In previous studies we demonstrated that chronic energy intake restriction (CEIR) by a diet relatively low in fat, relatively high in carbohydrate, and reduced 40% in total calories extends life span and delays development of autoimmune disease in autoimmunity-prone mice. To investigate a possible cellular basis for this dramatic action of CEIR, we analyzed the rate of incorporation of [3ll1thymidine by cells of the intestinal epithelium, thymus, spleen, and mesenteric lymph nodes in ad libitum-fed mice vs. CEIR mice of three autoimmunity-prone strains. In New Zealand Black (NZB), MRL/MP-lpr/lpr (MRL/lpr), and BXSB mice, CEIR slowed the rate of uptake of [3llthymidine and, by inference, the rate of cellular proliferation among epithelial cells along the entire length of the gastrointestinal tract. Furthermore, CEIR decreased the apparent proliferative rate of lymphoid cells of the thymus, spleen, and mesenteric lymph nodes. This action by CEIR on the proliferative rate of cells of these rapidly replicating cell populations may point to an important mechanism by which calorie restriction inhibits the development of autoimmune disease and extends longevity in autoimmunityprone mice.Chronic energy intake restriction (CEIR) prolongs life span and span of health in a number of long-lived rodents, including inbred mice (1-4). The influences of CEIR, or undernutrition without malnutrition, have been even more dramatic when genetically short-lived, autoimmunity-prone strains of mice have been investigated (5-10). Indeed, it has been possible regularly to double life span in mice of each of the autoimmunity-prone strains studied simply by restricting the total amount of food consumed (5-10). Prolongation of life in these strains is accompanied by the inhibition of development of chronic diseases associated with aging, as has also been observed in long-lived strains of inbred mice and in long-lived rats (1-4). By following a lead enunciated by Gabrielsen and Olsen (11,12) that the pathogenesis of autoimmunity in NZB mice might involve a problem of DNA disposal, we investigated the influence of diet in autoimmunity-prone strains of mice on the rates of proliferation and, by inference, perhaps on the rates of cell turnover in certain rapidly replicating tissues in the body. Previously, we studied the short-lived autoimmunity-prone (NZB x NZW)F1 (B/W) mouse (where NZB and NZW are New Zealand Black and White, respectively) and showed that uptake of [3H]thymidine by nuclei of cells of the intestinal mucosa, thymus, spleen, and mesenteric lymph nodes (MLNs) is greatly reduced by CEIR (ref. 13 and unpublished observations). In the present study we have investigated the incorporation of [3H]thymidine at numerous levels of the intestine and in thymus and other lymphoid tissues in mice at different ages from three additional autoimmune-prone short-lived strains, the NZB, BXSB, and MRL/Mp-lpr/lpr (MRL/lpr) strains. We show that CEIR greatly limits [3H]thymidine incorporation in the nuclei of cells at all levels of the gut (...
Chronic energy-intake restriction (CEIR) has been shown to increase life-span, delay disease expression, and inhibit immunological perturbations in all strains of autoimmunity-prone mice studied, including NZB, (NZB X NZW)Fj, MRL/Mp-lpr/lpr, BXSB, and kd/kd mice. In (NZB x NZB)F1 mice, increased percentages and increased absolute numbers of Ly-l+ B lymphocytes in spleen, mesenteric lymph nodes, thymus, and bone marrow as revealed by two-color immunofluorescence analysis were greatly reduced by CEIR with a diet high in carbohydrate and low in fat. This influence on a possibly crucial lymphocyte subpopulation was associated with delayed onset of disease and with greatly prolonged life-span. In the present investigation, the percentages and absolute numbers of Ly-l+ B lymphocytes in the spleen, peritoneal exudate, and peripheral blood were found to be increased in each autoimmunity-prone strain studied. CEIR decreased the absolute and relative numbers of the Ly-l+ B lymphocytes in mice of each of the autoimmunity-prone strains and returned the numbers and proportions of Ly-l+ B cells close to levels present in the same locations in genetically long-lived C57BL/6, DBA/2, or BALB/c mice fed a standard commercial diet ad libitum.Chronic energy-intake (calorie) restriction (CEIR) greatly prolongs the span of life and health of mice of autoimmunityprone strains (1-5). CEIR and a diet relatively high in carbohydrate and low in fat permitted doubling or tripling of the life-span of mice of each of the major autoimmunityprone, short-lived strains (4,5). CEIR delays the development of renal lesions (6), decreases the levels of circulating immune complexes (7,8), inhibits the immunological involution that occurs with aging (9), and maintains immunologic vigor while enhancing interleukin 2 production and increasing responsiveness of thymus cells to interleukin 2 (10).In studying human B-cell chronic lymphatic leukemia, Ledbetter et al. (11) noted that certain B-cell lymphomas bear the Leu-1 antigen at their surface, a finding in agreement with the report ofWang et al. (12) The present study attempts to relate the numbers of these Ly-1 B cells to the influences of CEIR on longevity and development of disease in several ofthe major autoimmunityprone strains of mice. It is shown that CEIR greatly reduces the numbers and the proportions of these Ly-1 B cells in lymphoid tissues, in blood, and among peritoneal exudate cells (PECs). This influence correlates well with the dramatic action of CEIR to prevent expression of autoimmune disease in mice of these short-lived strains.MATERIAL AND METHODS Mice. Inbred 6-week-old female (NZB x NZW)F1 (B/W), female NZB, female MRL/Mp-Ipr/Ipr (MRL/lpr), and male BXSB mice (The Jackson Laboratory) were maintained in the University of South Florida Animal Research Center, Saint Petersburg, FL. The mice were housed individually and fed as specified. Animal rooms were operated on a 12-hr light/ 12-hr dark cycle at 20'C. Long-lived, autoimmunity-resistant C57BL/6, DBA/2, and BALB/c mice use...
Our data demonstrate that IFN therapy, especially intranasal administration of IFN-gamma, dramatically improved the prognosis of acute murine viral myocarditis by suppressing virus replication and raises the possibility of antiviral therapy with IFN-gamma in patients with acute myocarditis.
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