Nuclear Receptors, Ligands and the Mammalian B Cell.

Questions concerning the influences of nuclear receptors and their ligands on mammalian B cells are vast in number. Here, we briefly review the effects of nuclear receptor ligands, including estrogen and vitamins, on immunoglobulin production and protection from infectious diseases. We describe nuclear receptor interactions with the B cell genome and the potential mechanisms of gene regulation. Attention to the nuclear receptor/ligand regulation of B cell function may help optimize B cell responses, improve pathogen clearance, and prevent damaging responses toward inert- and self-antigens.

Influência da suplementação de vitaminas A, D e E na função imune de bezerros alimentados com dieta á base de feno capim tifton (cynodon spp) / Influence of A, D and E vitamin supplements on immune function of calves fed diet tifton (cynodon spp) hay

As vitaminas são compostos orgânicos necessários em poucas quantidades no organismo, todavia indispensáveis para as funções metabólicas. Elas se inserem em inúmeras reações metabólicas, fisiológicas e imunes das células, necessárias para a manutenção da saúde animal, além de atuarem como imunoestimulante. Embora a dieta rica em folhagens verdes frescas forneça quantidades suficientes de vitaminas A, D e E a suplementação intensiva com alimentos conservados na forma de feno ou silagem pode reduzir em até 50 % dos teores destas vitaminas no alimento. Diante disso, a proposta do trabalho foi verificar se a administração parenteral de vitaminas A, D e E age como imunoestimulante em garrotes estabulados e alimentados exclusivamente com feno de tifton. Para tanto 14 bovinos foram divididos em dois grupos homogêneos, sendo o grupo S, suplementado com vitamina A, D e E em dose única de 30 mL por via intramuscular; e o grupo C, sem suplementação. Ambos os grupos foram alojados em baias parcialmente privadas de sol, e alimentados com feno por um período de três meses. A avaliação imune foi realizada por hemogramas e ensaio de função leucocitária (metabolismo oxidativo e fagocitose) nos momentos antes do tratamento, três e dez dias após os tratamentos. Tendo em vista que a suplementação com polivitamínicos A, D e E aumentou a porcentagem da atividade de células granulocítica e a intensidade da atividade de células mononucleares, além de intensificar o efeito antioxidante prolongando a sobrevida de hemácias e neutrófilos, conclui-se que esta suplementação promoveu efeito benéfico na resposta imune de bezerros da Raça Holandesa, apesar dos efeitos deletérios da alimentação exclusiva com feno e da privação parcial da incidência solar direta.

Vitamins are organic compounds which are required in small quantities in the body, however essential for the metabolic functions. They participate in numerous metabolic reactions, physiological and immune cells, needed to maintain animal health, as well as act as immunostimulants. Although the diet rich in fresh green foliage provides sufficient amounts of vitamin A, D and E, intensive supplementation with food stored in the form of hay or silage can reduce up to 50% of the levels of these vitamins in food. Given this, the proposal of this study was to verify how the parenteral administration of vitamins ADE acts as immunostimulant in steers fed exclusively with hay of tifton. For that, 14 cattle were divided into two homogeneous groups: Group S, supplemented with vitamin A, D e E given in a single intramuscular dose of 30mL, and Group C without supplementation. Both groups were housed in private stalls and fed with hay for a period of three months. Immune evaluation was performed by blood count and testing of leukocyte function (oxidative metabolism and phagocytosis) in the moments before treatment, three and ten days after the treatments. Considering that supplementation with vitamin A, D e E increased the percentage of granulocytic cell activity and the intensity of the activity of mononuclear cells, as well as intensified the antioxidant effect prolonging the survival of red blood cells and neutrophils, it can be concluded that this treatment had a beneficial effect on the immune response of Holstein calves, despite the damaging effects of exclusive feeding hay, and the partially deprivation of solar incidence.

The pleiotropic role of vitamin A in regulating mucosal immunity.

