Warren W. Jederberg’s research while affiliated with Army Research Laboratory and other places

The human skin grafted congenitally athymic (nude) mouse, pig skin grafted nude mouse, hairless dog, and weanling Yorkshire pig were evaluated as models for predicting skin penetration in man. Nine radiolabelled compounds previously tested on man were applied topically (4 micrograms/cm2) to each model. These compounds included caffeine, benzoic acid, N, N-diethyl-m-toluamide, three steroids, and three insecticides. To correct for incomplete excretion of the label following topical absorption, per cent penetration was calculated by dividing the per cent of the topically applied radioactive dose recovered in the excreta by the corresponding percentage after parenteral administration and multiplication by 100. Calculated values of per cent penetration were confirmed in the case of the grafted nude mouse because significant correlations (r = 0.78 for human skin grafted athymic nude mouse and r = 0.97 for pig skin grafted athymic nude mouse) were found between the calculated values and the actual values obtained by summing the radioactivity recovered in the urine, faeces, tissues, and carcass. The results also revealed a significant correlation between human skin grafted athymic nude mouse values and human values (r = 0.74, P = 0.05) and between weanling Yorkshire pig values and human values (r = 0.83, P = 0.05). In contrast, no significant correlation existed between human values and those of the hairless dog and the pig skin grafted athymic nude mouse.

The human skin grafted athymic nude mouse, pig skin grafted athymic nude mouse, hairless dog, and weanling Yorkshire pig were evaluated as models for predicting skin penetration in man. Nine radiolabeled compounds previously tested on man were applied topically (4 micrograms/cm2) to each animal. These compounds included caffeine, benzoic acid, N,N-diethyl-m-toluamide, three steroids, and three insecticides. To correct for incomplete excretion of the label following topical absorption, percentage penetration was calculated by dividing the percentage of the topically applied radioactive dose recovered in the excreta by the corresponding percentage after parenteral administration and multiplication by 100. In the case of the grafted athymic nude mouse, calculated values of percentage penetration were confirmed because significant correlations (r = 0.78 for the human skin grafted athymic nude mouse and r = 0.97 for the pig skin grafted athymic nude mouse) were found between the calculated values and percentage penetration determined by summing radioactivity recovered in the urine, feces, tissues, and carcass. The results revealed a significant correlation between human skin grafted athymic nude mouse values and human values (r = 0.74, p = 0.05), and between weanling Yorkshire pig values and human values (r = 0.83, p = 0.05). In contrast, no significant correlation existed between human values and those of the hairless dog and pig skin grafted athymic nude mouse. The disposition of radioactivity following topical application of the radiolabeled nerve agent analog ( diisopropylfluorophosphonate ) and simulant (diethyl malonate) was determined in the weanling pig and the human skin grafted athymic nude mouse.(ABSTRACT TRUNCATED AT 250 WORDS)

The human skin grafted athymic nude mouse, pig skin grafted athymic nude mouse, hairless dog, and weanling Yorkshire pig were evaluated as models for predicting skin penetration in man. Nine radiolabeled compounds previously tested on man were applied topically (4 μg/cm2) to each animal. These compounds included caffeine, benzoic acid, N,N-diethyl-m-toluamide, three steroids, and three insecticides. To correct for incomplete excretion of the label following topical absorption, percentage penetration was calculated by dividing the percentage of the topically applied radioactive dose recovered in the excreta by the corresponding percentage after parenteral administration and multiplication by 100. In the case of the grafted athymic nude mouse, calculated values of percentage penetration were confirmed because significant correlations (r = 0.78 for the human skin grafted athymic nude mouse and r = 0.97 for the pig skin grafted athymic nude mouse) were found between the calculated values and percentage penetration determined by summing radioactivity recovered in the urine, feces, tissues, and carcass. The results revealed a significant correlation between human skin grafted athymic nude mouse values and human values (r = 0.74, p = 0.05), and between weanling Yorkshire pig values and human values (r = 0.83, p = 0.05). In contrast, no significant correlation existed between human values and those of the hairless dog and pig skin grafted athymic nude mouse. The disposition of radioactivity following topical application of the radiolabeled nerve agent analog (diisopropylfluorophosphonate) and simulant(diethyl malonate) was determined in the weanling pig and the human skin grafted athymic nude mouse. After correction for efficiency of excretion of radiolabeled diisopropylfluorophosphonate, it was estimated that 3% of the label penetrated the human skin graft on the nude mouse and that 7% of the label penetrated the weanling pig skin. Corresponding values for diethyl malonate were 4 and 2.5%, respectively. These relatively low values are consistent with evaporation from the skin being the major route of loss from the skin surface.

