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SDZ 280.636, a nontoxic diacyl glycerol derivative of muramyl dipeptide (MDP), a component of the inner bacterial cell wall, which is suitable for use in man, suppressed hapten specific IgE antibody forming cell (AFC) responses in spleen, serum levels of hapten specific IgE and hapten specific immediate hypersensitivity (i.h.) responses in skin, when fed to mice at the peak of a hapten specific IgE AFC response. In addition, serum levels of IL-6 appeared increased while IFN gamma was decreased. To induce these IgE responses, BALB/c mice were injected i.p. with BPO-KLH (benzylpenicilloyl-keyhole limpet hemocyanin) (10 micrograms) in aluminum hydroxide gel (alum) on days 0, 21 and 42. Mice were fed (gavage) with either MDP or SDZ 280.636 (1.0 or 10 mg/kg) on day 44, or on days 44, 46 and 48, and killed on days 46 or 50. Numbers of BPO specific AFC in spleen, and serum levels of BPO specific immunoglobulins (IgG1, IgE and IgA) were determined (ELISPOT assay, ELISA). In addition, BPO specific IH responses were measured in these animals. Mice were injected in the right pinna with BPO-BSA (0.1 microgram) and in the left pinna with an equal volume of saline (0.05 ml). At 2 hr, pinnae were measured using a micrometer caliper. We found that 1 feeding with either MDP or SDZ 280.636 abrogated IgE AFC responses and dramatically suppressed serum levels of IgE, both in isotype specific fashion, and suppressed IH responses (> 50%). 3 feedings with SDZ 280.636 also abrogated IgE AFC responses and further decreased serum levels of IgE. In contrast to SDZ 280.636, 3 treatments with MDP had opposite effects in that IgE AFC responses and serum levels of IgE dramatically increased. A single treatment with SDZ 280.636 appeared to increase serum levels of IL-6 up to three fold, while IFN gamma levels decreased. Our data suggest that SDZ 280.636 may be useful in the therapeutic and prophylactic management of human atopic disease such as allergic rhinitis, asthma, and other atopic diseases.

The organs in which B cells bearing membrane-bound IgE (sIgE+) and benzylpenicilloyl (BPO)-specific IgE antibody-forming cells (AFC) first appeared were determined in BALB/c mice given BPO-keyhole limpet hemocyanin (10 micrograms) in aluminum hydroxide by various routes (i.p, gavage, s.c., i.v., or i.m.). In mice immunized by the i.p. route, the numbers and location of sIgE+ B cells and asialo GM1 ganglioside (AsGm1+) cells, the location of IgE/CD23 immune complexes, and the numbers of BPO-specific IgE AFC in lymphoid organs were determined. With all routes of immunization, no sIgE+ B cells or BPO-specific IgE AFC were ever detected in any organ before day 8. On day 8, with the s.c., i.v., or i.m. routes, sIgE+ B cells and IgE AFC appeared exclusively in Peyer's patches (PP); with the i.p. or gavage routes, sIgE+ B cells simultaneously appeared in both PP and mesenteric lymph nodes, whereas IgE AFC appeared only in PP. In mice immunized by the i.p. route, IgE/CD23 immune complexes and strikingly increased numbers of AsGm1+ cells transiently appeared only in PP after the appearance and preceding the "disappearance" of the sIgE+ B cells and IgE AFC. The data suggest that specific IgE responses originate in gut-associated lymphoid tissue and appear later in spleen. The data also associate the appearance of IgE/CD23 immune complexes and AsGm1+ cells with the "disappearance" of sIgE+ B cells and IgE AFC from PP.

Antigen specific IgE responses originate in gut associated lymphoid tissue (GALT) of mice sensitized with benzylpenicilloyl-keyhole limpet hemocyanin (BPO-KLH) in alum, regardless of the route (intraperitoneal [i.p.], oral [gavage], subcutaneous [s.c.], intramuscular [i.m.] or intravenous [i.v.]) used for immunization. When BALB/c mice were injected i.p. with BPO-KLH (10 micrograms) in alum, B lymphocytes bearing membrane bound IgE (sIgE+B cells) first appeared simultaneously in Peyer's patches (PP) and mesenteric lymph node (MLN) on day 8. BPO specific IgE antibody forming cells (AFC) also appeared in PP on day 8, but were not found in MLN until day 10. On day 8, no sIgE+B cells or IgE AFC were found in bone marrow (BM) or other lymphoid organs. The appearance of sIgE+B cells and IgE AFC in PP and MLN was transient; these cells were no longer detected in PP on days 14 and 24, respectively, or in MLN on days 14 and 36, respectively. sIgE+B cells and IgE AFC did not appear in spleen until day 12, where they were detected through day 70. Although sIgE+B cells were never found in BM, IgE AFC appeared in BM on day 18, where they were detected through day 70. No sIgE+B cells or IgE AFC were found in other lymph nodes (OLN) on days 0-70. Boosting did not induce the reappearance of sIgE+B cells or IgE AFC in PP, the reappearance of sIgE+B cells in MLN, the appearance of sIgE+B cells in BM, or the appearance of sIgE+B cells or IgE AFC in OLN.(ABSTRACT TRUNCATED AT 250 WORDS)

