E‐ADA activity in lymphocytes of an experimental model of pythiosis treated with immunotherapy

Abstract

Pythiosis is a life-threatening disease caused by the oomycete Pythium insidiosum. Some authors have suggested the involvement of a Th2-like immune response in the infected host, which leads to extensive tissue damage. The switch from a Th2 to a Th1 response pattern is one hypothesis to explain the curative properties of immunotherapy. Taking into account the importance of immunotherapy for pythiosis treatment and the contribution of adenine nucleotides in the immunoregulation of the host, we evaluated the ecto-adenosine deaminase (E-ADA; EC 3·5.4·4) activity in lymphocytes from rabbits inoculated with P. insidiosum. Rabbits were inoculated with 1 milliliter of zoospores subcutaneously injected into the lateral thorax; after developing lesions, the rabbits received eight doses of immunotherapy. E-ADA activity was measured in lymphocytes and the adenine nucleotides and adenosine levels were quantitatively determined in serum. Rabbits with characteristic lesions of pythiosis showed a decreased E-ADA activity (82·36%), a decreased adenosine triphosphate concentration (54·04%) and a higher adenosine concentration (2·51 fold), when compared with controls, after 28 days of inoculation. However, after the immunotherapy, the rabbits showed an increase in the E-ADA activity when compared with control (78·62%), contributing for the change in the immune response. Our results reinforce the hypothesis that the change from a Th2 to a Th1 immune response with the participation of the purinergic system could be responsible for the curative properties of immunotherapy.

Complex Interaction of Deferasirox and Pythium insidiosum: Iron-Dependent Attenuation of Growth In Vitro and Immunotherapy-Like Enhancement of Immune Responses In Vivo

“…3C). In support to our findings, a decreased lymphocyte ecto-ADA activity has been previously reported in rabbits with pythiosis, an effect that was also reversed by immunotherapy [3]. Our data also extend previous observations showing that 1) deferasirox treatment enhanced the host inflammatory response to mucormycosis [11], and 2) ADA therapy is able to increase the secretion of Th-1 pro-inflammatory cytokines, enhancing allogeneic T-cell proliferation and immunogenicity [6].…”

“…The elevated iron availability also impairs host immune responses, as observed in patients with thalassemia or hemochromatosis, which frequently have reduced CD8+ T-cell counts that respond positively to iron chelation therapy [7]. Current evidence shows that the mechanisms of cure of the immunotherapeutic treatment against pythiosis are based on the switch from a Th2 (eosinophils) to a Th1 (macrophages and lymphocytes) subset [3]. Therefore, the impact of deferasirox in modulating the immune response was compared to immunotherapy by histopathological analysis and by measuring ADA activity in the lesions of rabbits with experimental pythiosis.…”

“…It is known that the purinergic system participates in immune system modulation during infections, including in pythiosis [3]. In particular, an enhanced adenosine production results from the ATP released into the extracellular space by injured or pathogen-stimulated cells, thus limiting hyperergic inflammatory responses [3].…”

“…In particular, an enhanced adenosine production results from the ATP released into the extracellular space by injured or pathogen-stimulated cells, thus limiting hyperergic inflammatory responses [3]. In turn, the enzyme adenosine deaminase (ADA) represents a crucial immunomodulatory mechanism aimed at counteracting excessive extracellular adenosine production and avoiding excessive immunopathology [4, 5].…”

A Leishmania murine model to evaluate the immunomodulatory properties of Pythium insidiosum proteins

“…It was later found in successfully treated mammals that in addition to the switching from an eosinophilic to a mononuclear cell response, a shift from a Th2 to a Th1 cytokine profile occurred [2]. Moreover, when this hypothesis was tested in the experimental rabbit model, a similar profile was found with the expression of lymphocytic NTPDase [15] and ecto-adenosine deaminase [16], also pointing to a Th2 down-regulation.…”