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Inflammatory bowel disease is a familial disorder of unknown etiology, characterized by a variety of immunological abnormalities for which there are no proven genetic markers. Studies of immunoglobulin heavy chain and light chain allotypes were undertaken in 89 patients with Crohn's disease and in 18 families with ulcerative colitis or Crohn's disease in at least two first-degree relatives, to search for association and/or linkage between a postulated disease susceptibility locus and an immunoglobulin allotype locus. No evidence of association or linkage with a specific immunoglobulin allotype was found.

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Because little is known about eosinophils of the human intestine, we measured their C3b and Fc gamma receptor expression and phagocytic activity in mucosal suspensions from colon resections for large bowel neoplasms. Enzymatically dissociated suspensions were enriched for eosinophils by countercurrent centrifugation. C3b and Fc gamma receptors were measured by immunofluorescent assays with flow cytometry. Phagocytosis of Escherichia coli ON2 was determined by an in vitro microscopic method. Suspensions of normal tissue from neoplasm resections yielded 1.8 X 10(6) eosinophils/g mucosa, and these cells were more numerous than either macrophages or neutrophils. Fivefold enrichment was achieved by countercurrent centrifugation, and 75% of these cells expressed C3b receptors and 90% expressed Fc gamma receptors. Sixty-seven percent of mucosal eosinophils were phagocytic for E. coli ON2 and ingested a mean of 4.7 bacteria per cell. Eosinophils accounted for more overall phagocytic activity than either neutrophils or macrophages.

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To better characterize Crohn's disease in the elderly, 24 patients ranging in age from 64 to 85 years were reviewed and compared with a younger group (20 to 61 years of age) matched for sex and duration of disease. Forty-one variables encompassing clinical, laboratory, and radiologic data and medical and surgical aspects of treatment were analyzed. The older group was characterized by a longer delay in diagnosis, more hematochezia, and a higher incidence of diverticular and cardiovascular disease. Elderly patients had less pain, less often a palpable abdominal mass, less small-bowel disease, less drug treatment, and no family history of inflammatory bowel disease. Otherwise, the disease in the two groups had similar manifestations, and no discriminating features to enable easy diagnosis in the elderly were found. Crohn's disease must be considered when evaluating older patients with diarrhea, abdominal pain, weight loss, and bleeding.

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In vitro cellular cytotoxicity of mononuclear cells of intestinal mucosa and peripheral blood for a colon cancer cell target was measured in patients with colon cancer and other disorders requiring resection. Four- and 24-hour cytotoxicity assays were conducted using selenium 75 (75Se)-labeled RPMI-4788 human colon cancer target cells grown in culture. In the cancer group mean cytotoxicity was 30.4% at 24 hours for peripheral blood effectors and 8.0% for effectors from normal mucosa. Values in patients with Crohn's disease were 10.4% for blood and 17.2% for effectors from normal mucosa, and 13.6% and 18.5%, respectively, for blood and abnormal mucosa. Values in patients with other diseases were 25% for blood and 14.7% for mucosa. Mean cytotoxicity at 4 hours did not exceed 6.4% for any group, and assays in autologous serum gave results similar to tests in calf serum. In additional studies, K 562 chronic leukemia cells were somewhat more sensitive to lysis than RPMI-4788 by blood mononuclear cells, but there was no lysis of K 562 by mucosal populations that were cytotoxic for RPMI-4788. There was no competitive inhibition by either target cell for the other. It was concluded that 75Se RPMI-4788 colon cancer cells are suitable targets for evaluating in vitro cytotoxicity by intestinal mucosal cells and that mucosal cytotoxicity in patients with colon cancer is depressed compared to cytotoxicity by peripheral blood effectors.

