Serum Cytokines as Biomarkers of Early Trypanosoma cruzi infection by Congenital Exposure.

Trypanosoma cruzi, the causing agent of Chagas disease, leads to an activation of the immune system in congenitally infected infants. In this study, we measured a set of cytokines/chemokines and the levels of parasitemia by quantitative PCR in the circulation of neonates born to T. cruzi-infected mothers to evaluate the predictive value of these mediators as biomarkers of congenital transmission. We conducted a retrospective cohort study of 35 infants with congenital T. cruzi infection, of which 15 and 10 infants had been diagnosed by detection of parasites by microscopy in the first and sixth month after delivery, respectively, and the remaining 10 had been diagnosed by the presence of T. cruzi-specific Abs at 10-12 mo old. Uninfected infants born to either T. cruzi-infected or uninfected mothers were also evaluated as controls. The plasma levels of IL-17A, MCP-1, and monokine induced by IFN-γ were increased in infants congenitally infected with T. cruzi, even before they developed detectable parasitemia or seroconversion. Infants diagnosed between 6 and 12 mo old also showed increased levels of IL-6 and IL-17F at 1 mo of age. Conversely, infants who did not develop congenital T. cruzi infection had higher levels of IFN-γ than infected infants born to uninfected mothers. Monokine induced by IFN-γ, MCP-1, and IFN-γ production induced in T. cruzi-infected infants correlated with parasitemia, whereas the plasma levels of IL-17A, IL-17F, and IL-6 were less parasite load dependent. These findings support the existence of a distinct profile of cytokines and chemokines in the circulation of infants born to T. cruzi-infected mothers, which might predict congenital infection.

Diagnosis of congenital Trypanosoma cruzi infection: A serologic test using Shed Acute Phase Antigen (SAPA) in mother-child binomial samples.

Chagas congenital infection is an important health problem in endemic and non-endemic areas in which Trypanosoma cruzi-infected women can transmit the parasite to their offspring. In this study, we evaluated the antibody levels against the T. cruzi Shed Acute Phase Antigen (SAPA) in 91 binomial samples of seropositive pregnant women and their infected and non-infected children by ELISA. In 70 children without congenital T. cruzi transmission, the titers of anti-SAPA antibodies were lower than those of their seropositive mothers. In contrast, 90.5% of 21 congenitally infected children, at around 1 month of age, showed higher anti-SAPA antibody levels than their mothers. Subtracting the SAPA-ELISA mother OD value to the SAPA-ELISA child OD allowed efficient detection of most T. cruzi congenitally infected children immediately after birth, when total anti-parasite antibodies transferred during pregnancy are still present in all children born to seropositive women. A positive correlation was observed between parasitemia levels in mothers and infants evaluated by quantitative DNA amplification and anti-SAPA antibody titers by ELISA. As SAPA serology has proved to be very efficient to detect T. cruzi infection in mother-child binomial samples, it could be of extreme help for early diagnosis of newborns, in maternities and hospitals where DNA amplification is not available. This prompt diagnosis may prevent drop out of the long-term follow-up for future diagnosis and may ensure early trypanocidal treatment, which has proved to be efficient to cure infants with congenital Chagas disease.

How to improve the early diagnosis of Trypanosoma cruzi infection: relationship between validated conventional diagnosis and quantitative DNA amplification in congenitally infected children.

BACKGROUND: According to the Chagas congenital transmission guides, the diagnosis of infants, born to Trypanosoma cruzi infected mothers, relies on the detection of parasites by INP micromethod, and/or the persistence of T. cruzi specific antibody titers at 10-12 months of age. METHODOLOGY AND PRINCIPAL FINDINGS: Parasitemia levels were quantified by PCR in T. cruzi-infected children, grouped according to the results of one-year follow-up diagnosis: A) Neonates that were diagnosed in the first month after delivery by microscopic blood examination (INP micromethod) (n = 19) had a median parasitemia of 1,700 Pe/mL (equivalent amounts of parasite DNA per mL); B) Infants that required a second parasitological diagnosis at six months of age (n = 10) showed a median parasitemia of around 20 Pe/mL and 500 Pe/mL at 1 and 6 months old, respectively, and C) babies with undetectable parasitemia by three blood microscopic observations but diagnosed by specific anti - T. cruzi serology at around 1 year old, (n = 22), exhibited a parasitemia of around 5 Pe/mL, 800 Pe/mL and 20 Pe/mL 1, 6 and 12 month after delivery, respectively. T. cruzi parasites were isolated by hemoculture from 19 congenitally infected children, 18 of which were genotypified as DTU TcV, (former lineage TcIId) and only one as TcI. SIGNIFICANCE: This report is the first to quantify parasitemia levels in more than 50 children congenitally infected with T. cruzi, at three different diagnostic controls during one-year follow-up after delivery. Our results show that the parasite burden in some children (22 out of 51) is below the detection limit of the INP micromethod. As the current trypanocidal treatment proved to be very effective to cure T. cruzi - infected children, more sensitive parasitological methods should be developed to assure an early T. cruzi congenital diagnosis.

