The role of an anti-idiotype antibody in regulating hapten (azobenzenearsonate)-specific granuloma formation.

Antibody regulation of hapten-specific granulomas was studied in mice in order to assess the relationship between an anti-idiotypic antibody and granuloma formation. An anti-idiotypic antibody was raised against the idiotype of an azobenzenearsonate (ABA)-specific antibody of A/J mice. The anti-idiotypic antibody was subcutaneously (s.c.) administered to syngeneic mice prior to challenge with ABA-coupled polyacrylamide beads injected into the intestinal wall. The results of such a challenge were assessed histologically for granuloma formation at 24-h intervals. Mice primed with anti-Id antibody and challenged with ABA-linked beads developed epithelioid granulomas at 72 and 96 hr post-challenge. Unprimed mice or mice primed with control antibodies did not develop granulomas when challenged with ABA-linked beads. Moreover, we found that priming with anti-Id antibody intravenously (i.v.) resulted in suppression of intestinal granuloma formation that was similar to that observed previously after priming mice i.v. with ABA-coupled spleen cells (Ginsburg et al., 1982). This study demonstrates the induction and suppression of hapten-specific granuloma formation in the intestine by an anti-Id antibody. The observations indicate a role for the idiotype-anti-idiotype interaction in regulation of hapten-specific granuloma formation, and may have implications for the manner in which the host reacts against self in the autoimmune inflammatory process.

Prevention of granuloma development in the mouse by using T cell hybridoma products.

The ability of an azobenzenearsonate (ABA)-specific suppressor T cell factor, a soluble extract from first order suppressor T cells (Ts1), and suppressor molecules produced by a long-term T cell hybridoma to regulate ABA-specific granuloma formation was studied. ABA-derivatized syngeneic spleen cells (ABA-SC) administered subcutaneously induced persistent delayed-type hypersensitivity (DTH) responses, detected by footpad swelling and hapten-specific granuloma formation by 72 and 96 hr after challenge with ABA-bovine serum albumin coupled to polyacrylamide beads (ABA-BSA-PAB). Soluble factors from ABA-specific Ts1 prevented DTH and granulomatous development after subcutaneous administration of ABA-SC. Moreover, the in vivo administration of a factor that is derived from a Ts1 functioning hybrid cell line induced a second set of suppressor cells (Ts2) that upon transfer to syngeneic ABA-primed mice were able to inhibit granuloma formation in the footpad, as well as in the gastrointestinal tract after challenge with ABA-BSA-PAB. These experiments demonstrate the dependence of the granulomatous reaction on T cell-mediated events, as well as the potential therapeutic efficacy of an antigen-specific suppressor T cell factor and a hybridoma T cell product in limiting antigen-specific granuloma formation in vivo.

Impaired natural killer cell activity in patients with inflammatory bowel disease: evidence for a qualitative defect.

The natural killer cell lymphocyte may represent an important element in immune defense. Since host defense may be abnormal in patients with inflammatory bowel disease, we assessed natural killer cell function in 34 patients with ulcerative colitis and Crohn's disease. Lymphocytes from 31 of 34 patients (91%) exhibited decreased natural killer cell activity (mean cytotoxicity +/- SEM was 25% +/- 7.5% of the mean normal values, p less than 0.01). Disease activity, type of disease, and steroid therapy had no influence on these values. None of the 10 age-matched disease controls with other intestinal inflammatory conditions had natural killer cell activity outside the normal range. The numbers of circulating killer cells present in patients with impaired activity were quantified using a cytofluorometric detection system. All patients tested had normal numbers of cells binding nonaggregated immunoglobulin G (Fc receptor positive) despite decreased natural killer cell activity. It appears that by using this cytofluorometric detection technique, decreased natural killer cell activity is not the consequence of diminished numbers of natural killer cells.

Defective autologous mixed-lymphocyte reaction and suppressor cell generation in patients with inflammatory bowel disease.

