Typescript (photocopy). / Digitized by Kansas Correctional Industries

A murine model of AIDS (Acquired Immune Deficiency Syndrome) for study of immunomodulatory effects of alcohol on opportunistic infection was developed. C57BL-6 female mice were infected with murine retrovirus, LP-BM5. Mice were fed a liquid diet containing alcohol which produced withdrawal upon cessation. Controls were fed the diet with sucrose replacing ethanol. Dramatic differences were observed in spleen weight and thymus weight, but not body weight in virus infected or virus infected mice fed the alcohol diet. Ethanol suppressed the numbers of T-cells and macrophages. There was significant changes due to virus infection with and without alcohol treatment in T-subsets, B-cells and macrophages. However none were seen due to ethanol in uninfected controls. Alcohol further suppressed immune functions in retrovirally infected mice beyond that caused by the virus. Some mice were challenged with Streptococcus pneumoniae and Cryptosporodium. Adult mice that had been infected with LP-BM5 virus for 3, 4, or 5 months, when challenged by the oral route with Cryptosporidium, exhibited significant colonization on the intestinal villiae by this organism 10 days following oral challenge. Control mice did not show any oocyst in the villiae after 10 days following oral challenge. Resistance to S. pneumoniae was significantly reduced by retroviral infection, but not by short-term, binge, exposure to dietary ethanol. After 38 days of LP-BM5 infection, the virus infected alcohol fed group showed the shortest survival. The effects of immunization to S. pneumoniae antigens, as well as adoptively transferred cells in virally infected mice were studied. Survival of the mice to S. pneumoniae were influenced by different immunizations. The virus infected group had a much faster death rate in comparison than longer surviving unifected controls. Immunization played an important role in delaying the death rate in all treated groups. Transferring normal spleen cells from healthy, unimmunized mice also enabled the retrovirally infected mice to survive the bacterial infection longer than unimmunized, but retrovirally infected mice. This indicated the potential to enhance resistance by immunization and the transfer of immunocompetent cells to a system, immunosuppressed by retroviral infection. Clearly, retroviral infection modulates resistance with additional effects of ethanol. This model further expands and defines LP-BM5 infection as a murine model of retrovirally induced immune deficiency.

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Human peripheral blood monocytes provide a model for the in vivo exposure to, and immune functional damage caused by chronic UVB exposure at the skin surface. Retinoids and carotenoids are known immune function enhancers; they can also prevent cellular toxic product formation caused by UVB exposure. Application of these compounds in vitro may prevent functional damage to monocytes. Monocytes were exposed in vitro to UVB, then assayed for cytotoxic, phagocytic, and antigen presenting abilities. Phagocytic activity was protected from UVB damage by exposure to these compounds; cytotoxic activity was not altered by UVB exposure, but increased by retinoid or carotenoid exposure. Antigen presentation was not affected by either the UVB or these compounds. Protection of phagocytic function was not due to release of activating monokines or prostaglandins. Instead, the cell membrane antioxidant properties of these retinoids or carotenoids were the factors that protected the monocyte from phagocytic damage caused by UVB exposure.

Motivation and study design: Iron deficiency is a common condition in infancy, particularly in lower socio-economic groups. In Cape Town it remains a problem in spite of public health measures taken against it: a recent survey found a prevalence of iron deficiency anaemia of 34% in healthy 1-year old term infants who had ready access to a municipal health clinic where iron fortified milk formula is sold at subsidized prices. The consequences of iron deficiency extend beyond anaemia- to involve all organ systems including the immune system. Since Helen Mackay's report in 1928 of a striking decrease in incidents of infection in infants treated with iron, clinicians have assumed that iron deficiency predisposes to infection. Despite a sound theoretical basis for this belief, the clinical evidence for the assumption is poor as studies to date have displayed methodological deficiencies. On the other hand, iron is also essential for the growth of micro-organisms. As such, supplemental iron may predispose to infection. Indeed, there is much laboratory and clinical evidence to show that excess iron can result in the recrudescence of quiescent infections and increase the virulence of newly acquired infections. Thus, the competition between host and parasite may sometimes hinge on the relative availability of iron and it has been speculated that excess iron in infant milk formula may increase susceptibility to infectious diarrhoeal disease. The problem addressed by this thesis was to determine the utility of increasing the level of iron fortification of infant milk formula. Three questions were posed: Does increasing the level of iron fortification of conventional infant milk formula improve the iron nutrition of normal infants fed on the formula? Does increased iron fortification of infant milk formula alter immunity as reflected by incidence of infection and laboratory tests of immune function? Are there any handful effects of increasing the quantity of iron in conventional infant milk formula? A double blind randomized trial was carried out in 1983 and 1984 to answer these questions. A group of 149 healthy, well-nourished infants from a lower socio-economic community of so called Cape Coloureds were followed from the age of 3 months to 1 year. Half of the infants, the Control group, were given a commercially available infant milk formula (Lactogen Full Protein) which has 8.3 mg Fe/ 100 g formula and 37 mg ascorbic acid/ 100 g. The other half of subjects, the Test group, were given the same milk formula but fortified with iron to a concentration of 40 mg Fe/ 100 g. The children were examined every 3 or 4 weeks and any infection or history of infection was noted. Laboratory tests were done at the start of the trial and again on completion. During the trial, laboratory tests were performed only if clinically indicated. The tests included full blood count and differential analysis, red cell zinc protoporphyrin, plasma ferritin, plasma and hair zinc and lymphocyte subtyping with monoclonal antibodies. Within each group, half of the infants were randomly selected for assay of neutrophil bactericidal activity. The other half were assayed for lymphocyte blastogenic response to stimulation with phytohaemagglutinin. Tests of delayed cutaneous hypersensitivity to Candida antigen and PPD were done and all children and their mothers had antibodies to tetanus and polio determined. Results: 74 infants in the Control group started the trial and 62 completed it. In the Test group, 75 infants began and 70 completed the study. Intake of milk and solid foods was not quantified, but the ages of weaning and of introduction of new foods were determined. The Control and Test groups did not differ significantly on any test item. The mean age of completion of weaning was 3.60 months for the Control group and 4.04 months for the Test group. The Control group was first given meat or fish at a mean age of 5.19 months; the Test. group had meat or fish introduced to their diets at a mean age of 4.36 months. These differences were not statistically significant. The children in the Control group were lighter and shorter than the Test group at the end of the year. Mean standard deviation scores for weight were 0.23 and 0.48 respectively (P = 20%), while for length the SD scores were -0.13 and 0.06 (P = 20%).