Vertical transmission of Trypanosoma cruzi infection: quantification of parasite burden in mothers and their children by parasite DNA amplification.

The relationship between parasite burden and vertical transmission of Trypanosoma cruzi was studied in pairs of chronically infected women and their children in a non-endemic area. Parasitemia was quantified by quantitative polymerase chain reaction (qPCR) in the peripheral blood amplifying a nuclear T. cruzi DNA and expressed as equivalent amounts of CL Brener parasites DNA per ml (eP/ml). Similar levels of parasitemia were found in non-transmitting pregnant women and in non-pregnant women: 1.8 ± 0.5 and 1.5 ± 0.7 eP/ml, respectively. In women pregnant with infected children parasitemia was 11.0 ± 2.7 eP/ml (n=20). In 12 of their neonates the infection was detected by microscopic observation of the parasites in peripheral blood in the 1(st) month of age. These children had variable levels of parasitemia (13,000 ± 7000 eP/ml), that were about 600-fold higher than that found in their mothers. To our knowledge, this is the first quantitative evaluation of parasitemia in these three groups of women and in their congenitally infected children. These parasite quantifications could be a basis to plan the control of mother-to-child transmission of T. cruzi.

Benzonidazole therapy modulates interferon-γ and M2 muscarinic receptor autoantibody responses in Trypanosoma cruzi-infected children.

OBJECTIVE: The presence of autoantibodies with adrenergic and cholinergic activity, capable of triggering neurotransmitter receptor-mediated effects, has been associated with pathogenesis in T. cruzi-infected hosts. The goal of this study was to investigate the production of anti-M2 muscarinic receptor autoantibodies (Anti-M2R AAbs) as well as the IFN-γ profile in children at the early stage of Chagas disease, and to examine whether trypanocidal chemotherapy with benzonidazole (BZ) could modify both response patterns. METHODS: This study comprised 30 T. cruzi-infected children (mean age: 13.8 years) and 19 uninfected controls (mean age: 12.7 years). Infected patients were treated with BZ and followed-up. Blood samples collected at diagnosis-T0, end of treatment-T1, and six months later-T2 were analysed by ELISA for detection of Anti-M2R AAbs and circulating levels of IFN-γ. RESULTS: At T0, anti-M2R AAbs were demonstrated in 56.7% of T. cruzi-infected patients, whereas uninfected controls were 100% negative. The average age of Anti-M2R AAbs(+) patients was higher than that from negative population. Infected children also displayed significantly stronger serum IFN-γ responses than controls. Upon BZ treatment, a significant linear decreasing trend in Anti-M2R AAb reactivity was recorded throughout the follow-up, with 29.7-88.1% decrease at T2. IFN-γ circulating levels also declined by T2. CONCLUSION: Anti-M2R AAbs and IFN-γ raise early during chagasic infection in children and are downmodulated by BZ therapy. These findings reinforce the usefulness of early BZ treatment not only to eliminate the parasite but also to reduce potentially pathogenic immune responses.

[Maternal-fetal transmission of Trypanosoma cruzi in Argentina]. / La transmisión madre-hijo del Trypanosoma cruzi en la Argentina.

