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Lymph node histology and antigen transmission in the nu/nu mouse in response to animal inoculation with Crohn's disease tissue filtrates were re-evaluated. We found that a hyperplastic lymph node response in nu/nu mice occurred with Crohn's disease (CD), ulcerative colitis (UC), or other intestinal disease (OID) tissue inoculations. In addition, antigen transmission to lymph nodes as detected by indirect immunofluorescence using CD sera was observed in all inoculation groups. The immunofluorescent reaction also occurred independently of lymph node histology. Thus, we confirm that CD sera recognize an antigen(s) expressed in lymph nodes of athymic mice inoculated with CD tissue filtrates. The antibody (or antibodies) in CD sera was not specific for this 'CD antigen or antigens', however, as tested in the nu/nu mouse system, because the CD sera antibodies also recognised antigens in UC inoculated and OID inoculated animals.

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It is obvious from the above discussion that, whereas no really clear-cut animal model of IBD has been established, a number of specific insights into the nature of the human illness can be derived from the study of naturally occurring and induced gastrointestinal inflammations occurring in animals. One of the most important emerges from the finding that both immune complex deposition in the gastrointestinal tract as well as stimulation of the mucosal T-cell system results in an ulcerative colitis-like gastrointestinal inflammation. The simplest explanation of the fact that vastly different methods of inducing immune-mediated injury in the gastrointestinal tract can lead to a similar kind of gastrointestinal inflammation is that the inflammatory response in the gastrointestinal tract is rather restricted in its overall pathologic appearance and that the histologic lesions characteristic of ulcerative colitis and Crohn's disease can arise from primary disturbance of the B-cell system, the T-cell system, or both. Another explanation of this fact, however, is that no matter what the initial immunological disorder may be, the mechanism underlying the gastrointestinal inflammation ultimately comes to involve a response to materials in the mucosal environment so that pathologic events are inevitably channeled into an inflammatory pathway that is either ulcerative colitis-like or Crohn's disease-like in its final configuration. This second explanation is buttressed by other findings derived from the study of animal models which, in general, suggest that no matter what the initial result, an immunologic interaction against a constituent of the bowel flora determines the ultimate course of the gastrointestinal inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)

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This study was undertaken to demonstrate whether lymphocytes derived from patients with Crohn's disease and their household contacts would demonstrate increased reactivity upon exposure to tissue homogenates prepared from the terminal ileum of patients with Crohn's disease. It was demonstrated that 4 of 18 patients, 9 of 30 household contacts, and 0 of 13 control subjects exhibited statistically greater lymphocyte thymidine incorporation in response to Crohn's tissue homogenates (contacts vs control, P = 0.025) [Fisher Exact Test (FET)]. However, homogenates prepared from the terminal ileum of control subjects without inflammatory bowel disease also induced lymphocyte reactivity in 1 patient, 5 contacts, and 1 control subject. Factors may be present in homogenates prepared from human terminal ileum which induce lymphocyte reactivity in some patients with Crohn's disease and household contacts.

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Homogenates from the terminal ileum of a patient with Crohn's disease with granulomas were prepared as snap-frozen or fresh and were injected into the ascending colonic walls of New Zealand white rabbits. Control animals were injected with 1 per cent bovine serum albumin alone. The rabbit bowel was examined after 1 year, and lesions were noted in each of the rabbits injected with Crohn's disease homogenate, irrespective of the type of tissue preparation. The observed lesions were diffuse and occurred both at the injection site and in the terminal ileum. These changes were not noted in the control group. This work confirms earlier results in the same animal model and suggests that either fresh or snap-frozen homogenates will produce the intestinal lesion but that bovine albumin alone will not.

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Normal and immunodeficient CBA and A2G strain mice were inoculated with crude (100 to 20 to 30 micrometer), cell-free (0.2 micrometer) filtrates of Crohn's or noninflammatory bowel disease tissue homogenates, which were either fresh or frozen to -70 degree C. Mice of each strain developed epithelioid and giant cell granulomas both locally at the site of injection and systemically in response to crude and cell-free filtrates of Crohn's tissues. Control mice did not develop such changes. The granulomas evolved slowly, predominantly between 9 and 27 months. The granuloma-inciting agent has been shown to be present in ileum, colon, and mesenteric lymph nodes of patients with Crohn's disease and it withstands freezing to -70 degree C. The use of Crohn's tissues common to this study and one in rabbits previously reported, suggests that the induction of granulomas by this agent is not strain- or species-specific, and is independent of the immune status of CBA mice.

