Effect of treatment with cyclophosphamide in low doses upon the onset of delayed type hypersensitivity in mice chronically infected with Trypanosoma cruzi: involvement of heart interstitial dendritic cells

Abstract

Acute infection with Trypanosoma cruzi results in intense myocarditis, which progresses to a chronic, asymptomatic indeterminate form. The evolution toward this chronic cardiac form occurs in approximately 30% of all cases of T. cruzi infection. Suppression of delayed type hypersensitivity (DTH) has been proposed as a potential explanation of the indeterminate form. We investigated the effect of cyclophosphamide (CYCL) treatment on the regulatory mechanism of DTH and the participation of heart interstitial dendritic cells (IDCs) in this process using BALB/c mice chronically infected with T. cruzi. One group was treated with CYCL (20 mg/kg body weight) for one month. A DTH skin test was performed by intradermal injection of T. cruzi antigen (3 mg/mL) in the hind-footpad and measured the skin thickness after 24 h, 48 h and 72 h. The skin test revealed increased thickness in antigen-injected footpads, which was more evident in the mice treated with CYCL than in those mice that did not receive treatment. The thickened regions were characterised by perivascular infiltrates and areas of necrosis. Intense lesions of the myocardium were present in three/16 cases and included large areas of necrosis. Morphometric evaluation of lymphocytes showed a predominance of TCD8 cells. Heart IDCs were immunolabelled with specific antibodies (CD11b and CD11c) and T. cruzi antigens were detected using a specific anti-T. cruzi antibody. Identification of T. cruzi antigens, sequestered in these cells using specific anti-T. cruzi antibodies was done, showing a significant increase in the number of these cells in treated mice. These results indicate that IDCs participate in the regulatory mechanisms of DTH response to T. cruzi infection.

Immunological response to re-infections with clones of the Colombian strain of Trypanosoma cruzi with different degrees of virulence: influence on pathological features during chronic infection in mice

“…When studying the influence of the Colombian strain on chronic chagasic myocarditis using two different mouse strains, Pereira et al (2014) showed the presence of high levels of tumour necrosis factor and nitric oxide in the serum directly associated with intense diffuse and focal inflammatory infiltration, which are consistent with our findings. A similar effect on the intensity of the inflammatory infiltrate was previously observed in dogs during the indeterminate phase of infection ( Andrade et al 1987 ) and in mice subjected to treatment with cyclophosphamide at low doses, likely due to the influence of this drug on the regulatory mechanism of DTH ( Thé et al 2013 ). The response to low doses of cyclophosphamide are attributed to the suppression of the humoral and cellular responses and the result of the selective destruction of suppressor T lymphocytes, their precursor cells or other elements in the host immune suppressor network ( Andrade et al 1987 , Murata et al 2004 , Lutsiak et al 2005 , Thé et al 2013 ).…”

“…A similar effect on the intensity of the inflammatory infiltrate was previously observed in dogs during the indeterminate phase of infection ( Andrade et al 1987 ) and in mice subjected to treatment with cyclophosphamide at low doses, likely due to the influence of this drug on the regulatory mechanism of DTH ( Thé et al 2013 ). The response to low doses of cyclophosphamide are attributed to the suppression of the humoral and cellular responses and the result of the selective destruction of suppressor T lymphocytes, their precursor cells or other elements in the host immune suppressor network ( Andrade et al 1987 , Murata et al 2004 , Lutsiak et al 2005 , Thé et al 2013 ). These cells are identified as regulatory T-cells (Tregs), which express CD4 + CD25 + markers and are involved in the regulation or suppression of DTH ( Shevach et al 2001 ).…”

Humoral immune response and delayed-type hypersensitivity in rabbits infected with Trypanosoma equiperdum

“…Some authors evaluated the cellular immune response of laboratory animals (mice, rabbits) infected with T. cruzi or other Trypanosoma species using a delayed type hypersensitivity test 30 – 34 . Mansfield and Kreier 33 described positive skin test reactions of the Arthus type (type III hypersensitivity reactions) in rabbits infected with T. congolense .…”

“…Delayed hypersensitivity reactions were observed in rabbits and mice infected with T. brucei and T. rhodesiense 27 . Thé et al 34 described a DTH response in a skin test performed on mice infected with T. cruzi . Regarding the cell-mediated response induced by T. equiperdum in horse, to date no scientific data are available in the literature.…”

Análise Fenotípica De Populações Celulares Nos Infiltrados Inflamatórios No Miocárdio E Músculo Esquelético Provenientes De Cepas Trypanosoma Cruzi Resistente E Suscetívei Ao Benzonidazol

“…A miocardite e a miosite chagásica, observada na infecção pelo T. cruzi, e as lesões necrótico-inflamatórias focais e difusas de células cardíacas não-parasitadas e da musculatura esquelética, sugere a participação de mecanismos citotóxicos provenientes das citocinas liberadas pelas células do sistema imune são os geradores das lesões na fase aguda e tardia associados a imunopatogenia dessas lesões chagásicas. Estudos avaliando o perfil das lesões inflamatórias e das populações celulares no miocárdio e musculo esquelético, através da imunohistoquímica evidenciaram ampla destruição de fibras cardíacas com presença ou ausência de parasitismo, áreas necrótico-fibrosas, apoptose de miocélulas em associação com a presença de linfócitos T CD4+ e T CD8+, sendo essas células essenciais na imunoproteção e também na geração das lesões (ALVAREZ et al, 2008;ANDRADE, 2000;GUERREIRO et al, 2015;THÉ et al, 2013). Esses estudos corroboram com nossos achados quando analisamos V. 5, Nº 1, 2024 DOI: 10.51161/conbrapah2024/30800 as lesões no miocárdio e no musculo esquelético.…”