In the neonates born to T. cruzi infected mothers, the diagnosis of the congenital transmission relays on the detection of the parasites and/or the specific antibodies non-transferred by their mothers, in the absence of blood transfusion and vectorial transmission. In the early stage, approximately until the 7th month of life, when maternal immunoglobulins could be present, the diagnosis depends on the detection of the parasite. Then, in the late stage, from the 8th month, the detection of specific antibodies by at least 2 of 3 serological tests confirms the infection in the neonates. The diagnostic follow up of the children born to a group of sero-reactive pregnant women was carried out in the INP. The 11% of the mothers (29 out of 267) transmitted the infection to their children. The neonates of 20 of these mothers were diagnosed in the early stage, 14 and 6 in one or two controls, respectively. In the 9 remaining mothers the children were diagnosed in the late stage of the infection, mainly serologicaly. Our analisis of previously published reports stressed that the maternal-fetal transmission rate depends on the time of diagnostic follow up of the child. In this reports, mean values of mother to child transmission reported was 2% and 9% when the diagnosis of the neonates born to sero-reactive mothers was carried out only in the early stage or in the early and also the late stage, respectively.

La transmisión madre-hijo del Trypanosoma cruzi en la Argentina / Maternal fetal-transmission of Trypanosoma cruzi in Argentina

El diagnóstico de la transmisión congénita del T. cruzi en hijos de mujeres infectadas se realiza por detección de la parasitemia y/o de anticuerpos específicos no transferidos por la madre, en ausencia de transfusión sanguínea y transmisión vectorial. En la etapa temprana, aproximadamente hasta el 7° mes de vida, cuando es posible la presencia de inmunoglobulinas maternas, el diagnóstico depende de la detección del parásito. Luego, en la etapa tardía, a partir del 8° mes de vida, la detección de anticuerpos específicos con por lo menos 2 de 3 pruebas serológicas permiten el diagnóstico del niño. En el INP hemos realizado el seguimiento de los niños de un grupo de mujeres embarazadas sero-reactivas que concurrieron para el diagnóstico de la infección. El 11% de ellas (29 de 267) transmitieron la infección a sus niños. Los hijos de 20 de estas mujeres fueron diagnosticados en la etapa temprana, con 1 o 2 controles parasitológicos, en 14 y 6 casos respectivamente. En las 9 madres restantes los niños fueron diagnosticados principalmente por la serología en la etapa tardía de la infección. Nuestro análisis de los datos publicados anteriormente enfatizan que el porcentaje de la transmisión madre-hijo depende principalmente del tiempo de seguimiento diagnóstico del niño. En estos trabajos, cuando el diagnóstico del niño se realizó sólo en la etapa temprana se notificó aproximadamente un 2% de transmisión materno-fetal, mientras que cuando también se estudiaron a los niños en la etapa tardía se encontró un promedio de 9% de casos de transmisión congénita.

In the neonates born to T. cruzi infected mothers, the diagnosis of the congenital transmission relays on the detection of the parasites and/or the specific antibodies non-transferred by their mothers, in the absence of blood transfusion and vectorial transmission. In the early stage, approximately until the 7th month of life, when maternal immunoglobulins could be present, the diagnosis depends on the detection of the parasite. Then, in the late stage, from the 8th month, the detection of specific antibodies by at least 2 of 3 serological tests confirms the infection in the neonates. The diagnostic follow up of the children born to a group of sero-reactive pregnant women was carried out in the INP. The 11% of the mothers (29 out of 267) transmitted the infection to their children. The neonates of 20 of these mothers were diagnosed in the early stage, 14 and 6 in one or two controls, respectively. In the 9 remaining mothers the children were diagnosed in the late stage of the infection, mainly serologicaly. Our analisis of previously published reports stressed that the maternal-fetal transmission rate depends on the time of diagnostic follow up of the child. In this reports, mean values of mother to child transmission reported was 2% and 9% when the diagnosis of the neonates born to sero-reactive mothers was carried out only in the early stage or in the early and also the late stage, respectively.

Conversion from mycophenolate mofetil to delayed formulation in pediatric renal transplantation: higher mycophenolic acid predose level but no changes in the immune biomarkers.

