Microbe-associated immunomodulatory metabolites: Influence on T cell fate and function.

During the past two decades, a growing interest surrounding the interaction between microbe-associated molecular patterns (MAMPs) and pattern recognition receptors has occurred. This attention is now driven alongside bacterial-derived metabolites, which impact immune cell differentiation and function. Hence, this review introduces the term meta-MAMP as a means to classify the microbial derived-metabolites, which influence the immune response by affecting specific cellular processes. We discuss two prominent examples of meta-MAMPs: the first, rapamycin (isolated from Streptomyces), was discovered in the 1970s and since then has been thoroughly studied. The second, soraphen A (isolated from Myxobacteria), was discovered in the early 1990s but only recently identified as a promising immunomodulator. Both meta-MAMPs are similar in their remarkable capacity to modulate T cell fate by targeting key metabolic pathways triggered upon T cell activation. In this context, we highlight the progress made in the field of immunometabolism and the possibility of modulating metabolic pathways such as cellular fatty acid metabolism as a strategy for immunomodulation. We focus on the use of microbial metabolites as auspicious agents for T cell fate modulation.

Curcumin ameliorates autoimmune diabetes. Evidence in accelerated murine models of type 1 diabetes.

Type 1 diabetes (T1DM) is a T cell-mediated autoimmune disease that selectively destroys pancreatic ß cells. The only possible cure for T1DM is to control autoimmunity against ß cell-specific antigens. We explored whether the natural compound curcumin, with anti-oxidant and anti-inflammatory activities, might down-regulate the T cell response that destroys pancreatic ß cells to improve disease outcome in autoimmune diabetes. We employed two accelerated autoimmune diabetes models: (i) cyclophosphamide (CYP) administration to non-obese diabetic (NOD) mice and (ii) adoptive transfer of diabetogenic splenocytes into NODscid mice. Curcumin treatment led to significant delay of disease onset, and in some instances prevented autoimmune diabetes by inhibiting pancreatic leucocyte infiltration and preserving insulin-expressing cells. To investigate the mechanisms of protection we studied the effect of curcumin on key immune cell populations involved in the pathogenesis of the disease. Curcumin modulates the T lymphocyte response impairing proliferation and interferon (IFN)-γ production through modulation of T-box expressed in T cells (T-bet), a key transcription factor for proinflammatory T helper type 1 (Th1) lymphocyte differentiation, both at the transcriptional and translational levels. Also, curcumin reduces nuclear factor (NF)-κB activation in T cell receptor (TCR)-stimulated NOD lymphocytes. In addition, curcumin impairs the T cell stimulatory function of dendritic cells with reduced secretion of proinflammatory cytokines and nitric oxide (NO) and low surface expression of co-stimulatory molecules, leading to an overall diminished antigen-presenting cell activity. These in-vitro effects correlated with ex-vivo analysis of cells obtained from curcumin-treated mice during the course of autoimmune diabetes. These findings reveal an effective therapeutic effect of curcumin in autoimmune diabetes by its actions on key immune cells responsible for ß cell death.

Cell-based interventions to halt autoimmunity in type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) results from death of insulin-secreting ß cells mediated by self-immune cells, and the consequent inability of the body to maintain insulin levels for appropriate glucose homeostasis. Probably initiated by environmental factors, this disease takes place in genetically predisposed individuals. Given the autoimmune nature of T1DM, therapeutics targeting immune cells involved in disease progress have been explored over the last decade. Several high-cost trials have been attempted to prevent and/or reverse T1DM. Although a definitive solution to cure T1DM is not yet available, a large amount of information about its nature and development has contributed greatly to both the improvement of patient's health care and design of new treatments. In this study, we discuss the role of different types of immune cells involved in T1DM pathogenesis and their therapeutic potential as targets and/or modified tools to treat patients. Recently, encouraging results and new approaches to sustain remnant ß cell mass and to increase ß cell proliferation by different cell-based means have emerged. Results coming from ongoing clinical trials employing cell therapy designed to arrest T1DM will probably proliferate in the next few years. Strategies under consideration include infusion of several types of stem cells, dendritic cells and regulatory T cells, either manipulated genetically ex vivo or non-manipulated. Their use in combination approaches is another therapeutic alternative. Cell-based interventions, without undesirable side effects, directed to block the uncontrollable autoimmune response may become a clinical reality in the next few years for the treatment of patients with T1DM.

