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. 1985 Feb;75(2):502–512. doi: 10.1172/JCI111726

Structural and functional evolution of jejunal allograft rejection in rats and the ameliorating effects of cyclosporine therapy.

J L Madara, R L Kirkman
PMCID: PMC423525  PMID: 3973015

Abstract

We assessed the structural and functional evolution of small intestinal transplant rejection in a rat model by use of 1-micron section, electron microscopic, and in vitro electrophysiologic techniques to study jejunal mucosa 3, 6, and 9 d posttransplantation. The earliest structural abnormalities detected in jejunal loops transplanted from Lewis X Brown Norway F1 hybrids into Lewis rats occurred within 3 d posttransplantation and consisted of focal endothelial cell injury of the microvasculature and focal injury of crypt epithelial cells. Both alterations were associated with adjacent infiltration of large lymphoid cells, and both markedly progressed and became rather diffuse over the following 6 d. In contrast, villus absorptive cells were not markedly altered in structure until the 9th postoperative day. As compared with host jejuna, allograft jejunal epithelium demonstrated multiple functional abnormalities. Transepithelial resistance declined progressively by days 6 and 9 (both P less than 0.05), although baseline transepithelial spontaneous potential difference was only affected at day 9 (P less than 0.01). Stimulated absorption by allograft jejuna, as assessed by measuring electrical response to mucosal glucose, was not significantly diminished until day 9 (P less than 0.05). In contrast, stimulated secretion assessed by measurement of electrical response to serosal theophylline was diminished by day 6 (P less than .01). These data suggest that the earliest epithelial injury during rejection, as judged both structurally and functionally, occurs in the crypt and is paralleled by endothelial injury at the level of the microvasculature. Thus, the primary targets for rejection are most likely endothelial cells and crypt epithelial cells. In contrast, structural and functional impairment of villus epithelium is detectable only at substantially later times during rejection and are most likely secondary processes related to either ischemia produced by microvascular injury or decreased epithelial regenerative ability secondary to crypt injury. Last, we show that the detrimental structural and functional sequellae of jejunal transplantation across the major histocompatibility complex in this model is strikingly ameliorated with cyclosporine therapy.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alpers D. H., Tedesco F. J. The possible role of pancreatic proteases in the turnover of intestinal brush border proteins. Biochim Biophys Acta. 1975 Aug 5;401(1):28–40. doi: 10.1016/0005-2736(75)90338-7. [DOI] [PubMed] [Google Scholar]
  2. Anderson N. D., Wyllie R. G., Shaker I. J. Pathogenesis of vascular injury in rejecting rat renal allografts. Johns Hopkins Med J. 1977 Sep;141(3):135–147. [PubMed] [Google Scholar]
  3. Donowitz M., Madara J. L. Effect of extracellular calcium depletion on epithelial structure and function in rabbit ileum: a model for selective crypt or villus epithelial cell damage and suggestion of secretion by villus epithelial cells. Gastroenterology. 1982 Dec;83(6):1231–1243. [PubMed] [Google Scholar]
  4. Dvorak H. F., Mihm M. C., Jr, Dvorak A. M., Barnes B. A., Manseau E. J., Galli S. J. Rejection of first-set skin allografts in man. the microvasculature is the critical target of the immune response. J Exp Med. 1979 Aug 1;150(2):322–337. doi: 10.1084/jem.150.2.322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Epstein R. J., McDonald G. B., Sale G. E., Shulman H. M., Thomas E. D. The diagnostic accuracy of the rectal biopsy in acute graft-versus-host disease: a prospective study of thirteen patients. Gastroenterology. 1980 Apr;78(4):764–771. [PubMed] [Google Scholar]
  6. Forbes R. D., Guttmann R. D., Gomersall M., Hibberd J. A controlled serial ultrastructural tracer study of first-set cardiac allograft rejection in the rat. Evidence that the microvascular endothelium is the primary target of graft destruction. Am J Pathol. 1983 May;111(2):184–196. [PMC free article] [PubMed] [Google Scholar]
  7. Jonas A., Krishnan C., Forstner G. Pathogenesis of mucosal injury in the blind loop syndrome. Gastroenterology. 1978 Nov;75(5):791–795. [PubMed] [Google Scholar]
  8. Kirkman R. L., Lear P. A., Madara J. L., Tilney N. L. Small intestine transplantation in the rat--immunology and function. Surgery. 1984 Aug;96(2):280–287. [PubMed] [Google Scholar]
  9. MACDONALD W. C., TRIER J. S., EVERETT N. B. CELL PROLIFERATION AND MIGRATION IN THE STOMACH, DUODENUM, AND RECTUM OF MAN: RADIOAUTOGRAPHIC STUDIES. Gastroenterology. 1964 Apr;46:405–417. [PubMed] [Google Scholar]
  10. MESSIER B., LEBLOND C. P. Cell proliferation and migration as revealed by radioautography after injection of thymidine-H3 into male rats and mice. Am J Anat. 1960 May;106:247–285. doi: 10.1002/aja.1001060305. [DOI] [PubMed] [Google Scholar]
  11. Madara J. L. Increases in guinea pig small intestinal transepithelial resistance induced by osmotic loads are accompanied by rapid alterations in absorptive-cell tight-junction structure. J Cell Biol. 1983 Jul;97(1):125–136. doi: 10.1083/jcb.97.1.125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Madara J. L., Trier J. S. Structure and permeability of goblet cell tight junctions in rat small intestine. J Membr Biol. 1982;66(2):145–157. doi: 10.1007/BF01868490. [DOI] [PubMed] [Google Scholar]
  13. Orlando R. C., Powell D. W., Bryson J. C., Kinard H. B., 3rd, Carney C. N., Jones J. D., Bozymski E. M. Esophageal potential difference measurements in esophageal disease. Gastroenterology. 1982 Nov;83(5):1026–1032. [PubMed] [Google Scholar]
  14. Sale G. E., Shulman H. M., McDonald G. B., Thomas E. D. Gastrointestinal graft-versus-host disease in man. A clinicopathologic study of the rectal biopsy. Am J Surg Pathol. 1979 Aug;3(4):291–299. doi: 10.1097/00000478-197908000-00001. [DOI] [PubMed] [Google Scholar]
  15. Toskes P. P., Giannella R. A., Jervis H. R., Rout W. R., Takeuchi A. Small intestinal mucosal injury in the experimental blind loop syndrome. Light- and electron-microscopic and histochemical studies. Gastroenterology. 1975 May;68(5 Pt 1):1193–1203. [PubMed] [Google Scholar]
  16. Wagner R., Gabbert H., Höhn P. Ischemia and post-ischemic regeneration of the small intestinal mucosa. A light microscopic and autoradiographic study. Virchows Arch B Cell Pathol Incl Mol Pathol. 1979;31(3):259–276. doi: 10.1007/BF02889943. [DOI] [PubMed] [Google Scholar]
  17. Wehman H. J., Lifshitz F., Teichberg S. Effects of enteric microbial overgrowth on small intestinal ultrastructure in the rat. Am J Gastroenterol. 1978 Sep;70(3):249–258. [PubMed] [Google Scholar]
  18. Welsh M. J., Smith P. L., Fromm M., Frizzell R. A. Crypts are the site of intestinal fluid and electrolyte secretion. Science. 1982 Dec 17;218(4578):1219–1221. doi: 10.1126/science.6293054. [DOI] [PubMed] [Google Scholar]

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