The effect of vitamin A on mucosal immunity has never been subjected to extensive studies until recently. We started to work in this area in the early 1970s when we observed that children with protein-calorie malnutrition (PCM) often had defective mucosal immunity, judging from the incidence of respiratory tract infections and diarrhea. We reported that these children had depressed secretory IgA (sIgA) levels in their nasal wash fluids. The IgA level in specimens collected from those superimposed with some degrees of vitamin A deficiency state appeared to be more severely affected. In order to better understand the underlying mechanism associated with this condition, we started to study more detail the deficiency state using experimental vitamin A-deficient rats. From a series of experiments using this animal model, we proposed that vitamin A was needed for transport and/or secretion of sIgA across the mucosa. This conclusion was based on the observation that the secretory component of sIgA synthesized by the epithelial cells of these vitamin A deficient animals was adversely affected as compared to the control animals. From that time onward, much progress has been made by several other groups showing that other mechanisms could also influence the integrity and immune function of the mucosa. For instance, recent studies demonstrated that retinoic acid which is a biologically active form of vitamin A has an essential role in mucosal homeostasis, controlling tolerance and immunity in these non-lymphoid tissues. Such a conclusion was made possible by the availability of sophisticated new molecular biology and genetic engineering techniques together with advances in the field of immunoregulation, e.g., the discovery of dendritic cells (DCs) and T helper cell subsets in 1980s, and the role of Toll-like receptors (TLRs) together with other innate immune regulators in controlling adaptive immune response in the early 1990s. These advances provided considerable new insights into the pleiotropic roles of vitamin A including educating mucosal DCs, differentiation of lymphocyte lineages and imprinting them with mucosal-homing properties as well as in regulating tolerance and immunity. The identification of a novel lymphocyte subpopulation, innate lymphoid cells (ILCs), at the beginning of this century has provided us with an additional insight into a new role of vitamin A in regulating homeostasis at the mucosal surface through influencing ILCs. Another new player that regulates intestinal homeostasis and mucosal immune response is microbiota whose composition is known to vary with vitamin A status. So it appears now that the role of vitamin A on mucosal immunity is far beyond regulating the adaptive Th1-Th2 cell response, but is highly pleiotropic and more complicating, e.g., polarizing the phenotype of mucosal DCs and macrophages, directing gut-homing migration of T and B cells, inducing differentiation of effector T cells and Treg subpopulation, balancing mucosal ILCs subpopulation and influencing the composition of microbiota. In this review, I will attempt to bring together these important advances to provide a comprehensive and contemporary perspective on the role of vitamin A in regulating mucosal immunity.

Impact of dietary components on NK and Treg cell function for cancer prevention.

An important characteristic of cancer is that the disease can overcome the surveillance of the immune system. A possible explanation for this resistance arises from the ability of tumor cells to block the tumoricidal activity of host immune cells such as natural killer (NK) cells by inducing the localized accumulation of regulatory T (Treg) cells. Evidence exists that components in commonly consumed foods including vitamins A, D, and E, water-soluble constituents of mushrooms, polyphenolics in fruits and vegetables, and n-3 fatty acids in fish oil can modulate NK cell activities, Treg cell properties, and the interactions between those two cell types. Thus, it is extremely important for cancer prevention to understand the involvement of dietary components with the early stage dynamics of interactions among these immune cells. This review addresses the potential significance of diet in supporting the function of NK cells, Treg cells, and the balance between those two cell types, which ultimately results in decreased cancer risk.

Human gastric epithelial cells contribute to gastric immune regulation by providing retinoic acid to dendritic cells.

Despite the high prevalence of chronic gastritis caused by Helicobacter pylori, the gastric mucosa has received little investigative attention as a unique immune environment. Here, we analyzed whether retinoic acid (RA), an important homeostatic factor in the small intestinal mucosa, also contributes to gastric immune regulation. We report that human gastric tissue contains high levels of the RA precursor molecule retinol (ROL), and that gastric epithelial cells express both RA biosynthesis genes and RA response genes, indicative of active RA biosynthesis. Moreover, primary gastric epithelial cells cultured in the presence of ROL synthesized RA in vitro and induced RA biosynthesis in co-cultured monocytes through an RA-dependent mechanism, suggesting that gastric epithelial cells may also confer the ability to generate RA on gastric dendritic cells (DCs). Indeed, DCs purified from gastric mucosa had similar levels of aldehyde dehydrogenase activity and RA biosynthesis gene expression as small intestinal DCs, although gastric DCs lacked CD103. In H. pylori-infected gastric mucosa, gastric RA biosynthesis gene expression was severely disrupted, which may lead to reduced RA signaling and thus contribute to disease progression. Collectively, our results support a critical role for RA in human gastric immune regulation.