Impaired regulation of immune function may contribute to the abnormal immune responses associated with idiopathic inflammatory bowel disease. We examined the autologous mixed-lymphocyte culture in inflammatory bowel disease patients because this reaction may reflect self regulation of immune responses in vivo and results in activation of suppressor T cells in vitro. We also examined suppressor T-cell generation in two separate assays. In contrast to healthy and disease controls who had normal values, the autologous mixed-lymphocyte culture response was diminished in 44 of 51 (86%) patients with inflammatory bowel disease, independent of disease type, activity, or steroid therapy. Fourteen of 17 inflammatory bowel disease patients (83%) had decreased suppressor T-cell generation. These results show a distinct abnormality in autologous mixed-lymphocyte culture reactivity and in generation of suppressor cells in inflammatory bowel disease. Such impaired immune regulation may be partly responsible for the immunologic aberrations observed in patients with inflammatory bowel disease.

Antigen- and receptor-driven regulatory mechanisms. X. The induction and suppression of hapten-specific granulomas.

We have investigated the induction and suppression of granuloma formation elicited by the azobenzenearsonate (ABA) determinant in A/J Mice. ABA-derived syngeneic spleen cells (ABA-SC) administered subcutaneously induced hapten-specific delayed hypersensitivity (DTH), detected by footpad swelling, upon challenge with ABA-bovine serum albumin (BSA) coupled to polyacrylamide beads (PAB). The reactions elicited by ABA-BSA-PAB reached maximal intensity at 24 hours but were relatively persistent and were still marked at 96 hours. Histopathologic examination of footpad responses at 24 and 48 hours after challenge revealed compact collections around beads of mononuclear cells and granulocytes, which were characteristic of DTH reactions. Discrete epithelioid granulomas became apparent by 72 or 96 hours. Unprimed mice or mice primed with ABA-SC and challenged with uncoupled beads did not develop either substantial leukocytic infiltrates or granulomas. Persistent delayed responses were only apparent if the mice were challenged with the homologous hapten-coupled bead, indicating the fine specificity of the reaction. Immune cells were shown to be capable of transferring DTH and granulomatous responsiveness to ABA; the cells were sensitive to anti-Thy 1.2 antiserum and complement, which indicates that the response was thymic-dependent. The intravenous injection of ABA-SC, which is known to induce suppressor cells, prevented the development of DTH or granulomatous responsiveness followinggg subcutaneous immunization with ABA-SC. In addition, the transfer of suspensions containing suppressor T cells into syngeneic mice primed with ABA-SC prevented the development of DTH reactions and granuloma formation followin challenge with ABA-BSA-PAB. Furthermore, only hapten-specific suppressor T cells limited persistent delayed hypersensitivity responses. Having successfully developed granulomas in the footpad, the authors induced and suppressed granulomatous lesions in the gastrointestinal tract in a similar fashion. These experiments establish a model in inbred mice for the study of granulomatous diseases, including those of the gastrointestinal tract.

Monoclonal B lymphocytes in the peripheral blood of patients with inflammatory bowel disease.

Abnormalities in the B lymphocyte population may be relevant to certain altered in vitro immune responses in patients with inflammatory bowel disease. Using a cytofluorometric detection system, we looked for lymphocytes having homogeneous amounts of surface immunoglobulin of only one light-chain class. We studied the peripheral blood lymphocytes from 20 patients with ulcerative colitis and Crohn's disease. Lymphocytes from 12 of 20 patients (60%) with inflammatory bowel disease expressed abnormal light-chain distributions regardless of disease activity, type of disease, or steroid therapy. None of the 15 age-matched normal controls or 12 patients with other intestinal inflammatory conditions showed abnormal light-chain distributions (p greater than 0.01). The data indicate that there are increased numbers of monoclonal lymphocytes in the peripheral blood of some patients with inflammatory bowel disease. One explanation to account for these findings is the possible presence of an abnormality of immune regulation that permits proliferation of such clones.

Oral clotrimazole in the treatment of esophageal candidiasis.

Several antifungal regimens had failed to relieve severe, recurrent esophageal candidiasis in a 75 year old woman without predisposing disease whose serum transiently inhibited the candidacidal capacity of her polymorphonuclear leukocytes. Treatment with oral nystatin suspension was unsuccessful, whereas intravenous amphotericin B and miconazole induced only transient responses. Oral 5-fluorocytosine induced severe nausea and vomiting, and was discontinued. Oral clotrimazole troches produced prompt and sustained eradication of the patient's candidal esophagitis.