EC-MPS was designed to improve MPA-related GII because of MMF, by delaying the release of MPA until reaching the small intestine. At present, its immunosuppressive activity in pediatric renal transplant recipients with GII has not been clarified. We studied eight renal transplant recipients before and after three months of the conversion from MMF to equimolar doses of EC-MPS. After three months of treatment with EC-MPA, GII decreased between 100% and 12.5%. The predose levels of MPA were about 60% higher on EC-MPS (6.9 +/- 1.1 microg/mL) compared with MMF administration (4.2 +/- 0.9 microg/mL). Hemoglobin decreased significantly post-conversion (12.0 +/- 0.4 to 11.0 +/- 0.5 g/dL). Serum creatinine, creatinine clearance, and urinary protein excretion did not change. Also, proliferative response and cytotoxic antibodies showed no significant change. The release of interleukin-10 was strikingly augmented with MMF or EC-MPS therapy; meanwhile, gamma-interferon and TNF were low under both treatments. Our data indicate that conversion from MMF to EC-MPS leads to an improvement in GII without altering key elements of immunosuppression.

Soluble tumor necrosis factor (TNF) receptors (sTNF-R1 and -R2) in pregnant women chronically infected with Trypanosoma cruzi and their children.

Most congenital transmissions of Trypanosoma cruzi are not detected. As the levels of mediators regulating the immune response might be different in the absence or in the presence of transmission, we explored the levels of tumor necrosis factor (TNF) and soluble TNF receptors TNF-R1 and -R2 in T. cruzi-infected pregnant women and the neonates. We previously found that the circulating levels of TNF were higher in non-transmitting than in transmitting pregnant women. This observation has now been extended to the spontaneous release of TNF by peripheral blood leukocytes (PBLs) that was also higher in non-transmitting than in transmitting pregnant women. As their mothers, non-infected neonates had higher circulating levels of TNF than congenitally infected children. The circulating levels of sTNF-R1 increased in non-transmitting and transmitting mothers and in infected and non-infected neonates. The circulating levels of sTNF-R2 were approximately 60% higher in infected than in non-infected neonates (1,635 +/- 101 and 1,027 +/- 100 pg/mL, respectively) and remained higher at 1 year of age. This important increase, only observed in infected neonates, could be useful to orientate to the presence of vertical transmission of T. cruzi infection.

[Regulatory cytokines in the response to the allogeneic renal transplant]. / Citoquinas reguladoras de la respuesta al trasplante renal alogénico.

The outcome of the kidney allograft mainly depends on the immune response and on its complex regulation, where the cytokine network and other mediators play an important role. At present, kidney biopsy is the most useful tool for monitoring the transplant rejection and the diagnosis of the associated nephropathies, in spite of the invasiveness of the procedure. Thus, it is of great interest to find alternative tools for diagnosis. The evaluation of regulatory cytokines is a simple procedure of low cost that could be useful to increase the sensitivity of the detection of polymorphic differences, to predict the graft acceptance and for the early detection of rejection. Recent studies suggest that the high production of pro-inflammatory mediators, such as Th1 cytokines, could be detrimental, whereas the production of anti-inflammatory regulatory cytokines, such as interleukin (IL)-10 and tumor necrosis factor (TGF)-beta, could be beneficial for graft survival. In the early stages, the cellular cytotoxicity is activated by the Th1 response and the detection of cytotoxic molecules is associated to the acute rejection. Later, the balance between pro and anti-inflammatory mediators and the regulation of their levels could be more important. In this regard, TGF-beta is also fibrogenic and a high local production can contribute to kidney damage. On the other hand, the increased production of IL-10 in response to the allogeneic stimuli could be, in most cases, an important marker of long-term acceptance.

Citoquinas reguladoras de la respuesta al trasplante renal alogénico. / [Regulatory cytokines in the response to the allogeneic renal transplant]

The outcome of the kidney allograft mainly depends on the immune response and on its complex regulation, where the cytokine network and other mediators play an important role. At present, kidney biopsy is the most useful tool for monitoring the transplant rejection and the diagnosis of the associated nephropathies, in spite of the invasiveness of the procedure. Thus, it is of great interest to find alternative tools for diagnosis. The evaluation of regulatory cytokines is a simple procedure of low cost that could be useful to increase the sensitivity of the detection of polymorphic differences, to predict the graft acceptance and for the early detection of rejection. Recent studies suggest that the high production of pro-inflammatory mediators, such as Th1 cytokines, could be detrimental, whereas the production of anti-inflammatory regulatory cytokines, such as interleukin (IL)-10 and tumor necrosis factor (TGF)-beta, could be beneficial for graft survival. In the early stages, the cellular cytotoxicity is activated by the Th1 response and the detection of cytotoxic molecules is associated to the acute rejection. Later, the balance between pro and anti-inflammatory mediators and the regulation of their levels could be more important. In this regard, TGF-beta is also fibrogenic and a high local production can contribute to kidney damage. On the other hand, the increased production of IL-10 in response to the allogeneic stimuli could be, in most cases, an important marker of long-term acceptance.

