Arthur S. Watnick

Characterization of a murine model of allergic pulmonary inflammation.

Pulmonary inflammation with eosinophil (EOs) infiltration is a prominent feature of allergic respiratory diseases such as asthma. In order to study the cellular response during the disease development, an animal model of IgE-mediated pulmonary inflammation with characteristic eosinophilia is needed. We developed a method for inducing severe pulmonary eosinophilia in the mouse and also studied the numbers of EOs in blood and bone marrow and the response to corticosteroid treatment. Animals were sensitized with alum-precipitated ovalbumin (OVA) and challenged with aerosolized OVA 12 days later when serum IgE levels were significantly elevated. Four to eight hours after challenge there were moderate increases in the number of EOs in the bone marrow and peripheral blood, but only a few EOs were observed in the lung tissue and in bronchoalveolar lavage (BAL) fluid. Twenty-four hours after challenge, there was a marked reduction of EOs in bone marrow, while the number of EOs peaked in the perivascular and peribronchial regions of the lung. Forty-eight hours after challenge, the highest number of EOs was found in the BAL fluid, making up > 80% of all cells in that compartment. The high levels of EOs in the lung tissue and BAL fluid lasted for 2-3 days and was followed by a more moderate but persistent eosinophilia for another 10 days. Nonsensitized animals showed no significant changes in the number of EOs in BAL fluid, lungs, blood or bone marrow. Histopathological evaluation also revealed epithelial damage, excessive mucus in the lumen and edema in the submucosa of the airways.(ABSTRACT TRUNCATED AT 250 WORDS)

Survival of Skin Homografts in Uteri of Pregnant and Progesterone-Estrogen Treated Rats

Summary Skin homografts placed in uteri of nonpregnant intact or castrate rats evoke a local inflammatory reaction followed by rejection with 9 days. Similar results are obtained with rats treated with either progesterone or estrone alone, Homografts in pregnant or in nonpregnant rats treated with both progesterone and estrone, however, survive for the 12-day duration of the experiment.

ETHYNYL ESTRADIOL: A POTENT ORALLY ACTIVE CONTRACEPTIVE IN RATS.

Summary The minimum protective dose of ethynyl estradiol (EE) which prevented pregnancy in all female rats treated before mating (MPDioo) was found to be 0.05 mg/kg body weight. This concentration of EE appeared to increase the sexual receptivity of some of the females. In attempting to clarify the mode of contraceptive action at the MPD100, EE was found to inhibit pituitary gonadotropin release but not ova transport or ova nidation. This was concluded from the facts that EE inhibited compensatory ovarian hypertrophy of the unilateral ovariectomized rat but did not prevent implantation when given after coitus, although a high rate of resorption was noted. In addition/ the MPD100 of EE did not inhibit formation of deciduomata.

A study of the mechanism of Con A-induced immunosuppression in vivo

The plaque-forming cell (PFC) response to sheep erythrocytes (SRBC) is suppressed in a dose-related manner when concanavalin A (Con A) is administered intravenously to mice prior to or after immunization with antigen. The magnitude of suppression as well as the duration of the Con A effect greatly depends on the concentration of antigen used for immunization. Although profound suppression of the anti-SRBC PFC response is observed in intact mice pretreated with Con A for 4-24 hr, spleen cells from these mice do not exhibit suppressive activity when transferred into normal recipients or when cotransferred with normal spleen cells into irradiated recipients. Moreover, the cells from Con A-treated mice respond as normal spleen cells to SRBC when transferred alone into irradiated hosts. Suppression of the anti-SRBC PFC is only observed when adoptive hosts of cells from Con A-treated mice are also injected with Con A within 48 hr (but not 72 hr) of cell transfer and immunization. This time course of responsiveness to the suppressive effects of Con A is similar to that observed in normal mice and in irradiated recipients of normal spleen cells. The immune response to SRBC is also suppressed in adoptive hosts of normal spleen cells that are pretreated with Con A 4-24 hr prior to irradiation and cell transfer. Although functionally inactive when transferred into adoptive hosts, spleen cells from mice pretreated with Con A for 4-24 hr can suppress a primary antibody response to SRBC in vitro. The suppressive activity, which cannot be detected in the spleens of mice when the interval between pretreatment and assay is longer than 24 hr, is present in a subpopulation that bears the Thy 1.2 and Lyt 2 phenotype. Taken together the results obtained in in vivo and in vitro functional assays suggest that a suppressor cell population is activated following in vivo treatment with Con A, but that the cells rapidly lose their state of activation when removed from a Con A environment. This phenomenon is in all probability responsible for the failure to demonstrate suppressive activity in the spleens of Con A-treated mice using in vivo functional assays.