Epidermis instructs skin homing receptor expression in human T cells.

The localization of memory T cells to human skin is essential for long-term immune surveillance and the maintenance of barrier integrity. Although the mechanisms controlling memory T-cell migration to peripheral tissues are poorly understood, the current paradigm includes the localized secretion of "imprinting" signals from tissue-resident dendritic cells in the draining lymph nodes. Here we show that CCR8 expression by newly activated naive T cells is regulated by skin-specific factor(s) derived primarily from epidermal keratinocytes, thereby providing a mechanism for the preferential expression of CCR8 by skin-resident memory T cells. Importantly, no such effects were observed after coculture with primary cells from skin-unrelated epithelia, including mesothelium and small intestine. The keratinocyte-derived CCR8-inducing factor(s) were soluble, and independent of vitamins A and D. Furthermore, the induction of CCR8 under these conditions correlated with an increase in cutaneous lymphocyte-associated antigen expression. Our findings challenge current tissue homing paradigms, especially those involving CCR10, and emphasize the importance of steady-state epidermis rather than tissue-resident dendritic cells in controlling the localization of memory T cells within human skin.

Retinoid and TGF-ß families: crosstalk in development, neoplasia, immunity, and tissue repair.

Transforming growth factor-ß (TGF-ß) isoforms are profibrotic cytokines, par excellence, and have complex multifunctional effects on many systems, depending on the biologic setting. Retinoids are vitamin A derivatives that also have diverse effects in development, physiology, and disease. The interactions between these classes of molecules are, not surprisingly, highly complex and are dependent on the tissue, cellular, and molecular settings.

Regulation of B cell proliferation and differentiation by retinoic acid.

Vitamin A protects against development of infectious diseases, and B cells are important players in this process. Keys to the protective role of retinoic acid (RA) against infections appear to be its ability to enhance antibody responses against T-cell dependent and independent type 2 antigens, as well as to locally stimulate IgA production in mucosal tissues. The elucidation of molecular mechanisms involved in RA-mediated regulation of proliferation and differentiation of B cells not only helps us to understand how RA differentially regulates subsets of B cells, but might also lead to more targeted treatment of selected immune disorders and B cell malignancies.

From the diet to the nucleus: vitamin A and TGF-beta join efforts at the mucosal interface of the intestine.

The vitamin A metabolites, including retinoic acid (RA), form ligands for retinoic acid-related nuclear receptors and together they play pleiotropic roles in various biological processes. Recently, we described that RA also functions as a key modulator of transforming growth factor-beta (TGF-beta)-driven immune deviation, capable of suppressing the differentiation of interleukin-17 secreting T helper cells (T(H)17) and conversely promoting the generation of Foxp3(+) T regulatory (Treg) cells. This review will focus on the role of RA in the reciprocal TGF-beta-driven differentiation of T(H)17 and Treg and on the importance of such regulatory mechanism to control a functional immune system, in particular at the mucosal interface of the intestine.

Vitamin A rewrites the ABCs of oral tolerance.