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Several animal transmission studies have indicated that Crohn's disease may be caused by a filterable agent. Filtrates of homogenized tissues were prepared from 8 patients with Crohn's disease, 9 patients with chronic ulcerative colitis, and 20 control patients without inflammatory bowel disease. Conventional bacteriological cultures and hypertonic cultures for cell wall-defective bacterial variants were performed on the filtrates. Bacterial revertants (parent forms) of cell wall-defective variants were obtained from filtrates of various tissues including mesenteric lymph nodes of all patients with Crohn's disease. In no instance were revertants cultured from tissue filtrates of the other patients. The 11 revertants isolated from the 8 patients were identified as Pseudomonas-like bacteria, most closely identifiable with group Va.

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Affected lymph nodes from 3 patients with Crohn's disease were homogenised and inoculated intramurally into the distal ileum of five piglets. The homogenates were also inoculated intramurally in the distal ileum of 15 rats and also by percutaneous injection intraabdominally in 15 rats and compared with the same number of animals of each species inoculated in the same manner with homogenates prepared from 3 patients with caecal cancer. There was no difference in weight increase between the animals inoculated with Crohn's tissue homogenate or control tissue homogenate. Neither did we find any macroscopic or microscopic changes in the animals inoculated with Crohn's tissue homogenate. We found a rather high frequency of mammary tumors in the rats inoculated with Crohn's tissue homogenate, although compared to the rats inoculated with control tissue homogenate there was no statistically significant difference. The negative results may be due to the method of preparing the tissue homogenate or to the use of lymph nodes instead of the bowel in preparing the homogenate, but may also be taken as support against the suggestion that a transmissible agent is present in Crohn's disease.

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The preliminary results of one of a series of prospective studies in the investigation of a possible transmissible agent in Crohn's disease are presented. Filtered human Crohn tissue homogenates was inoculated into eight germfree Sprague-Dawley rats, to test the reproducibility of recent reports suggesting a transmissible agent in regional ileitis. No histological changes were evident after 150 days, and no changes were observed in animals inoculated with non-Crohn tissue homogenates.

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Serum lymphocytotoxic antibodies (LCA) were detected in twenty-seven out of fifty-three (51%) patients with inflammatory bowel disease (IBD) and in twenty-three out of their fifty-three (43%) unaffected spouses. The prevalence of LCA in both groups was significantly increased (P less than 0.001) compared to that in age- and sex-matched controls (11%) or in control spouses (6%). Concordant expression of LCA occurred in sixteen out of the fifty-three (30%) patient-spouse pairs compared to only one out of the fifty-three (2%) control-spouse pairs (P less than 0.001). In contrast to the LCA results, heterophile antibody titres were similarly distributed in all four study groups. It is suggested that LCA may represent markers of infectious agents in IBD and that their occurrence in unaffected close contacts of patients may indicate transmission of such agents to these subjects.

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Recent reports have suggested a transmissible factor in the etiology of Crohn's disease, which had yet to be confirmed. The specificity of the transmission was tested with a disease control of ulcerative colitis as well as normal bowel. Twenty New Zealand White rabbits received inoculum of tissue homogenates from the terminal ileum of normal, ulcerative colitic, and Crohn's disease patients. This inoculum was injected into the wall of the ascending colon and the animals were examined after one year. Changes were noted consistently only in those animals receiving the Crohn's disease inoculum. These changes consisted of thickened bowel wall with increased mucosal folds, thickened mesenteric fat with some creeping, irregular areas of thin colonic mucosa, and hyperplastic mesenteric lymph nodes. The terminal ileum distant from the inoculum site was smooth with atrophic changes only in the Crohn's inoculated group of animals. These animals also had discrete collections of macrophages in colon or sacculus, mucosal and submucosal edema, and chronic inflammation of the colon. However, the characteristic features of Crohn's disease were not reproduced.

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The injection of rabbits' ileum with homogenates of both normal and Crohn's affected human bowel tissue gave Crohn's-like changes in 11 of 27 animals after six months, but 12 months after injection the rabbit bowel had reverted to normal. The addition of ampicillin to the homogenates prevented the appearance of these Crohn's-like changes in 12 out of 12 rabbits. These results are interpreted as providing evidence for a transmissible factor present in both normal and Crohn's affected bowel in the aetiology of Crohn's disease.

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All cases of Crohn's disease in the Nottingham area were ascertained and dates and places of domicile and work before and after onset of symptoms were noted. Similar information was taken from matched control subjects and the Pike and Smith (Biometrics 30:263-279, 1974) case control technique for evaluating clustering of patients in time and space was applied. These results do not support the infectious hypothesis.

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