. Lutsky I, Mor N, Yagen B, Joffe AZ: The role of T-2toxin in experimental alimentary toxic aleukia: A toxic-ity study in cats. Toxicol Appl Pharmacol 1978, 43:111-124

13. Lutsky I, Mor N: Experimental alimentary toxic aleu-kia in the cat. Lab Animal Science 1981, 31:43-47

14. Chu FS, Grossman S, Wei RD, Mirocha CJ: Produc-tion of antibody against T-2 toxin. Appl Environ Mi-crobiol 1979, 37:104-108