[The pupil in the chronic phase of Chagas disease and the reaction to pilocarpine and phenylephrine]. / A pupila na fase crônica da doença de Chagas e reação à pilocarpina e à fenilefrina.

To develop a method to analyse pupillary disturbances in patients with chronic Chagas disease in an endemic area, ten chagasic and ten normal subjects were matched according to sex, age and race. Pupillary diameter and area were determined using projection and topography techniques and compared between groups. Both pupils were visualised simultaneously. In each case three photographs were taken under standardised illumination. The first photo was obtained without medication, the second, 30 minutes after instillation of 0,1% pilocarpine and the last 30 minutes after instillation of 3% phenylephrine (60 minutes after pilocarpine). Pupils of chagasic patients had a statistically significant greater initial diameter and area, irregularity of the pupil border, greater percentual reduction in diameter and area after pilocarpine 0.1% and greater percentual increase in diameter and area after 3% phenylephrine eyedrops. The method developed for this study was considered satisfactory. The results suggest ocular autonomic nervous system disturbances in chagasic patients.

[Anisocoria in the chronic phase of Chagas' disease]. / Anisocoria na fase crônica da doença de Chagas.

To compare the frequency of anisocoria in patients with chronic Chagas' disease a prospective double-blind study was done in 131 patients with positive serology for Chagas' disease and 138 negative, at Mambaí (GO-Brazil), which is an endemic area for Chagas' disease. To detect anisocoria, pupillometry was done with a millimetric ruler. Anisocoria was seen in 10(7.6%) patients with Chagas' disease and in 3(2.1%) normal subjects. The chi-square test showed statistical significance at level of 5%. Chagas' disease must be included among the causes of anisocoria.

The effect of plastering in a house persistently infested with Triatoma infestans (Klug) 1934.

The replastering of a house in Mambai-Goias, Brazil, as a measure to wall-in Triatoma infestans, is briefly described. Unfortunately, because the houseowner would not cooperate the roof tiles were not improved and eventually T. infestans reappeared at this site. A brief discussion follows of some aspects of house improvement in the vigilance phase of a Chagas Disease Control Programme. T. infestans appeared in the house described 51 and 258 days after the replastering.

Serum albumin and gamma globulin in Trypanosoma cruzi infections.

This paper examines the association between serum protein levels and infection with Trypanosoma cruzi in a region of Central Brazil. 148 people 6 to 78 years of age, were included in this study. There were no statistically significant difference in albumin levels between those with positive T. cruzi serology (2.94 +/- 0.74 g/100 ml) and those with negative serology (3.04 +/- 0.61 g/100 ml). Thus the null hypothesis of no association between infection with T. cruzi and serum albumin is accepted. Gamma-globulin levels were elevated in both groups and were significantly greater (p less than 0.05) in the group with positive T. cruzi serology (1.91 +/- 0.41 g/100 ml) than in the group with negative serology (1.75 +/- 0.41 g/100 ml). The serum albumin levels suggest that malnutrition (either associated with low protein intake or increased loss due to hookworm) is a major problem and unlikely to change if T. cruzi transmission was controlled.

Importancia da repeticao do xenodiagnostico para avaliacao da parasitemia na fase cronica da doenca de Chagas. / The importance of repetition of xenodiagnosis for evaluation of parasitemia in the chronic phase of Chagas' disease

Selecionamos em Mambai (GO) 303 chagasicos com sorologia reagente, para estudo da parasitemia, realizada atraves de tres xenodiagnosticos feitos com Dipetalogaster maximus e Triatoma infestans. Duzentos e dez (69,3%) pessoas apresentaram xenodiagnosticos positivos. O primeiro exame detectou parasitemia em 125 (41,2%) chagasicos, o segundo em outros 59 (19,5%). Classificamos os chagasicos em tres graus de parasitemia conforme a relacao de "pools" examinados. Deste modo, 28 (9,2%) tiveram alta parasitemia e 202 (66,7%) baixa parasitemia, 73 (24,1%) media parasitemia e 202 (66,7%) baixa parasitemia. Nos individuos de alta e media parasitemia o Trypanosoma cruzi foi detectado nos dois primeiros xenodiagnosticos, enquanto nos de baixa parasitemia, a positividade de 22,8% no primeiro exame elevou-se para 41,1% e 54% no segundo e terceiro xenodiagnosticos, respectivamente. A repeticao do xenodiagnostico, especialmente nos individuos de baixa parasitemia, mostrou uma elevacao significativa da positividade