One of the chief requirements of an immune system, the mucosal immune system, that lies juxtaposed to a mass of potentially immunogenic commensal organisms is a well-developed mechanism to limit or negatively regulate nascent immune responses to those organisms. This mechanism, long subsumed under the name oral tolerance, is now understood to consist of a complex of factors, not the least of which is the ready ability to induce immunosuppressive regulatory T cells or Tregs. The emphasis here is on the "ability to induce" because the real individuality of the mucosal regulatory response lies not in the Tregs themselves, which after all can be induced anywhere and are mere tools of regulatory response. Now, as shown initially by the fact that oral tolerance is dependent on the size and mobility of its dendritic cell (DC) population, the individuality of the mucosal immune system is inherent in its inducing cells, i.e., the antigen-presenting DCs (or macrophages) of the mucosal immune system.(1, 2)Recently, new data have emerged that provide much more specific information on how mucosal DCs (or macrophages) are different in this respect and thus why they have a special tendency to facilitate the development of Tregs that then mediate oral tolerance. This is the subject of this brief review. The unresponsiveness of mucosal immune system to mucosal antigens is due to a process known as oral tolerance. Recent studies addressing the mechanism of such tolerance show that mucosal tissues are replete with a unique subset of dendritic cells that secrete factors such as, TGF-beta1 and retinoic acid, that induce foxp3+ regulatory T cells. Thus, we arrive at the somewhat surprising realization that mucosal unresponsiveness is, appropriately enough, related to the availability of a factor in the food stream.

Men with low vitamin A stores respond adequately to primary yellow fever and secondary tetanus toxoid vaccination.

Current recommendations for vitamin A intake and liver stores (0.07 micromol/g) are based on maintaining normal vision. Higher levels may be required for maintaining normal immune function. The objective of this study was to assess the relationship between total body vitamin A stores in adult men and measures of adaptive immune function. We conducted an 8-wk residential study among 36 healthy Bangladeshi men with low vitamin A stores. Subjects received a standard diet and were randomized in a double-blind fashion to receive vitamin A (240 mg) or placebo during wk 2 and 3. Subjects received Yellow Fever Virus (YFV) and tetanus toxoid (TT) vaccines during wk 5. Vitamin A stores were estimated by isotopic dilution during wk 8. Vaccine-specific lymphocyte proliferation, cytokine production, and serum antibody responses were evaluated before and after vaccination. Vitamin A supplementation increased YFV- and TT-specific lymphocyte proliferation and YFV-specific interleukin (IL)-5, IL-10, and tumor necrosis factor-alpha production but inhibited development of a TT-specific IL-10 response. Both groups developed protective antibody responses to both vaccines. Some responses correlated positively with vitamin A stores. These findings indicate that the currently recommended vitamin A intake is sufficient to sustain a protective response to YFV and TT vaccination. However, YFV-specific lymphocyte proliferation, some cytokine responses, and neutralizing antibody were positively associated with liver vitamin A stores > 0.084 micromol/g. Such increases may enhance vaccine protection but raise the question of whether immune-mediated chronic diseases may by exacerbated by high-level dietary vitamin A.

Estado de vitamina A y su relación con antecedentes infecciosos en escolares venezolanos / Vitamin A status and the relationship with morbidity in venezuelan school children

La vitamina A (VA) cumple una función importante sobre el sistema inmunológico demostrándose una relación sinérgica entre estado corporal de VA, y procesos infecciosos. El objetivo fue evaluar la relación entre niveles séricos de retinol y la Citología de Impresión Conjuntival (CIC) con el estado nutricional antropométrico y antecedentes infecciosos en escolares de bajos recursos económicos de una zona urbana de Valencia. Se evaluaron 445 niños (4-13 años de edad), de ambos géneros. Se determinó: retinol sérico (HPLC-r), proteína C reactiva (nefelometría), CIC (ICEPO), los indicadores antropométricos peso-talla (PT) y talla-edad (TE) según referencia nacional y el registro de enfermedades infecciosas (diarrea, enfermedades respiratorias, sarampión y parasitosis) dos meses previos al estudio. El 92,3 por ciento estaban en situación de pobreza, 7 por ciento presentó déficit nutricional (PT ≤ p10), 10,8 por ciento exceso (PT > p90) y 1,5 por ciento talla baja (TE = p3); 18 por ciento de los niños presentó al menos un episodio de diarrea, 39,8 por ciento infección respiratoria superior, 28,1 por ciento inferior y 32,8 por ciento parasitosis. El 10,3 por ciento mostró niveles altos de PCR (> 10 mg/L), el valor promedio de retinol fue 35,7 ± 9,2 μg/dL con una prevalencia de valores bajos (< 20 μg/dL) de 0,7 por ciento, niveles marginales (20-30 μg/dL) de 27,4 por ciento y 9,5 por ciento déficit de VA según CIC. Se encontró correlación significativa entre retinol sérico y CIC y asociación significativa entre retinol sérico y las enfermedades respiratorias superiores únicamente. No se encontró asociación entre los indicadores antropométricos con el estado de vitamina A ni con la morbilidad. No fue posible demostrar la relación entre el estado de vitamina A y los antecedentes infecciosos como diarrea, enfermedades del tracto respiratorio inferior y sarampión, sin embargo, la alta prevalencia de morbilidad y de niveles marginales de VA, hacen que el grupo estudiado...