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Phagocytosis and cellular cytotoxicity by mononuclear phagocytes of blood and intestinal mucosa were studied in patients with Crohn's disease and large bowel neoplasms. Antibody coated sheep erythrocytes were used for phagocytic assays and cellular cytotoxicity in vitro was measured by 24 hour isotope release from 75Selenium methionine-labelled RPMI 4788 human cancer cell cultures in the presence of mononuclear phagocyte-enriched effector populations. The mean percent of mononuclear phagocytes in Ficoll-Hypaque purified mononuclear cell suspensions of blood of healthy controls was 25.9 compared with 44.6 in patients with Crohn's disease, 45.6 in patients with colon neoplasms and 11.6 in intestinal mucosa. Phagocytic indices were similar in all groups, but the phagocytic capacity of mucosal macrophages was twice that of blood monocytes. Mean cytotoxicity of monocytes of patients with Crohn's disease was 12.8% compared with 22.9% for monocytes from normal controls, and 29.4% for patients with colon tumours. Mean cytotoxicity by mucosal macrophages was 18.0% compared with 13.2% by mucosal lymphocyte populations. Exposure of monocytes of Crohn's disease patients to bacterial lipopolysaccharide modestly increased cytotoxicity, but exposure did not alter phagocytosis by monocytes of patients or controls. The results indicate that monocytes of patients with Crohn's disease exhibit subnormal in vitro cytotoxicity. Mucosal macrophages from patients with various diseases show enhanced phagocytosis compared with blood monocytes, and they can mediate cellular cytotoxicity in vitro.

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Cytotoxicity of peripheral blood mononuclear cells of 30 patients with Crohn's disease (CD) and 30 matched controls was assayed by measuring isotope release from 75Se-L-methionine labelled RPMI 4788 human colon cancer cells. Effector populations were studied with and without monocyte depletion after 4 and 24 hr incubations in 10% fetal calf serum or autologous serum or plasma. Cytotoxicity was negligible at 4 hr. Twenty-four hour cytotoxicity was consistently lower in CD patients than in healthy controls, mean values ranging from 13.6 +/- 2.7% (s.e.m.) to 19.5 +/- 3.7% in patients and from 27.2 +/- 4.1% to 33.6 +/- 5.3% in controls. Cytotoxicity of disease controls was not significantly different from that of healthy subjects. Cytotoxicity was reduced by monocyte depletion, was weakly and inversely related to disease activity, was relatively stable for up to 24 months and was not HLA restricted. Cell lysis was attributable to spontaneous cell-mediated cytotoxicity. Antibody-dependent cellular cytotoxicity and antibody-complement-dependent cytotoxicity were not detected.

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In a retrospective survey, patients with Crohn's disease who were HLA B8 were found to have significantly fewer granulomas in rectal biopsies (p less than 0.002) and in resected bowel specimens (p less than 0.02) than non-HLA B8 patients. No statistically significant difference was found between HLA B12 and non-B12 patients. This in vivo evidence of differing immune response capabilities between HLA B8 and non-HLA B8 individuals is compatible with previously reported in vitro studies. Despite these differences, the clinical manifestations and disease course of the two groups of patients was similar, suggesting that neither the presence of HLA B8 nor the development of granuloma directly influence the course of Crohn's disease.

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Based upon studies of patients with inflammatory bowel disease, Clostridium difficile and an associated cytotoxin have been proposed as contributory factors in relapse of disease. These studies have not included a comprehensive search for other bacterial pathogens. Fifty patients with Crohn's disease were investigated to determine if selected enteric pathogens colonize the bowel and if they play a role in the activity of the disease. Clostridium difficile was recovered from 8% of patients, all with inactive disease, and recovery of the organism did not presage relapse. Except for Salmonella species in one asymptomatic patient, no other bacterial pathogens were isolated. It was concluded that Clostridium difficile may be part of the bowel flora of patients with Crohn's disease without relationship to activity of disease.

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Mechanical, enzymatic and chelating methods for isolating rat intestinal epithelial cells were compared to determine the best technique for obtaining high yields of viable cells. The mechanical techniques resulted in consistently poor viability compared with the other methods. There was excellent agreement between viability determinations made by trypan blue exclusion and by cytofluorochromasia. Incubation with EDTA, citrate and dithiothreitol, combined with mechanical extrusion of dissociated cells provided the highest yields of viable cells in these studies.