Thesis (Mnutr)--Stellenbosch University, 2003. / ENGLISH ABSTRACT: INTRODUCTION: The objective of this pilot study was to evaluate the effects of a new micronutrient, glutamine, pre- and probiotic enriched liquid nutritional supplement on the nutritional status and immunity of adults living with HIV/AIDS. The study was designed as a prospective randomised double-blind placebo-controlled trial. Subjects were HIV-infected male and female adult volunteers (n = 47) from a community-based hospice centre in a peri-urban area in a resource-poor setting and were included irrespective of duration or clinical stage of HIV/AIDS. None of the subjects received antiretroviral therapy. METHOD: The intervention involved the daily ingestion of 40g (200 ml reconstituted) of either the enriched test product or an lsocalorie carbohydrate placebo for a period of 12 weeks. Anthropometric assessment (weight, height and triceps skinfold thickness; mid-upper arm, waist and hip circumferences) was performed at baseline and thereafter every 4 weeks (4 times). Biochemical (serum total protein, serum albumin and C-reactive protein) and haematological (full blood count and immunophenotyping) assessment was performed at baseline and again after week 12. RESULTS: Statistical analysis of baseline values was performed with Wilcoxon two-sample tests for comparison between the supplemented and placebo groups. Outcomes were evaluated using analysis of variance with Shapiro-Wilk tests and thereafter either pair-wise t-tests or sign tests (for nonparametric data) were used. Thirty-two subjects completed the trial, 14 in the supplemented group and 18 in the placebo group. Weight increased significantly in the supplemented group (2.73 ± 3.53 kg, P = 0.013). Triceps skinfold thickness increased significantly in both the supplemented (p = 0.047) and placebo group (p = 0.001). No other significant anthropometric change was observed. Serum albumin increased significantly in the supplemented group (p = 0.003) and was associated with a significant decline in C-reactive protein (p = 0.028). Haemoglobin decreased significantly in both groups. A significant decline in CD4+ count was observed in the placebo group while the decline in the supplemented group did not reach significance. CONCLUSION: Oral nutritional supplementation in limited quantities was well tolerated for a period of 3 months. This study demonstrated that an enriched nutritional supplement was able to promote weight gain and ameliorate hypoalbuminaemia and possibly inflammation in adults living with HIV/AIDS in the short to medium term. The enriched nutritional supplement does not appear to have an effect on the immunity of people with HIV/AIDS. The small sample is a limitation of the study and the conclusions pertain to the test product as a whole and not to any of its respective ingredients. Although further studies are required to evaluate long-term feasibility, these findings suggest that the use of an enriched nutritional supplement has a role in the management of weight loss in persons with HIV/AIDS. / AFRIKAANSE OPSOMMING: INLEIDING: Die doel van hierdie loodsstudie was om die uitwerking van 'n nuwe mikronutriënt, glutamien, pre- en probiotika verrykte voedingsaanvulling in vloeistof vorm te ondersoek. Die studie is ontwerp as 'n prospektiewe ewekansige dubbelblinde plasebogekontroleerde toets. Proefpersone was MIV-geïnfekteerde manlike and vroulike vrywilligers (n = 47) van 'n gemeenskapsgebaseerde hospitium in a semi-stedelike gebied in 'n hulpbron-arme omgewing. Proefpersone is ingesluit ongeag die duur of kliniese graad van MIVNIGS. Geen proefpersoon het antiretrovirale behandeling ontvang nie. METODE: Die intervensie het die daaglikse inname van 40g (200 ml gerekonstitueer) van óf die toetsproduk óf 'n isokaloriese koolhidraatplasebo gedurende 'n 12 week periode behels. Antropometriese evaluering (gewig, lengte en trisepsvelvoudikte; midbo-arm-, middel- en heupomtrekke) is uitgevoer met aanvang en daarna weer elke 4 weke (4 keer). Biochemiese (serum totale protein, serumalbumien en C-reaktiewe protein) en hematologiese (volbloedtelling en immunofenotipering) evaluering is uitgevoer met aanvang en weer na 12 weke. RESULTATE: Statistiese verwerking van basislyndata is gedoen deur middel van Wilcoxon twee-steekproef toetse waarmee vergelyking tussen die aangevulde en plasebogroep uitgevoer is. Studiegevolge is geëvalueer deur verspeidingsanalise met behulp van Shapiro-Wilk toetse waarna óf paargewyse t-toetse óf tekentoetse (vir nie-parametriese data) gebruik is. Twee-en-dertig proefpersone het die studietydperk voltooi, 14 in die aangevulde groep en 18 in die plasebogroep. Gewig het betekenisvol toegeneem in die aangevulde groep (2.73 ± 3.53 kg, p = 0.013). Triseps velvoudikte het betekenisvol toegeneem in beide die aangevulde (p = 0.047) en die plasebogroep (p = 0.001). Geen ander betekenisvolle antropometriese veranderinge is waargeneem nie. Serumalbumien het betekenisvol gestyg in die aangevulde groep (p = 0.003) en het gepaard gegaan met 'n betekenisvolle daling in C-reaktiewe protein (p = 0.028). Hemoglobienwaardes het in beide groepe betekenisvol gedaal. 'n Betekenisvolle daling in CD4+ telling is waargeneem in die plasebogroep terwyl die daling in die aangevulde groep nie betekenisvol was nie. GEVOLGTREKKING: Mondelingse voedingsaanvulling van 'n beperkte hoeveelheid was goed aanvaar en verdra oor 'n 3-maande tydperk. Hierdie studie toon dat 'n verrykte voedingsaanvulling in staat is om gewigstoename te bevorder en om hipoalbumienemie en moontlik ook inflammasie te verlig in volwassenes met MIVNIGS oor 'n kort tot medium tydperk. Die verrykte voedingsaanvulling blyk nie 'n effek op die immuniteit van mense met MIVNIGS te hê nie. Die klein steekproef is 'n beperking van die studie en die gevolgtrekkinge is slegs van toepassing op die toetsproduk as 'n geheel en nie op enige van die onderskeie bestanddele daarvan nie. Hoewel verdere studies nodig geag word om langtermyn uitvoerbaarheid te ondersoek, dui hierdie bevindinge daarop dat die gebruik van 'n verrykte voedingsaanvulling 'n rol speel in die beheer van gewigverlies in persone met MIVNIGS.