Vitamin A (VA) is an essential micronutrient for the immune system and several researchs have shown a synergic relationship between vitamin A status and morbidity. The aim was to show the relationship between serum retinol level, Conjunctival Impression Cytology (CIC), anthropometric status, and morbidity in low income school children. 445 children (both genders) between 4 and 13 years old were assessed. Serum retinol levels (HPLC-r), C-reactive protein (nefelometry) and CIC (ICEPO), anthropometric indicators (Weight-height (WH), height-age (HA)according to national references values), morbidity (diarrhea, respiratory tract infections, measles, and parasitosis) two months prior to the evaluation, were determined. The poverty was 92.3%, wasting (WH ≤ p10) 7%, overweight (WH > p90) 10.8%, and stunting (HA = p3) 1.5%. 18% had one or more diarrhea episodes, 39.8% upper respiratory tract infections, 28.1% lower respiratory tract infections, and 32.8% intestinal parasitosis; 10.3% showed ahigh level of C-reactive protein (CRP > 10 mg/L). The average retinol level was 35.7 ± 9.2 μg/dL, with 0.7% low level(< 20 μg/dL), 27.4% of the children at risk of vitamin A deficiency (20-30 μg/dL), and 9.5% deficient according CIC. There was a significant correlation between serum retinol and CIC, and a significant association between serum retinol and upper respiratory tract infections, but not between morbidity and CIC. There was not a significant association between anthropometric indicators and vitamin A status and morbidity. In this study it was not possible to demonstrate the relationship between vitamin A status and diarrhea, measles, lower respiratory tract infections and parasitosis but the high prevalence of marginal serum retinol levels and morbidity in this group makes it susceptible to nutritional surveillance.

Regulation of CD8+ T lymphocyte effector function and macrophage inflammatory cytokine production by retinoic acid receptor gamma.

Vitamin A and its derivatives regulate a broad array of immune functions. The effects of these retinoids are mediated through members of retinoic acid receptors (RARs) and retinoid X receptors. However, the role of individual retinoid receptors in the pleiotropic effects of retinoids remains unclear. To dissect the role of these receptors in the immune system, we analyzed immune cell development and function in mice conditionally lacking RARgamma, the third member of the RAR family. We show that RARgamma is dispensable for T and B lymphocyte development, the humoral immune response to a T-dependent Ag and in vitro Th cell differentiation. However, RARgamma-deficient mice had a defective primary and memory CD8(+) T cell response to Listeria monocytogenes infection. Unexpectedly, RARgamma-deficient macrophages exhibited impaired inflammatory cytokine production upon TLR stimulation. These results suggest that under physiological condition, RARgamma is a positive regulator of inflammatory cytokine production.

Vitamin A supplementation increases ratios of proinflammatory to anti-inflammatory cytokine responses in pregnancy and lactation.

Vitamin A supplementation reduces child mortality in populations at risk of vitamin A deficiency and may also reduce maternal mortality. One possible explanation for this is that vitamin A deficiency is associated with altered immune function and cytokine dysregulation. Vitamin A deficiency in pregnancy may thus compound the pregnancy-associated bias of cellular immune responses towards Th-2-like responses and exacerbate susceptibility to intracellular pathogens. We assessed mitogen and antigen-induced cytokine responses during pregnancy and lactation in Ghanaian primigravidae receiving either vitamin A supplementation or placebo. This was a double-blind, randomized, placebo-controlled trial of weekly vitamin A supplementation in pregnant and lactating women. Pregnancy compared to postpartum was associated with a suppression of cytokine responses, in particular of the proinflammatory cytokines interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha. Mitogen-induced TNF-alpha responses were associated with a decreased risk of peripheral parasitaemia during pregnancy. Furthermore, vitamin A supplementation was significantly associated with an increased ratio of mitogen-induced proinflammatory cytokine (IFN-gamma) to anti-inflammatory cytokine (IL-10) during pregnancy and in the postpartum period. The results of this study indicate that suppression of proinflammatory type 1 immune responses and hence immunity to intracellular infections, resulting from the combined effects of pregnancy and vitamin A deficiency, might be ameliorated by vitamin A supplementation.