Praziquantel no tratamento da esquistossomose mansoni. / Praziquantel in the treatment of schistosomiasis mansoni

Tratamos de 135 pacientes, portadores de esquistossomose mansoni, com o praziquantel por via oral. Os doentes foram divididos em tres grupos de 45 casos, conforme o nemero de ovos por grama de fezes: I com 95 a 500, II com 501 a 1000 e III com mais de 1000. As doses empregadas, em 15 pacientes de cada grupo, foram, respectivamente, 30 e 40 mg/kg de peso corporal, em dose unica, e 50 mg/kg divididos em duas tomadas com intervalo de 6 a 8 horas.Oitenta e dois doentes permaneceram internados em uma instituicao de ensino e 53 voltaram para a area endemica apos o tratamento. O controle de cura, em media de seis meses, baseou-se em exames de fezes, pelos metodos de Kato-Katz, Hoffman, Pons & Janer e ecdise.Com a dose de 1 x 30 mg/kg as porcentagens de cura para os grupos I, II e III foram,respectivamente, 53,3%, 26,6%, 20%, com a de 1 x 40 mg/kg 66,7%, 60% e 46,7% e com a de 2 x 25 mg/kg 86,7%, 73,3% e 46,7%. A tolerancia foi excelente em 19 pacientes, boa em 78, regular em 37 e ruim em um paciente. As queixas mais frequentes foram dor abdominal e diarreia. Em se considerando essa nova experiencia,concluimos que o praziquantel e uma boa droga para o tratamento da esquistossomose mansoni

Ecologia domestica do Triatoma infestans em Mambai, Goias-Brasil. / Domestic ecology of Triatoma infestans in Mambai, Goias-Brazil

Em Mambai, Goias, em 1975-1979 as casas foram investigadas com o fim de avaliar a prevalencia do Triatoma infestans, sendo visitadas todas as residencias do municipio naqueles anos. Os resultados sao analisados em relacao a varios aspectos domesticos, que possam influenciar na populacao de triatomineos. A presenca de infestacao domestica com triatomineos foi significantemente relacionada com casas mais velhas, com familias numerosas, com alto numero de visitantes e com baixo nivel de higiene domestica. As casas construidas de tijolos sem caiacao mostraram alta infestacao. A infestacao domiciliar pelo T. infestans, durante os 4 anos, entre as duas investigacoes, apresentou aumento significativo do numero de casas infestadas, embora os moradores, com seus proprios recursos, intensificassem o uso de inseticidas e reboco

Tentativa de controle da esquistossomose em uma area endemica atraves de quatro tratamentos em massa da populacao. / Schistosomiasis control trial in an endemic area by 4 mass treatments of the population

O autores apresentam os resultados obtidos em quatro grupos de pacientes numa area endemica de esquistossomose, tratados com uma ou mais doses de oxamniquine, no periodo de um ano.Com um tratamento, a prevalencia caiu de 66,6% para 33,3% (30 individuos), com dois tratamentos, de 54,1% para 25,0% (49 individuos), com tres, de 72,0% para 13,9% (62 individuos) e com quatro, de 73,0% para 16,2% (209 individuos). Nao houve diferenca nos grupos que fizeram tres e quatro tratamentos

Esquistossomose aguda adquirida na Lagoa Feia (Formosa-Goias). / Acute schistosomiasis acquired in the Lagoa Feia) Formosa, Goias, Brazil)

Os autores relatam quatro casos de esquistossomose aguda adquiridos simultaneamente na Lagoa Feia (Formosa-Goias), a 80 km do Plano Piloto, D.F. Tres pacientes residiam no Plano Piloto e outro, procedente de Porto Alegre, estava a passeio em Brasilia O trabalho realca a importancia epidemiologica desta Lagoa por se um ponto turistico proximo aos contingentes populacionais do Distrito Federal