Indiana University-Purdue University Indianapolis (IUPUI) / Globally, protein malnutrition remains problematic, adversely affecting several systems including the immune system. Although poorly understood, protein restriction severely disrupts host immunity and responses to infection. Induction of high-affinity, long-lasting immunity depends upon interactions between B and T lymphocytes. B lymphocytes exploit several pathways including endocytosis, macroautophagy, and chaperone-mediated autophagy to capture and deliver antigens to the endosomal network. Within the endosomal network antigens are processed and loaded onto major histocompatibility complex (MHC) class II molecules for display and recognition by T lymphocytes. To examine the effect of macronutrient malnutrition on MHC class II antigen presentation, we grew B lymphocytes in media containing amino acids, sugars and vitamins but lacking serum, which contains several types of macronutrients. Our studies show macronutrient stress amplified macroautophagy, favoring MHC class II presentation of cytoplasmic antigens targeted to autophagosomes. By contrast, macronutrient stress diminished MHC class II presentation of membrane antigens including the B cell receptor (BCR) and cytoplasmic proteins that utilize the chaperone-mediated autophagy pathway. The BCR plays a critical role in MHC class II antigen presentation, as it captures exogenous antigens leading to internalization and degradation within the endosomal network. While intracellular protease activity increased with macronutrient stress, endocytic trafficking and proteolytic turnover of the BCR was impaired. Addition of high molecular mass macronutrients restored endocytosis and antigen presentation, evidence of tightly regulated membrane trafficking dependent on macronutrient status. Cytosolic chaperone HSC70 has been shown to play a role in endocytosis, macroautophagy, chaperone-mediated autophagy and proteolysis by the proteasome, potentially connecting distinct routes of antigen presentation. Here, altering the abundance of HSC70 was sufficient to overcome the inhibitory effects of nutritional stress on BCR trafficking and antigen presentation suggesting macronutrient deprivation alters the availability of HSC70. Together, these results reveal a key role for macronutrient sensing in regulating immune recognition and the importance of HSC70 in modulating distinct membrane trafficking pathways during cellular stress. These results offer a new explanation for impaired immune responses in protein malnourished individuals.