Circulating levels of cyclooxygenase metabolites in experimental Trypanosoma cruzi infections.

Trypanosoma cruzi induces inflammatory reactions in several tissues. The production of prostaglandin F2alpha, 6-keto-prostaglandin F1alpha and thromboxane B2, known to regulate the immune response and to participate in inflammatory reactions, was studied in mice experimentally infected with T. cruzi. The generation of nitric oxide (NO), which could be regulated by cyclooxygenase metabolites, was also evaluated. In the acute infection the extension of inflammatory infiltrates in skeletal muscle as well as the circulating levels of cyclooxygenase metabolites and NO were higher in resistant C3H mice than in susceptible BALB/c mice. In addition, the spontaneous release of NO by spleen cells increased earlier in the C3H mouse strain. In the chronic infections, the tissue inflammatory reaction was still prominent in both groups of mice, but a moderate increase of thromboxane B2 concentration and in NO released by spleen cells was observed only in C3H mice. This comparative study shows that these mediators could be mainly related to protective mechanisms in the acute phase, but seem not to be involved in its maintenance in the chronic T. cruzi infections.

Mycophenolate mofetil and reduced doses of cyclosporine in pediatric liver transplantation with chronic renal dysfunction: changes in the immune responses.

The aim of this study was to study the incidence of chronic renal dysfunction in patients with more than 5 yr of follow-up following liver transplantation and to evaluate the benefit of decreasing cyclosporine A (CsA) dose combined with mycophenolate mofetil (MMF) on renal function and immune response in these patients. Between 1988 and 1994, 60 children were transplanted, and 86% survived >5 yr post-liver transplantation. Fourteen patients developed chronic renal dysfunction secondary to CsA toxicity as evaluated by renal biopsy. In 11 patients CsA dose was decreased to 40-90 mg/ml target levels and MMF 600 mg/m(2) twice daily was added to the immunosuppressive regimen. Plasma creatinine decreased (from 1.0 +/- 0.03 to 0.8 +/- 0.03 ng/dl, p < 0.007), creatinine clearance increased (from 66.8 +/- 3.0 to 99.2 +/- 6.3 ml/min/1.73 m(2), p < 0.002) and microalbuminuria decreased (from 21.0 +/- 8.6 to 3.6 +/- 1.1 mg/24 h, p < 0.05) after 12 months of CsA combined with MMF therapy. During combined therapy the proliferative, cytolytic response and cytotoxic antibodies showed no significant changes, whereas CD4/CD8 ratio increased (from 1.2 +/- 0.2 to 1.4 +/- 0.1, p < 0.05). Tumor necrosis factor-alpha secretion increased (p < 0.005) during MMF therapy. The release of interleukin-10 was strikingly augmented under both immunosuppressive regimens, but the release of transforming growth factor-beta and interferon-gamma did not change. Our findings indicate that initiation of MMF combined with reduced doses of CsA allowed the recovery of renal function with minor changes in the immune response.

Trypanosoma cruzi: the expansion of NK, T, and NKT cells in the experimental infection.

T and NK cells play a key role in resistance to Trypanosoma cruzi infections, mainly through IFN-gamma production. The expression of T and NK cells surface markers was studied in NWNA spleen cells of resistant C3H and susceptible BALB/c mice that release IFN-gamma in the early and late acute infection, respectively. In the progressively enlarged spleens, we found: (a) an increased percentage and number of NK blast cells as early as at 2 days post-infection (pi), (b) an enrichment of T and NK cells, in both the total and blast populations, during the late acute phase. At 17 days pi, there was also an accumulation of TCR- alphabeta+DX5+, NKT cells, mainly in resistant mice. At 21 days pi, the enrichment of NK cells ceased, while spleen cells and the T cell compartment continued their expansion. In the chronic stage, TCR-alphabeta+ blasts were expanded in both mouse strains, but NK blasts increased only in BALB/c that, unlike C3H mice, release IFN-gamma. As T and NK cell proliferation is not always associated to IFN-gamma release the experimental downregulation of their expansion to avoid tissue damage could be explored.