The adjuvant effect of Bordetella pertussis vaccine (PV) on the antibody response to sheep erythrocytes (SRBC) has been studied in vitro with the Mishell-Dutton immunization technique. The addition of PV to cultures of spleen cells obtained from normal non-immunized mice markedly enhanced the plaque-forming cell response to SRBC. The greatest enhancement was evident at 24 hr of culture. PV was also shown to enhance the antibody response of spleen cells that had been depleted of either T lymphocytes or adherent cells, presumably macrophages. In addition, it was found that PV, per se, released into the culture medium a soluble cell-free component(s) that contributed significantly to adjuvanticity. The results suggest that at least one of the ways that PV enhances the in vitro immune response to SRBC is by direct stimulation of precursors of antibody-forming cells.

The subcutaneous route (s.c.) was used to study the adjuvant effect of Bordetella pertussis vaccine (PV) on cell-mediated immunity to sheep erythorcytes (SRBC). The immune response was measured by a sensitive assay procedure in which the antigen is injected intracutaneously into the mouse ear and the inflammatory swelling is measured with calipers. PV significantly enhanced cell-mediated immunity to SRBC, and the enhancement persisted for at least 3 weeks. PV administered up to 6 days before SRBC also significantly enhanced the response; PV injected 1 or more days after SRBC was not effective. In addition, it was found that PV per se released into the suspension medium a cell-free component(s) (pertussis supernatant) that contributed significantly to adjuvanticity. The adjuvanticity of both PV and PS was completely eliminated by heat.

The subcutaneous route (s.c.) was used to study the adjuvant effect of Bordetella pertussis vaccine (pv) on the primary antibody response to sheep erythrocytes. The reasons for using the s.c. route are discussed. PV, besides enhancing the hemagglutinin response, also markedly increased the number of plaque-forming cells in the draining lymph nodes. A heated preparation of PV was tested and found to possess significant adjuvant activity. Interestingly, the enhancement occurred in the absence of marked enlargement of the lymph nodes, which was characteristic of the unheated preparation. In addition, a crude solubilized cell-free preparation of PV was tested and also found to possess significant adjuvant activity. The activity was only partially abolished by heat. Hence, it was concluded that both heat-labile as well as heat-stable factors contributed to the adjuvanticity of PV. The studies also support the view that the draining lymph nodes represent a principal locus of action of PV and that the s.c. route of administration of adjuvant and antigen provides a suitable model for studying and assaying the adjuvanticity of PV.

Nongranulomatous, nonspecific interstitial pneumonitis was a predominating or prominent histopathologic finding in 62 percent of 128 granuloma-containing specimens from open lung biopsies obtained from patients with sarcoidosis. Data from this study, combined with observations by others on the evolution of experimentally induced granulomas, indicate that interstitial pneumonitis represents a very early lesion, possibly the initial lesion, in pulmonary sarcoidosis. Because of the relatively large error of sampling inherent in the currently increasing practice of obtaining small specimens for lung biopsy via the flexible fiberoptic bronchoscope, we anticipate that interstitial pneumonitis will be seen as the only histopathologic finding in these specimens with increasing frequency. It is therefore important to recognize that interstitial pneumonitis is a characteristic, although nondiagnostic, morphologic feature of pulmonary sarcoidosis.

The sc route was used to study the adjuvant effect of vitamin A palmitate (VA) and the retinoids isotretinoin (Ro 4-3780), etretinate (Ro 10-9359), and motretinide (Ro 11-1430) on cell-mediated immunity to sheep red blood cells (SRBC) in outbred Mai:NIH(S) mice. The immune response was quantified by a sensitive assay procedure in which the antigen is injected intracutaneously into the pinna of the mouse, and the subsequent inflammatory swelling is measured with calipers. A single simultaneous injection of 150 microgram VA enhanced cell-mediated immunity to SRBC as early as 3 days following immunization, and the enhancement persisted for at least 3 weeks. Administered as a single injection 1 day or more before or after SRBC or as an ip injection, VA was not effective. Single injections of 100 microgram isotretinoin and motretinide but not etretinate also enhanced the response. The effective agents possessed adjuvanticity comparable in magnitude to that of Bordetella pertussis vaccine.