The effect of 400 mg/M2/day of hydrocortisone, given alternatively from day 7 to day 19, was studied in the immunologically immature rat, a steroid-sensitive species. Animals, sacrificed 2 days following the completion of treatment, suffered from an underweight thymus and spleen, leucocytosis, and peripheral lymphocytopenia, probably not due to redistribution of lymphocytes from blood to tissues. In addition, a significant decrease in serum IgM concentration, reflecting a deficit in primary immune response, was evidenced. Although the percentage of lymphocytes returned to normal in rats sacrificed 23 days after treatment, an overweight thymus and spleen and persistent leucocytosis may reflect a compensatory overactivity of the developing immune system. In contrast, serum IgM concentration increased, but to a value less than normal. An indirect effect of hydrocortisone on lymphocytes through its action on thymus, as well as a direct effect on B cells, is suggested. Unlike humans, alternate-day steroid therapy delayed the normal growth pattern of rat, with a defective rate of growth only during the treatment period.

The histologic effect of 400 mg/M*/day of hydrocortisone, given alternatively from day 7 to day 19 after birth, was studied on the spleen of the immunologically immature rat. Two days after the cessation of treatment, the penarteriolar lymphatic sheaths were found to be largely depleted of small lymphocytes. Immunoperoxidase studies confirmed a depletion of T lymphocytes. The effects of hydrocortisone on the thymus seem to be more important than its direct lymphocytolytic effect in producing this splenic lesion. In contrast, no apparent change in the number of medium-sized B lymphocytes in the marginal zone was detected. Medium-sized B lymphocytes of the spleen, reported to be responsible for IgM synthesis, appeared to be subjected to a different mechanism of hydrocortisone action, other than lysis, resulting in a decrease in antibody production. Primary folliclcs were not seen in spleens of hydrocortisone-treated rats. Twentythree days after treatment, spleens had a histologically normal appearance.Keywords. Lcwis rat; hydrocortisone sc; spleen; histology; T and B lymphocytes; immunoperoxidase INTRODUC~~ON In the previous article, we showed that immunologically immature rats treated with alternate-day hydrocortisone followed by a recovery period suffered from overall growth retardation, undergrowth followed by overgrowth of the thymus and spleen, slowly reversible Iymphocytopenia, and reduced IgM concentrations.The effect of hydrocortisone on the immature immune system may be partially due to its action on the thymus (6) as well as a possible direct effect on antibody-forming cells in tissues.To complete the picture, it is necessary to investigate the effect of such a regimen on lymphoid organs. Many studies have confirmed the destructiveeffects of corticosteroid on lymphoid tissue of steroid-sensitive species (2, 1 I , 12). Others have reported the sensitivity of small lymphocytes present in lymphoid organs to the effect of hydrocortisone (1, 14). In the present article, the effect of alternateday hydrocortisone therapy on the histology of the

ABSTKACTThe histologic effects of the alternate-day hydrocortisone therapy (400 mg/M2 from day 7 to day 19 after birth) were studied on the mesenteric lymph nodes of immunologically immature rats. In rats sacrificed 2 days following the cessation of therapy, depletion of lymphocytes of the thymus-independent area was apparent. Smaller lymphocytes were more susceptible to the effect of hydrocortisone than larger ones. The absence of primary follicles, normally present at this age, suggested a possible retardation in development of the immune system. B lymphocytes appeared to be the target of the direct lymphocytolytic effect of hydrocortisone. In rats sacrificed 23 days following the treatment, immunological maturity was achieved, indicating the reversibility of the hydrocortisone effect.

The ultrastructural effects of 400 mg/M2/day of hydrocortisone sc, given alternatively from day 7 through day 19, were studied on the lymphocyte populations in the white pulp of the spleen and in the cortex of the mesenteric lymph nodes of the immunologically immature rat. Results were consistent with both a direct lytic effect of hydrocortisone on small lymphocytes of the nodular cortex of the mesenteric lymph nodes and an indirect effect on small lymphocytes of the periarterial lymphatic sheath (PALS) of the spleen supplied via the thymus. In contrast, medium-sized lymphocytes in the PALS appeared to be unaffected by hydrocortisone, while medium-sized lymphocytes of the nodular cortex of the mesenteric lymph nodes exhibited a temporary depletion of cytoplasmic organelles. Hydrocortisone appeared to depress protein synthesis in these latter cells. The decrease in numbers of lymphoblasts and plasmablasts observed in the nodular cortex of the mesenteric lymph nodes and the white pulp of the spleen is consistent with hydrocortisone interference with proliferation and differentiation of activated B cells.