Conversion from cyclosporine A to tacrolimus in pediatric kidney transplant recipients with chronic rejection: changes in the immune responses.

BACKGROUND: Tacrolimus (Tac) has immunosuppressant properties similar to those of cyclosporine A (CsA), but it is more potent. At present, however, its immunosuppressive activity in renal transplant recipients with ongoing chronic rejection has not been clarified. METHODS: We studied changes in kidney function, mixed lymphocyte culture, cell-mediated lympholysis, cytotoxic antibodies, lymphocyte population, and cytokine response before and after the conversion from CsA to Tac in 14 pediatric renal transplant recipients with chronic rejection. CsA (5.9+/-0.2 mg/kg/d) was replaced by Tac (0.1+/-0.004 mg/kg/d). RESULTS: Serum creatinine decreased (2.3+/-0.2-1.9+/-0.2 mg/dL, P <0.005), creatinine clearance increased (36.8+/-2.5-46.1+/-4.4 mL/min/1.73 m, P <0.005), and urinary protein excretion decreased (0.4+/-0.01-0.2+/-0.04 g/24 hr, P <0.03) after 6 months, and these values were maintained after 2 years with Tac treatment. During Tac therapy, anti-donor and anti-control mixed lymphocyte culture decreased 38% and 31% (P <0.05), respectively. Cell-mediated lympholysis did not change. CD3 decreased from 87%+/-2% to 80%+/-2% (P <0.005), and CD8 decreased from 34%+/-3% to 27%+/-2% (P <0.005). The switch to Tac decreased the interferon-gamma production in vitro (P <0.05) and increased tumor necrosis factor-alpha levels (P <0.05). The release of interleukin-10 was strikingly augmented with CsA or Tac therapy (P <0.01), but transforming growth factor-beta secretion was similar. CONCLUSIONS: Our data indicate that conversion from CsA to Tac therapy leads to an improvement in renal function without altering key elements of the immunosuppression in children with ongoing chronic rejection.

Respuesta TH1 en la infeccion experimental con Trypanosoma cruzi / TH1 response in the experimental infection with Trypanosoma cruzi

En el huésped infectado con Trypanosoma cruzi, la respuesta inmune protectora involucra principalmente la producción de anticuerpos específicos y la activación de células fagocíticas por interferon-gamma (IFN-gamma). El efecto central del IFN-gamma in vivo sería la activación de la sintetasa inducible de óxido nítrico de macrófagos (iNOS) y la generación de óxido nítrico (NOº) que participa en la destrucción intracelular de los parásitos. En la infección aguda, la inducción de la respuesta TH1 sería llevada a cabo por la interleuquemia 12 (IL-12), que estimula la producción de IFN-gamma en células NK. En la liberación de IFN-

Respuesta TH1 en la infeccion experimental con Trypanosoma cruzi / TH1 response in the experimental infection with Trypanosoma cruzi

En el huésped infectado con Trypanosoma cruzi, la respuesta inmune protectora involucra principalmente la producción de anticuerpos específicos y la activación de células fagocíticas por interferon-gamma (IFN-gamma). El efecto central del IFN-gamma in vivo sería la activación de la sintetasa inducible de óxido nítrico de macrófagos (iNOS) y la generación de óxido nítrico (NO§) que participa en la destrucción intracelular de los parásitos. En la infección aguda, la inducción de la respuesta TH1 sería llevada a cabo por la interleuquemia 12 (IL-12), que estimula la producción de IFN-gamma en células NK. En la liberación de IFN-gamma también intervienen otros tipos de células, como los linfocitos Thy-1 +CD4-CD4-CD8-, CD4+ y CD8+. El control de la respuesta TH1, podría ser, en parte, el resultado de la menor activación de macrófagos, por la disminución de la carga parasitaria, y de la producción de IL-10 y del factor de trasnformación del crecimiento beta (TGF-beta). La respuesta protectora TH1 también estaría implicada en el daño tisular y en las alteraciones de la respuesta inmune observadas durante la infección. Nosotros estudiamos la cinética de la actividad NK y de la producción de IL-12 e IFN-gamma por células de bazo, así como los niveles séricos de estas citoquinas centrales de la respuesta TH1, en ratones BALB/c y C3H infectados con T. cruzi, cepa Tulahuén. Inmediatamente después de la infección encontramos que, en las células de bazo, incrementó tanto la producción de IL-12 como la actividad NK, y este efecto fue mayor en ratones C3H que en BALB/c. En los C3H, el IFN-gamma aumentó simultáneamente, a diferencia de los BALB/c en los que la citoquina incrementó más tardíamente en la fase aguda. Em ambas cepas, la infección indujo muy rápidamente altos niveles séricos de IL-12 que se mantuvieron elevados durante toda la fase aguda. Por otro lado, el IFN-gamma sérico incrementó unos días antes del pico de parasitemia y alcanzó mayor concentración, y más tempranamente, en los ratones BALB/c que en los C3H. Para nuestra sorpresa, en la fase crónica de la infección, la producción de IL-12 seguía alta en ambas cepas, a pesar de ello, el IFN-gamma sólo continuó elevado en los ratones BALB/c. Aunque en la fase aguda la respuesta global fue predominantemente TH1 en las dos cepas de ratones, los BALB/c tienen una mayor susceptibilidad que los C3H...