IN VITRO AND IN VIVO IMMUNOPHARMACOLOGICAL PROFILE OF SCH 40120

Sch 40120 (10-(3-chlorophenyl) - 6,8,9,10- tetrahydrobenzo [b] [1,8] naphthyridin-5 (7H)-one) is a leukotriene inhibitor that is also a potent inhibitor of acute inflammatory responses in rodent systems. In the present study, we have evaluated the effects of this drug on immune function as well as its activity in models of immune mediated chronic inflammatory disease. Sch 40120 was particularly effective in suppressing T cell proliferative responses in vitro. Antigen-specific and poly-clonally-induced in vitro antibody responses were also inhibited by the drug. However, the in vivo potency of Sch 40120 in suppressing immune responses and in inhibiting the pathological changes seen in rodent models of autoimmune disease (EAE and adjuvant arthritis) was somewhat less than that previously observed in models of acute inflammation. Nevertheless, the spectrum of activities exhibited by Sch 40120 suggests that it will be particularly useful in the treatment of psoriasis where T lymphocytes have been implicated in the development of disease and leukotrienes appear to have a role in the persistence of psoriatic plaques.

A Study of the Immunosuppressive Properties of Sch 24937

Sch 24937 (6-bromo-5-chloro-2-1[(methylsulfonyl) acetyl] 3-(2-pyridyl indole) was previously shown to be an immunosuppressant with potent inhibitory effects on B lymphocyte mediated immune responses. The present investigation was primarily designed to compare the immunopharmacological profile of Sch 24937 with that of cyclosporin A (CSA) a well-known immunosuppressive drug that has selective effects on T-lymphocyte-mediated immune responses. The results show that while the immunosuppressive activity of CSA in vitro is superior to that of Sch 24937, in general the latter agent is a more potent inhibitor of immune responses in vivo. The activity of Sch 24937 in rat models of adjuvant arthritis and experimental allergic encephalomyelitis is also described. While Sch 24937 exhibits the type of immunopharmacological profile that is likely to yield a good therapeutic effect in the treatment of immune-mediated chronic inflammatory diseases, hepatotoxicity associated with the compound precludes its development for the treatment of non-life threatening human autoimmune conditions.

Edema formation and neutrophil mobilization in the neutropenic rat.

The relationship between leucocyte mobilization and edema formation was evaluated in the carrageenan pleurisy model. In normal rats carrageenan was able to mobilize between 80 and 100 million cells per ml of fluid. In neutropenic rats the concentration fell to between 20 and 50 million cells per ml, suggesting that edema formed after carrageenan injection is not directly correlated with cellular mobilization.

Inhibition of collagen II arthritis by stimultaneous administration of concanavalin A and other substances with antigen emulsion

Several pharmacological agents, some of which are known to have effects on the immune system, decrease the incidence of collagen II-induced arthritis when added to the antigen emulsion. Concanavalin A, which has been reported to exert suppressive effects on the immune system in vivo, consistently reduced the immune response to the collagen antigen. These effects were dose and time dependent. The suppressive effects of pokeweed mitogen, tilorone and carrageenan on anti-collagen II responses were somewhat variable. Suppressive activity could be observed with concanavalin A and levamisole when the drugs were injected at a site distant from the collagen emulsion. These studies indicate that local administration of drugs is an effective approach for demonstrating the activity of some agents that may alter the course of collagen II disease through an effect on the immune system.

Effects of Sch 9122 HCl, a Hypocholesterolemic Compound, on Mammary Tissue, Libido, and Fertility of Male Rats

Summary Sch 9122 HCl (2-(p-anisyl)-3-(2-pyridyl)-pentane hydrochloride), a compound structurally related to diethylstilbestrol, had significant hypocholesterolemic activity on prolonged administration to male rats. At oral doses which lowered serum cholesterol by as much as 30%, Sch 9122 HCl did not produce estrogenic effects on secondary sex structures, stimulate mammary tissue, or have adverse effects on mating behavior and fertility. Standard estrogenic substances had significant effects on these parameters at comparable hypocholesterolemic doses.