Immunomodulatory Role of Chloroquine and Pyrimethamine in Plasmodium yoelii 17XL Infected Mice

Abstract

Chloroquine (CLQ) and Pyrimethamine (PYR) are used for the treatment of malaria and some autoimmune diseases; although their mechanism of action is only partially understood, their therapeutic effectiveness in the second case has been attributed to their ability to increase apoptosis of T lymphocytes. In view of the potential for immunomodulation during malaria chemotherapy, we investigated the effects of CLQ and PYR treatment on lymphocyte apoptosis and cytokine expression during infection with blood‐stage Plasmodium. This work shows that infection of BALB/c mice with Plasmodium yoelii 17XL (Py17XL) reduced apoptosis in spleen cells but when infected mice were treated with CLQ, apoptosis of B and T lymphocytes increased significantly via a Fas‐mRNA expression independent mechanism associated with downregulation of Bcl‐2 expression, whereas treatment with PYR increased apoptosis to a lesser extent and only in B lymphocytes. CLQ treatment of Py17XL infected mice upregulated tumour necrosis factor‐α mRNA expression, while PYR treatment increased interferon‐γ mRNA expression. In infected mice, treatment with CLQ downregulated expression of the anti‐inflammatory cytokines, interleukin‐10 and transforming growth factor‐β (TGF‐β), while PYR treatment upregulated TGF‐β. Thus, in addition to their anti‐malarial effects, both drugs modulate the immune response in malaria by increasing apoptosis and modulating the mRNA expression of cytokines involved in parasite elimination and regulation of inflammatory responses.

Treatment of Murine Cerebral Malaria by Artemisone in Combination with Conventional Antimalarial Drugs: Antiplasmodial Effects and Immune Responses

“…Artemisinins also have the ability to induce immunosuppression by inhibiting delayed-type hypersensitivity, lymphocyte proliferation, and a rise in antibody level (51). Immune deviation caused by chloroquine and other antimalarial drugs has been reported (52,53). We found that the plasma levels of the proinflammatory cytokines TNF and IFN-␥ increased in P. berghei ANKA-infected mice ( Fig.…”

Redefining an epitope of a malaria vaccine candidate, with antibodies against the N-terminal MSA-2 antigen of Plasmodium harboring non-natural peptide bonds

“…The obtained strain, having 80 % viability, was centrifuged at 1,500 rpm for 5 min, as previously reported (Ramos-Avila et al 2007; Spencer-Valero et al 1998; Lewis-Hughes and Howell 1984; Mons et al 1983); the pellet containing about 1 × 10 7 infected red blood cells (iRBCs) was suspended in 1 mL RPMI and immediately used for intraperitoneally inoculating five BALB/c mice, each administered with an average of 2 × 10 6 iRBCs. Parasitemia in all infected animals was monitored by Wright staining of blood smear, showing that mice became parasitized by the second to sixth day after infection, and that parasitemia levels increased slowly until animals died 10–12 days after having been infected (Ramaiya et al 1987; Smalley and Butcher 1975).…”

Nitric Oxide is Involved in the Upregulation of IFN-γ and IL-10 mRNA Expression by CD8+ T Cells During the Blood Stages of P. chabaudi AS Infection in CBA/Ca Mice

“…Externalisation of phosphatidylserine was detected by annexin-V-FLUOS (Roche Diagnostics, Basel, Switzerland), as described previously 24. Briefly, 1 x 10 6 spleen cells were suspended in 200 µL reaction buffer (10 mM HEPES/NaOH, pH 7.4; 140 mM NaCl and 5 mM CaCl 2 ) and 2 µL of annexin-V-FLUOS.…”