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We recently reported that pregnancy affects age-related changes in the distribution of lymphoid and macrophage populations in the spleen of C57Bl/6 mice. In the present study, we examined the influence of pregnancies on the generation of various developmental B-cell subsets and granulocyte/macrophage lineage cells during murine ageing. Using flow cytometry, changes in lymphoid (mature and early B-cell precursors: B220high, B220low, surface immunoglobulin M (sIgM) mu chain +/-) and myeloid (monocyte/macrophage Mac-1/CD11b, granulocyte Gr-1/Ly-6G) compartments were monitored in the bone marrow of young (2 months) and 15- and 23-month-old mice including male, multiparous and virgin female mice. Pregnancies delayed the age-related decline in murine B lymphopoiesis and maintained B-cell reserve capacity during ageing. We also found an increased production of myeloid cells induced by pregnancies at middle (15 months) and advanced (23 months) ages. This comparative study provides new information on changes in marrow lymphopoiesis and myelopoiesis with age. Our data emphasizes that the onset, magnitude and kinetics of age-related changes in the haematopoietic marrow are parity dependent. These changes could influence the incidence of age-related diseases and may account for the greater longevity of females.

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Healthy elderly (80+/-5 years) with different nutritional status were compared to young healthy adults (25+/-5 years) to quantify the relative influences of aging and nutrition on immune response. Aged persons, without alteration of their nutritional status, had lower CD3+, CD8+, and CD45RA+ as well as higher CD2+CD3-, CD2+CD4-CD8-, and CD45RO+ T cell subsets and IL-6 release than their younger counterparts. T cell proliferation and IL-2 production were comparable in the two healthiest groups. Aged subjects with low nutritional status expressed similar but more marked changes in immune response while nutritional status did not influence the immune response in young subjects. Furthermore, lower nutritional status was associated with lower CD4+ counts and lower T cell functions in aged persons. These results indicate that the influences of aging and undernutrition in humans are cumulative and suggest that some changes in immune response that have been attributed to aging may, in fact, be related to nutrition and not aging.

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Nutrition has a strong influence on the immune system of the elderly. Aging induces dysregulation of the immune system, mainly as a result of changes in cell-mediated immunity. Aging is associated with changes to the equilibrium of peripheral T and B lymphocyte subsets, such as decreases in the ratios of mature to immature, naive to memory, T helper 1 subset (TH1) to TH2, and CD5- to CD5+ cells. As a consequence, cell-mediated immune responses are weaker and neither cell-mediated nor humoral responses are as well adapted to the antigen stimulus. Undernutrition, common in aged populations, also induces lower immune responses, particularly in cell-mediated immunity. Protein-energy malnutrition is associated with decreased lymphocyte proliferation, reduced cytokine release, and lower antibody response to vaccines. Micronutrient deficits, namely of zinc, selenium, and vitamin B-6, all of which are prevalent in aged populations, have the same influence on immune responses. Because aging and malnutrition exert cumulative influences on immune responses, many elderly people have poor cell-mediated immune responses and are therefore at a high risk of infection. Nutritional therapy may improve immune responses of elderly patients with protein-energy malnutrition. Supplementation with high pharmacologic doses of a single nutrient (zinc or vitamin E) may be useful for improving immune responses of self-sufficient elderly people living at home. Therefore, nutritional deficiency must be treated in the elderly to reduce infectious risk and possibly slow the aging process.

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So far all studies on the murine ageing process have been conducted on virgin mice. Immune ageing may be influenced by sex hormone differences related to sex or pregnancies. The aim of this study was to investigate whether pregnancies and gender influence the cell changes observed during ageing in a peripheral lymphoid compartment of C57B1/6 mice. Using flow cytometry, changes in (Thy1.2+) T cell, (B220+) B cell and (CD 11b/Mac-1) macrophage spleen populations were monitored in 2, 8 (3 months after last pregnancy) 15 and 23-month-old mice including males, virgin and multiparous females. The development of naive (CD44(low)), memory (CD44(high)), activated/memory (MEL-14, CD62L) cells were investigated in CD4+ and CD8+ T cell subsets. Both short term (at 8 months) and long term (at 15 and 23 months) effects of multiparity were obvious in the lymphocyte/macrophage population changes associated with the ageing process. Short-term effects included delayed appearance of CD4+CD44(high) memory lymphocytes and increased numbers of both CD4+MEL-14(1ow) activated/memory cells and Mac-1+ macrophages when compared with virgin control mice. Later effects of multiparity were increased CD8alpha(dull) populations and increased T/B cell ratios and the ratio of memory to naive CD4+ cells (CD44+(high)/CD44+(low). A sex effect was noticed: males exhibited lower Mac-1+ levels and memory/naive ratio in CD4+ subset than virgin females throughout life. These results suggest that gender and/or pregnancies affect the age-related distribution of lymphoid and macrophage cell populations in the spleen of C57B1/6 mice.