Alteraciones en las poblaciones de linfocitos T inducidas por la infección con Trypanosoma cruzi / Alterations in the T lymphocyte populations induced by the infection with Trypanosoma cruzi

La infección murina con Trypanosoma cruzi induce una serie de alteraciones inmunológicas que podrían deberse a las variaciones en las subpoblaciones de linfocitos T. Nuestro primer objetivo fue realizar un estudio de estas subpoblaciones en el timo, bazo, ganglios linfáticos inguinales y placas de Peyer de ratones a los 10, 20 y 100 días de infección con T. cruzi. Encontramos que en la etapa aguda tanto el timo como las placas de Peyer disminuyeron su celularidad, mientras que el bazo y los ganglios linfáticos incrementaron su tamaño. La disminución del timo se debió a la depleción de la población T inmadura CD4+CD8+, que expresa CD3 con baja densidad, mientras que en las placas de Peyer disminuyeron tanto las células T como las B. El timo se pareció a un órgano linfático periférico, constituido en su mayoría por células maduras CD4+CD8- y CD4-CD8+ que expresaron una alta densidad del CD3 y del TCROá. La zona timo-dependiente de las placas con intensa linfocitolisis... (TRUNCADO)(AU)

La respuesta inflamatoria en la infección aguda con Trypanosoma cruzi / Inflammatory response to acute Trypanosoma cruzi infection

La etapa aguda de las infecciones con Trypanosoma cruzi asociadas a altas parasitemias, se caracteriza por la presencia de infiltrados inflamatorios en varios tejidos, incluyendo el corazón y músculo esquelético, así como por el incremento de la produción de mediadores inflamatorios. Al mismo tiempo ocurre una activación generalizada de células fagocíticas que estaría relacionada tanto con los procesos inflamatorios como con la resistencia a la infección. Esta es una breve revisión sobre los mediadores inflamatorios que se producen in vivo y su relación con el daño tisular y con la respuesta inmune TH1. (AU)

Superantigenos: una particular interaccion entre microorganismos y el sistema inmune / Superantigens: a particular interaction between microorganisms and the immune system

El descubrimiento de los superatígenos (SAgs) aportó nuevos conceptos en el estudio de las interacciones entre los microorganismos y el sistema inmune. Se trata de moléculas que, asociadas a las de Clase II del Complejo Mayor de Histocompatibilidad (CMH), se unen al dominio variable de la cadena Beta Vbeta) del receptor de antígenos Ags) de los linfocitos T alphaBeta (TCRalphaBeta) que les confiere la especialidad de familia. Así, los SAgs son capaces de activar a un alto número de linfocitos T y de células portadoras de las moléculas de Classe II del CMH, generando una masiva liberación de linfoquinas y mediadores inflamatorios que ha sido relaciona con sus efectos tóxicos. Los SAgs endógenos están codificados por los provirus de tumores murinos (Mtv) que se hallan integrados al genoma de los ratones. Los exógenos son producidos por bacterias y virus, siendo los mejor caracterizados los relacionados con las intoxicaciones alimentarias. Aun no se han hallado datos concluyentes en cuanto a la existencia de SAgs de parásitos y se requieren estudos más detallados para establecer su presencia y posible efecto en las infecciones parasitarias. (AU)