CpG ODN D35 improves the response to abbreviated low-dose pentavalent antimonial treatment in non-human primate model of cutaneous leishmaniasis

Abstract

Cutaneous leishmaniasis (CL) affects the lives of 0.7-1 million people every year causing lesions that take months to heal. These lesions can result in disfiguring scars with psychological, social and economic consequences. Antimonials are the first line of therapy for CL, however the treatment is lengthy and linked to significant toxicities; further, its efficacy is variable and resistant parasites are emerging. Shorter or lower dose antimonial treatment regimens, which would decrease the risk of adverse events and improve patient compliance, have shown reduced efficacy and further increase the risk emergence of antimonial-resistant strains. The progression of lesions in CL is partly determined by the immune response it elicits, and previous studies showed that administration of immunomodulatory type D CpG ODNs, magnifies the immune response to Leishmania and reduces lesion severity in nonhuman primates (NHP) challenged with Leishmania major or Leishmania amazonensis. Here we explored whether the addition of a single dose of immunomodulating CpG ODN D35 augments the efficacy of a short-course, low-dose pentavalent antimonial treatment regimen. Results show that macaques treated with D35 plus 5mg/kg sodium stibogluconate (Sb V) for 10 days had smaller lesions and reduced time to re-epithelization after infection with Leishmania major. No toxicities were evident during the studies, even at doses of D35 10 times higher than those used in treatment. Critically, pentavalent antimonial treatment did not modify the ability of D35 to induce type I IFNs. The findings support the efficacy of D35 as adjuvant therapy for shorter, low dose pentavalent antimonial treatment.

Non-human primates and Leishmania immunity

“…Whereas the immune parameters associated with immune protection in NHP with cutaneous leishmaniasis (CL) remains elusive [57] , [61] , it has been shown that macaques immunized with the sand-fly PdSP15 salivary protein are protected against cutaneous leishmaniasis [62] . The administration of pentavalent antimonial sodium stibogluconate (20 mg/kg for 20 days) in infected macaques, reduced the lesion severity and accelerated healing, which was associated with the modulation in the expression of hundred genes in the skin biopsies from the lesion site [63] . These findings are in agreement with data from human biopsies, which demonstrated that treatment failure was linked to the excessive activation of the cytolytic pathway activated during infection [64] , [65] .…”

High Content Analysis of Macrophage-Targeting EhPIb-Compounds against Cutaneous and Visceral Leishmania Species

“…Since it is well known that Leishmania has evolved mechanisms to subvert the immune response by reprogramming host cells such as macrophages [ 12 ], there are several studies on immunomodulatory drugs [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. These studies mainly address the cutaneous form of leishmaniasis, with compounds such as imiquimod (Toll-like receptor TLR 7/8 agonist) [ 15 , 20 ] or CpG D35, an oligodeoxynucleotide containing CpG motif, which reduces the severity of cutaneous lesions by TLR9 engagement [ 13 , 14 ]. All the investigations of immune modulators led to the assumption, that their use in combination with conventional anti-leishmanial drugs may allow shorter treatment periods, reduce cytotoxicity, and may lower the risk of resistance.…”

“…As macrophages are the key host and sentinel cells for Leishmania, they constitute an optimal target for immunotherapy due to their innate immune functions [11]. Since it is well known that Leishmania has evolved mechanisms to subvert the immune response by reprogramming host cells such as macrophages [12], there are several studies on immunomodulatory drugs [13][14][15][16][17][18][19]. These studies mainly address the cutaneous form of leishmaniasis, with compounds such as imiquimod (Toll-like receptor TLR 7/8 agonist) [15,20] or CpG D35, an oligodeoxynucleotide containing CpG motif, which reduces the severity of cutaneous lesions by TLR9 engagement [13,14].…”

New Pyrano‐4H‐benzo[g]chromene‐5,10‐diones with Antiparasitic and Antioxidant Activities

“…Current treatment options for CL patients include pentavalent antimonials (sodium stibogluconate, meglumine antimoniate), miltefosine, amphotericin, and pentamidine. Recent works disclosed interesting preclinical results for benzoxaborole, nitroimidazoles and aminopyrazoles as well as for the antimonial drug activity enhancer D35 (a CpG oligonucleotide) [9,12] . Aside of the toxicity of the currently applied drugs, the emergence of drug‐resistant parasite forms poses a growing problem to the clinician and, thus, the search for new potent anti‐parasitic drugs is ongoing.…”

“…Recent works disclosed interesting preclinical results for benzoxaborole, nitroimidazoles and aminopyrazoles as well as for the antimonial drug activity enhancer D35 (a CpG oligonucleotide). [9,12] Aside of the toxicity of the currently applied drugs, the emergence of drugresistant parasite forms poses a growing problem to the clinician and, thus, the search for new potent antiparasitic drugs is ongoing. The treatment of trypanosomiasis and leishmaniasis with natural products or with drugs derived from them appears promising.…”