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Protein-energy malnutrition (PEM) is a worldwide problem. Infants and children from developing countries and elderly people from all around the world are the two main groups suffering from PEM. PEM induces profound immunodeficiency, characterized mainly by decreased cell-mediated immunity, and also by decreased humoral and non-specific immunity. Non-specific immune deficiency is of particular importance for defences against infections and its decrease in PEM may further deteriorate nutritional and immune status, pushing patients into a vicious and dramatic circle. Refeeding such patients and the restoration of their nutritional status lead to improvement in all immune responses: a strong association between the evolution of these two responses is always observed during refeeding. The need for specific nutrients to restore immune functions during refeeding of PEM patient has been extensively studied in the past years. This review describes the pathophysiological mechanisms of immune consequences of PEM and of immune restoration with refeeding, and in addition focuses upon some nutrients of particular importance, namely glutamine, zinc and vitamin E. Particular attention is directed at the elderly patients with PEM, a growing population for which the importance of undernutrition on prognosis is not yet fully recognized.

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Decreased T-cell functions with ageing have been extensively described. This review focuses on recent data on changes in T-cell subpopulations related to ageing and their consequences on T-cell proliferation. Increase of immature T cells CD2+ CD3- is an ageing phenomenon related to T-cell declining proliferation. Recently it was shown that increase of immature T cells was due to an increase in different subtypes of the CD2+ CD3- population, double-negative CD2+ CD4- CD8- and double-positive CD2+ CD4+ CD8+ subpopulations, the former being associated with nutritional deficit, the latter with associated diseases. Other authors have focused on decreases of native T cells with parallel increase of memory T cells; such a switch is also relevant to declining T-cell proliferation. This review focuses on two major factors which influence immune ageing; nutritional parameters and antigen exposure.

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Aging is characterized by decreased T-cell functions partly related to increase of T-cell immature subsets. In carefully selected populations we explored influences of decreased nutritional levels and/or diseases on the appearance of T-cell immaturity in elderly persons. Decrease of nutritional status is associated in healthy elderly fitting the "SENIEUR" protocol with decreased mature T-cells (CD3+), (CD8+) and increased immature double-negative T-cells (CD2+CD4-CD8-). Diseased undernourished patients express the same variations in T-cell subsets plus decreased CD4+ and increased double-positive T-cells (CD2+CD4+CD8+). This seems to indicate that aging-associated immature T-cells in peripheral blood are generated at two different, thymic and extra-thymic sites of maturation.

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Ageing leads to decrease of immune functions. The T lymphocyte is more susceptible to ageing than the B lymphocyte for which in vitro functions are almost preserved. All functions of cell mediated immunity are decreased in elderly. T lymphocyte are less mature, present decreased T helper and T suppressive functions, decreased T proliferative ability responses to stimuli and lower interleukin synthesis. T dependent antibody responses are also decreased: primary responses are diminished and secondary responses less specific. Nevertheless in healthy elderly such immune deficiency remains minor. Underdiminution whatever it concerns (mostly proteins but also vitamin or trace elements) also leads to immunodeficiency. When it occurs in aged individuals, undernutrition rapidly induces a profound immunodeficit. Prevention of prompt treatment of all undernutrition states is a major concern in geriatrics.

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To improve influenza vaccine efficacy in hospitalized elderly, we compared the evolution of antibody level after vaccination in three patient groups. A sample of apparently primo vaccinated elderly were randomized to receive either Imuthiol (Na diethyldithiocarbamate: group 1) or a placebo (group P). They were compared to patients who had been vaccinated annually for several years (group C). All patients were immunized in the same week. Antibody responses increase within 15 days to reach a plateau in group P and C, while they continue to increase in the Imuthiol treated group, reaching higher antibody levels 30 days after vaccination. This higher antibody rise in group I is essentially due to higher antibody responses in patients with initially low antibody levels and who exhibited at least a four-fold antibody rise. This effect of Imuthiol on influenza antibody responses was observed in spite of a lower nutritional status in this group, a condition that induces lower antibody responses. The higher antibody responses observed in the Imuthiol treated group allow longer protection against influenza.

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Delayed-type hypersensitivity (DTH) skin testing as an assay of immune competence is a widely used technique. Accordingly, clinical situations frequently occur which require that skin tests be performed many times on the same patient. In the present investigation, in vivo and in vitro immune responses were studied over a 7-month period in 22 normal human volunteers, each of whom were skin tested 6 times at monthly intervals with multiple antigens. Patterns of responses to the 7 specific skin test antigens observed during repeated skin testing in vivo indicated non-significant, but detectable, declines in skin test reactivity to tetanus, diphtheria and streptococcus antigens and increases in reactivity to trichophyton, tuberculin, candida and proteus antigens. In vitro lymphocyte transformation assays (LTAs) of cell-mediated immune (CMI) activities revealed that repeated skin testing, e.g., 3-5 serial skin tests, induced significantly increased levels of CMI reactions with 3 of the 4 skin test antigens used as challenge antigens. Since no significant changes in in vitro CMI responses were detected using 3 control "non-skin test" antigens, the effects observed were confirmed to be antigen specific. Increased IgG antibody responses were detected for only the toxoid antigens during the skin testing period. For the group of 22 normal volunteers, positive statistical correlations were not observed between any individual skin test antigen and the immune reactions assayed specifically for that antigen, including DTH responses and levels of circulating antigen-specific antibodies. Short term differences were detected between tetanus, diphtheria and streptococcus antigens in their LTA response patterns.(ABSTRACT TRUNCATED AT 250 WORDS)