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To look for possible HLA linkage in familial Crohn's disease, HLA haplotype segregation patterns were determined in 70 members of five kindreds, each having 2 or more patients with Crohn's disease (total number: 13 with Crohn's disease, 1 with ulcerative colitis). Concordant segregation of HLA haplotypes and disease was not observed. Study of HLA A and B locus phenotypes in 64 additional patients with documented Crohn's disease failed to show any significant disease association. We conclude that in these kindreds, HLA linkage does not account for the familial susceptibiltiy to Crohn's disease and that HLA A and B locus antigens are not associated with Crohn's disease.

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Lymphocyte subpopulations in peripheral blood (PBL) and intestinal mucosa (IML) of 10 patients with inflammatory bowel disease (IBD) were compared with those of 11 non-IBD controls. PBL were separated on Ficoll/hypaque gradients, and IML were isolated by incubation in dithiothreitol, EDTA, and collagenase. These methods yielded cells of good viability and with intact HLA A and B-antigens. T-cells, identified by neuraminidase-treated sheep RBC rosettes and non-specific esterase staining, comprised approximately 91% of the IML from normal mucosa of all groups. B-cells, identified by erythrocyte-antibody-complement rosettes and surface immunoglobulins, were only 7% of these IML populations. Cell yields were two-fold or more greater from abnormal IBD mucosa, with T-cells ranging from 55 to 95% and B-cells from 2 to 36%. The percentage of Fc receptor bearing cells was low in all specimens. By these methods, T-lymphocytes predominated in intestinal mucosa of both IBD and non-IBD patients, but there is marked increase in the percentage of B-cells isolated from abnormal mucosa in IBD.

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Peripheral blood leukocyte counts, percentages of lymphocytes and granulocytes, serum albumin levels, and results of skin tests with five antigens were examined in patients randomized in the National Cooperative Crohn's Disease Study. Inspection for differences from normal and correlations with a variety of variables showed no unusual characteristics except for a high incidence of anergy (31%) at randomization, and ranging up to 47.5% after treatment.

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Rectal biopsies from healthy control subjects, and from patients with Crohn's disease whose rectal mucosa appeared normal by sigmoidoscopy and light microscopy, were examined by scanning electron microscopy. Appearances within both groups were quite variable, and no clear differences between the groups could be distinguished.

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A 63-year-old man with Waldenstrom's macroglobulinemia had severe steatorrhea, marked protein-losing enteropathy, and excessive endogenous fecal calcium clearance. The malabsorption and protein loss resulted in weight loss and hypoalbuminemia. In contrast, the striking enteric calcium loss was completely compensated by an increase in calcium absorption resulting in a positive calcium balance.

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Crohn's-disease tissue was tested by indirect immunofluorescence for antigens of rotavirus, Pseudomonas maltophilia, and Mycobacterium kansasii. No reactions were obtained with anti-serum to P. maltophilia and M. kansasii, and a granular fluorescence seen with rotavirus antibody was probably non-specific.

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220 nm filtrates of intestinal resections from 6 of 10 patients with Crohn's disease produced a cytopathic effect in WI-38 tissue-culture monolayers, whereas controls had no effect. Characterisation of the virus responsible has been completed in 3 of the 6 positive isolates and indicates that it is an R.N.A. virus, 55-60 nm in diameter, heat, ether, and acid stable, and antigenically related to Nebraska calf-diarrhoea virus. It therefore belongs to the Reoviridae family.

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Calcium absorption and endogenous loss of calcium were measured in a group of patients with Crohn's disease, using a simultaneous metabolic balance and calcium isotope regimen. Calcium malabsorption resulting in negative calcium balance was found in only 4 of 31 patients with Crohn's disease. No elevation of endogenous fecal calcium or total secreted intestinal calcium was observed in 10 patients studied, regardless of the level of net or true calcium absorption. Correlation between calcium balance and serum protein loss was observed, but no association was noted with intestinal fat excretion, d-xylose absorption, bacterial colonization of the jejunum, or glucocorticosteroid therapy. The results indicate that in this group of patients with Crohn's disease involving different areas of the intestine, calcium malabsorption occurred infrequently and that the levels of calcium excretion correlated best with enteric protein loss.

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