Vitamin A levels and immunity in humans.

In animal studies, vitamin A deficiency induces a shift from type 2 (humoral) to type 1 (cellular) cytokines; there are no similar data for humans. Control of human immunodeficiency virus (HIV) and Mycobacterium tuberculosis infections requires type 1 cytokine (cellular) immunity. These infections and vitamin A deficiency are highly prevalent in Africa. We therefore examined the interactions among serum vitamin A levels, immune parameters, HIV infection status, Mycobacterium bovis BCG vaccine scarring (as an indicator of a type 1 cytokine profile), and clinical findings for 70 hospitalized children in Malawi, Africa. Directly conjugated monoclonal antibodies and flow cytometry were used to assess cell-specific cytokine production by peripheral blood monocytes and lymphocyte subpopulations. The statistical techniques employed included nonparametric statistics and logistic regression analyses. Thirty percent of the participants had severe vitamin A deficiency (<10 microg/dl), 34% had moderate deficiency (10 to <20 microg/dl), and 36% had normal levels (> or = 20 microg/dl). Vitamin A levels were lower for HIV-positive than for HIV-negative children (median, 10 and 17 microg/dl, respectively). Vitamin A-deficient children (<20 microg/dl) were more likely than non-vitamin A-deficient children to have higher proportions of natural killer (NK) cells (median, 8.3 and 5.2%, respectively) and lower ratios of interleukin-10-producing monocytes to tumor necrosis factor alpha-producing monocytes after induction (median, 1.0 and 2.3, respectively). Vitamin A-deficient children were also more likely than non-vitamin A-deficient children to exhibit respiratory symptoms (47% versus 12%) and visible BCG vaccine scars (83% versus 48%), which are indicative of a type 1 response to vaccination. Vitamin A status did not vary with gender, age, incidence of malaria parasitemia, blood culture positivity, or rates of mortality (6% of vitamin A-deficient children died versus 20% of non-vitamin A-deficient children). Lower vitamin A levels were associated with a relative type 1 cytokine dominance and proportionately more NK cells, both of which may be somewhat beneficial to persons who are exposed to HIV, M. tuberculosis, or other type 1 pathogens.

Chronic marginal vitamin A status affects the distribution and function of T cells and natural T cells in aging Lewis rats.

Although both vitamin A (VA) deficiency and aging are independently associated with alterations in immune function, the effects of marginal VA status or VA supplementation on the immune system during aging were not studied. A long-term dietary study was conducted in a rat model of aging to quantify changes in T-cell populations in blood and spleen, including T-cells bearing a marker of natural killer (NKT) cells. The study included nine treatment groups [three levels of dietary VA: marginal (0.35 RE/kg diet), control (4.0 RE/kg diet), and supplemented (50 RE/kg diet); and three age groups: young (2-3 mo), middle-aged (8-10 mo), and old 20-22 mo); diets were fed continuously from weaning to the end of the study period. CD3(+)/CD4(+) T-cells decreased in percentage and number in blood with age, CD8(+) cells increased (%), and the CD4/CD8 ratio decreased. Conversely, aging was associated with increased NKT cells (phenotype CD3(intermediate)/NKR-P1(+)). Based on regression analysis of flow cytometry data, the phenotype of most NKT cells was CD3(intermediate)/NKR-P1(+)/CD28(-). NKT cells, which are most likely of extrathymic origin, accounted for most of the decrease in the CD4/CD8 ratio. Marginal VA status, particularly in older rats, was associated with increases in the percentage of CD8(+) T cells, percentage and number of NKT cells, and peripheral blood cell anti-CD3epsilon-stimulated proliferative response, and decreases in the CD4/CD8 T-cell ratio and splenic cell interleukin-2 production. These differences and the reciprocal changes observed for NKT cells vs. T- and classical NK cells in aging VA-marginal rats suggest that low VA status during aging may increase the risk of infectious or neoplastic diseases that require a normal balance of T-cell or NK-cell responses.