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Delayed-type hypersensitivity (DTH) responses following in vivo multiple-antigen skin testing in healthy individuals have been well described as indicators of immune responsiveness. In contrast, little information is available about how repeated in vivo multiple antigen skin testing could effect major non-specific parameters of immune responses. In a prospective study of 22 healthy adult volunteers, DTH skin tests were performed 6 times at 4-week intervals over a 28-week course. Prior to each skin test, blood specimens were collected and evaluated by in vitro assays of non-specific parameters related to humoral and cell-mediated immune (CMI) responses. Sustained effects of repeated skin tests in the volunteers included decreased numbers of circulating polymorphonuclear leukocytes (PMNLs), increased serum IgM levels and decreased DTH responses in those individuals originally designated as high DTH responders. Increased lymphocyte transformation with PHA was transiently observed in the study group at 4-12 weeks into the study. In contrast, numbers of T, B and total lymphocytes, levels of IgG, IgA, and circulating immune complexes, and serum blocking activity did not change. This study suggests that few alterations in non-specific immune parameters may be expected to occur in normal, adult individuals as a result of repeated multiple-antigen skin tests.

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Booster effects on delayed cutaneous hypersensitivity (DCH) responses have been demonstrated for various antigens when DCH is measured by the Mantoux technique. In the present study, we investigated this possibility when assessing DCH responses using the Multitest CMI multipuncture technique with simultaneous injections of seven test antigens and a control. The DCH responses were quantified for each antigen and for the overall DCH response expressed as a DCH score. In a group of healthy volunteers, DCH was repeatedly tested either 1 month apart or 2 months apart at least six times. When volunteers remained healthy, DCH variations were observed with only two of seven tested antigens: streptococcus which slowly decreased (P = .012) and proteus which slowly increased (P = .04). Responses to the other antigens and the DCH score remained stable. In contrast, greater DCH variations were observed when infections occurred. The results with the Multitest CMI multipuncture show that repeated application had minimal booster effect on DCH responses and may be used to evaluate and follow immunocompetence of patients.

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Two hundred twenty-one healthy children, from 6 months to 7 years of age, were tested for delayed-type hypersensitivity (DTH) by the Multitest CMI (cell-mediated immunity) (Merieux Institute, Miami). This device permits the simultaneous application of seven standardized recall antigens and a glycerol diluent control. Younger children were tested on the back and older children on the volar surface of the forearm. Only 6.8% of the children were anergic, and most of them (11/15) were female. The DTH responses were present for one or more antigens in 93% of the infants. The DTH responses increased tremendously during the second year of life and increased slowly thereafter. A relatively high incidence of positive reactions was found for three of the tested antigens--diphtheria toxoid (79%), tetanus toxoid (62%), and Proteus (57%), in children in the preschool years, and accounted for three fourths of all positive reactions. Much lower levels were found for Streptococcus (25%), Candida (16%), Trichophyton (5%), and tuberculin (4%). Measurement of DTH by the standardized Multitest CMI system seems to be a convenient and reliable tool for assessing CMI function in infants and small children. The tool permitted us to measure patterns of DTH responses from infancy onward in a healthy population and to develop index values in a normal reference population with which any tested preschool child can be compared.

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The Multitest CMI system was used to measure cutaneous delayed type hypersensitivity (DTH) to a standardized battery of seven recall antigens in 448 healthy school children in relation to sex, age, race, and socioeconomic groups. Blacks demonstrated highest overall DTH, hispanics were intermediate, and whites were lowest. There was a trend for males to be more reactive than females at certain ages in each race. Incidence of reduced DTH scores (relative to adult values) was somewhat increased in the youngest school children, chiefly whites. Incidence and size of DTH responses to certain antigens were consistently higher in the blacks and/or hispanics as compared with whites. Blacks lived almost exclusively in the "poorer" school district, hispanics were evenly divided in both districts, while whites were mostly from the "affluent" district. Level of DTH appeared to be greatest in children from relatively poor homes possibly reflecting more intense and frequent exposure to ubiquitous microorganisms.

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Measurement of cutaneous delayed-type hypersensitivity (DTH) to a battery of ubiquitous antigens is an accepted means of assessing cell-mediated immunity (CMI). The recently introduced Multitest CMI system consists of a plastic multiple puncture device that simultaneously applies seven standardized recall antigens in a reproducible manner. A representative population of 448 healthy US schoolchildren was tested to determine incidence and size of DTH responses to each of the seven antigens. All responded to one or more antigens, the number and size of reactions generally increasing with age. Incidence of positive DTH tests was highest for tetanus and diphtheria toxoids, intermediate for streptococcal, Candida, and Proteus antigens, and lowest for tuberculin and Trichophyton antigens. These normal values, related to age and sex, can be a foundation for immunologic evaluation and are the basis of a proposed scoring system that distinguishes between normal DTH reactivity and diminished responsiveness.

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