Because a large body of evidence suggests that the presence of circulating humoral factors could play a role in the induction/maintenance/resolution of psoriasis and because few investigators have explored their potential, we elected to conduct a survey analysis of the effects of the noncellular component of blood, serum, from normal and psoriatic subjects on assays of the inflammatory/immune system and on cell proliferation. Sera from psoriatic subjects are less chemotactic for monocytes than normal; this does not appear to be secondary to excess inhibitors for the chemoattractants, ZAS and bacterial factor. Preincubation of monocytes in psoriasis sera and normal sera results in an equal degree of inhibition of subsequent chemotaxis by monocytes. Relative to media alone, both normal and psoriasis sera equally inhibit DNA synthesis of HeLa cells. The addition of psoriasis sera to mitogenically stimulated lymphocytes will selectively suppress the blastogenic response in comparison to normal sera. These differences prompted a 2-d gel electrophoresis analysis of sera of psoriatic subjects. Specific differences are noted in the group of proteins migrating in the area of alpha 1 antitrypsin. These findings suggest that the noncellular component of the humoral system must also be factored into considerations of the etiopathology of psoriasis.

The possibility that products released by inflammatory cells may play a role in the induction/maintenance of psoriasis is suggested by the observation that psoriasis, a disease of excess epidermal proliferation, is linked to inflammatory events. As an assessment of this possibility, the effects of supernatants from antigen stimulated and unstimulated peripheral blood mononuclear cells from normal and psoriatic subjects on the proliferation of HeLa cell cultures are presented. Data demonstrate that supernatants contain factors which both inhibit and enhance cell proliferation, both of which are released in greater quantities from antigen stimulated peripheral blood mononuclear cells. Dilutional and pulsing experiments show that proliferation enhancing factors present in these supernatants have an apparent greater affinity for HeLa cells than does the inhibitory component. Relative to HeLa cell proliferation in fresh media, both antigen stimulated and control supernatants from peripheral blood mononuclear cells of subjects with psoriasis have significantly less inhibitory and more of the enhancing effect than similar supernatants from normal subjects. Individual, as well as pooled, supernatants from subjects with psoriasis demonstrate these differences. The kinetics of this response are the same, normal vs. psoriasis. This “net effect” of supernatants from patients with psoriasis favoring proliferation is in harmony with the concept of inflammatory events playing a role in cell proliferation, and may be important in the induction/maintenance of psoriasis.

We have previously confirmed that subjects with psoriasis have an alteration of cell-mediated immune responses. We now report a possible in vitro corollary; the amount of lymphokine (lymphocyte-derived chemotactic factor) released by both antigen-stimulated and control lymphocytes is decreased in psoriatic subjects; 61% of similar values for normal subjects. Monocyte migration to complement-derived chemotactic factors is reported to directly correlate to skin tests; however, in psoriasis the relation is inverse, i.e., a 200% increase in complement factors and 136% increase to lymphocyte-derived chemotactic factor in monocyte migration is noted in psoriatic subjects when compared with normal subjects. This increased migration does not correlate with amount of disease and is still present in "disease-free" subjects. Culturing monocytes from psoriatic subjects in media alone demonstrates they reduce more (205%) nitroblue tetrazolium than do monocytes of normal subjects. These data demonstrate that monocytes from subjects with psoriasis are altered and suggest an apparent inherent metabolic disorder.

Intradermal skin testing of normal and psoriatic subjects with common antigens, SKSD, Derm-O and PPD, reveals psoriatic subjects to have a decrease in both the amount (not incidence) of erythema (p less than 0.005) and in-duration (p less 0.005) to SKSD. Among all subjects having more than 10 mm erythema to Derm-O and SKSD, 49% of psoriatic and 77% of normal subjects have more than 10 mm induration (p less than 0.001). After sensitization, the response to 30 microgram challenge dose of dinitrochlorobenzene is positive in 50% of psoriatic and 88% of normal subjects (p less than 0.02). Uptake of (3)H thymidine by mitogen stimulated lymphocytes from psoriatic subjects is suppressed at each point of the linear component of a dose response curve. The mitogen dose to produce peak responses in psoriatics was 125% greater than that for normal subjects. In one-way mixed lymphocyte responses to pooled allogeneic stimulator lymphocytes, peripheral blood mononuclear cells from psoriatic subjects show suppression, the mean stimulation index was 55% of that of normal (p less than 0.01). Finally, in vitro polymorphonuclear leukocyte functions (chemotaxis, phagocytosis, and NBT reduction) appear to be within normal limits. When the foregoing parameters were compared with disease activity, there was no correlation.