Chronic marginal vitamin A status reduces natural killer cell number and function in aging Lewis rats.

Natural killer (NK) cells function in the regulation of immune responses and in the surveillance of malignant or other abnormal cells. Little is known of the effects of chronic marginal vitamin A (VA) status or VA supplementation, or their interaction with age, on NK cell number and cytolytic activity. We have conducted a two-factor (diet, age) study in which male Lewis rats were fed AIN-93M diet, modified to contain either 0.3 (designated marginal), 4.0 (control) or 50 (supplemented) mg retinol equivalents (RE)/kg diet, from the time of weaning until the ages of 2.5 mo (young), 8-10 mo (middle-aged) or 18-20 mo (old). Natural killer cells were identified and quantified in peripheral blood mononuclear cells (PBMC) and spleen with the use of flow cytometry, and NK cell cytotoxicity was assayed. The number and percentage of PBMC NK cells increased with age (P < 0.0001 by two-way ANOVA). For all age groups, values were lowest in rats with marginal VA status (P < 0.0001 vs. controls). NK cell lytic activity also declined with age (P = 0. 0003). As a result, NK cell lytic efficiency (lytic activity per NK cell) decreased markedly with age (P < 0.0001). Regardless of the donor's age or VA status, PBMC NK cell cytotoxicity doubled (100 +/- 25% increase) after exposure to interferon-alpha (5 x 10(5) U/L for 1 h before assay), indicating that IFN-stimulated lytic activity was related directly to basal NK cell activity. If the relationships observed in this animal model can be applied to humans, these data suggest that elderly people consuming diets chronically low in VA may be at increased risk for infectious or neoplastic diseases.

Retinol (vitamin A) is a cofactor in CD3-induced human T-lymphocyte activation.

Immunomodulatory effects of different retinoids have been demonstrated, both in vivo and in vitro, in different cellular lineages including human and murine thymocytes, human lung fibroblasts, Langerhans' cells, tumoral cells and natural killer (NK) cells; however, any attempt to demonstrate the effect of retinoids on human peripheral blood mononuclear cells (PBMC) resulted in negative results. In the present work, it is shown that retinol and retinoic acid induce a marked increase of proliferation on human PBMC from 32 unrelated healthy individuals, which had previously been stimulated with anti-CD3 antibodies 48 hr before. Serum-free medium, specific retinoid concentration (10(-7) M) and a particular timing of retinol addition to the cultures (48 hr after CD3 stimulation) was necessary clearly to detect this retinol-enhancing effect. The increased proliferative response is specifically mediated via the clonotipic T-cell receptor-CD3 complex and correlates with the up-regulation of certain adhesion/activation markers on the T-lymphocyte surface: CD18, CD45RO and CD25; also Th1-type of cytokines (interleukin-2 and interferon-gamma) are found concordantly increased after retinoid costimulation, both measured by a direct protein measurement and by a specific mRNA increase. In addition, it is shown that the in vitro retinol costimulation is only present in immunodeficient patients who have no defect on CD3 molecules and activation pathway. The fact that retinol costimulate lymphocytes only via CD3 (and not via CD2 or CD28) and the lack of response enhancement in immunodeficients with impaired CD3 activation pathway indicates that retinoids may be used as therapeutic agents in immune system deficiencies that do not affect the clonotypic T-cell receptor.

Surgically significant nutritional supplements.

This is not an exhaustive study of all nutritional supplements that patients may be taking. The most frequently used and those potentially most detrimental or most beneficial for surgical patients have been chosen for review of pertinent effects. It is essential to ask patients specifically about supplements or unusual dietary habits that may affect their surgical outcome prior to their invasive procedure and to keep in mind the supplements that may improve their outcome.